Zealand Pharma Aktie

Cool. Well, thank you all for being here. I'm James Machin from the Morgan Stanley banking team and delighted to have Adam from Zealand Pharma here this morning. I guess over the next 30, 35 minutes, we'll dive into a number of areas across the portfolio. But maybe to kick off, and start with a quick intro to yourself, maybe a short overview on what you're doing as a business, and then we can start to get into some of the detail.

Absolutely. Pleased to be here. And yes, Zealand Pharma is a Danish-founded company. We've been 27 years in the making, and we are on a journey towards becoming a leader in metabolic health. In December last year, we kicked off our new ambition, which is called the Metabolic Frontier 2030 with an ambition of having actually 5 products on the market in 2030, having a pipeline of 10 clinical programs and then also having industry-leading times from idea to clinic.

So we are on a very, very, you can say, ambitious journey towards addressing what we believe is the biggest health care challenge of our time, not only the obesity pandemic we are seeing, but all the health consequences that follows obesity. So going beyond weight loss, looking into how we can help people improving their health span, living longer with a healthy life, the way people want to live their lives. That's what motivates us, and we are on a good journey towards delivering on that.

Okay. Great. No, very exciting times for yourselves and for the broader industry. You hinted at it with how the market is changing. And clearly, you as really one of the leaders within amylin biology and all the benefits that, that makes, which is really cementing it as one of the leading next-generation mechanisms in obesity.

Can you maybe dive into a little bit more detail on why the profile of amylin is so well suited for obesity patients and really how it starts to meet the needs that the consumers are needing in the market?

Right. We were, I guess, one of the first to kind of clearly articulate the need to introduce medicines for patients living with obesity that they can actually tolerate and not only tolerate during the most -- the period where they're the most motivated, meaning the first few months where you lose weight, but also once you get into the weight maintenance phase because living with obesity is a chronic condition for most people, meaning that if you start taking a treatment, you will rebound in weight, and you will not get all the health benefits.

So we -- when we saw the profile of petrelintide, we already at that time knew that we had something that would be a logical first choice, but also a product that patients would likely appreciate to stay on, overcoming the issues we see with the GLP-1s today where many patients stop within a month and after a year, probably only 20% to 30% of patients are still on treatment, meaning we don't achieve the health outcomes. The interesting perspective when looking and thinking about the future landscape of weight management and treatment of obesity is actually it would -- if I'm right here, it would not be dissimilar from what we have seen in other chronic disease areas.

If you think about obesity, type 2 diabetes, dyslipidemia, hypertension, when we introduced the first therapeutic opportunities for these patients, we were always targeting the most difficult-to-treat patients, and it was often with very cumbersome but also effective medicines. As they fill and matured, you will see more tolerable, more easy to be on medicines being introduced and actually becoming the therapeutic leaders and the go-to products for most patients.

You also see that physicians start to treat earlier and earlier. And what we are hearing -- actually starting to hear more so this year is that people say, why are we waiting or physicians are saying, why do we wait with treatment until you get to the highest BMI? Why not start to treat when you pass the 27 or approach the 30?

And that is completely in line with the positioning that we are thinking about within the amylin as a broader class that you want to start on a medicine that gives you the weight loss that most are looking for in the most pleasant way. And with petrelintide, we have a profile which has delivered double-digit weight loss and a placebo-like tolerability profile. So we really think we are -- that profile is the profile that most patients would actually appreciate to be on. And only if you desire an even higher weight loss, you would start to think about combination products of getting on the more cumbersome GLP-1s.

Okay. Great. And I guess that profile is now really starting to emerge with your positive ZUPREME-1 data, which emerged earlier this year. Can you remind us all in a little bit more what came through from that data and then really translating that through to clearly going into the pivotal trial, the design of that and the way that you're thinking about optimizing that route to market?

Absolutely. So it was a pretty comprehensive Phase II program testing 5 different doses of petrelintide and also with a lot of patients in each arm, including a balanced exposure to males and females. So we have a very good understanding of how the product behaves also at the different dose levels. So we are moving into Phase III together with Roche now with a lot of confidence that we actually have the dose setting right and also that we understand the profile of this double-digit weight loss and placebo-like tolerability.

So the focus of the program will, of course, be speed to market because we think it's important, of course, to be among the first to launch into a new category and help defining the amylin class as a first choice therapeutic class. One of the things that really excites me, but also where I know we may still be a little bit ahead of the curve is this thing that if you ask patients, 4 out of 5 patients would give you a weight loss number below 20%. So most people are looking for weight loss in the teens.

Very few are actually looking for weight loss above 20%. However, many companies and many working in this space have been focused on what I've addressed as the weight loss Olympics being excited when you saw a higher weight loss number, not realizing that, that is actually not what patients are looking for.

Even with the current use of the GLP-1s that are available today, most often, the average dose is half what is approved, meaning that patients never get to those impressive weight loss numbers because they're not interested. At the end of the day, we need to develop medicines that fits the patient's lives, the lives that patients want to live. We don't -- we cannot think about managing the obesity pandemic if we require people to fit the lives of the product. It has to be products that fits the lives of patients.

Okay. Great. And I guess that translates through to really there's clearly a commercial edge that's coming with tolerability of different agents. Where do you think that will be once we roll a few years into the future, once petre is on market, really, how do you think consumers are going to start to differentiate between medicines and really make those choices?

I think, yes, we are already starting to hear the conversation that more and more people are starting to kind of articulate that the next battle is actually not going to be who delivers a few percent more weight loss. It's going to be around who can deliver the weight loss that patients are looking for with the best tolerability profile. And the one thing that could actually cause a change in perception faster than what you would normally see in other chronic disease areas is that we know that patients are so engaged in this category.

So I think it's like around 60% to 70% of all scripts is actually a patient-initiated conversation. So it's a patient who goes up to the doctor and say, I would like to get on a weight loss medication, and I would like to try this product out. So if we can think about a product now which delivers the weight loss that patients are looking for, but in a more pleasant way where people can actually feel great when they're losing weight, that is a situation where we would envision that the conversations on social media would be very, very firm early on.

So you could imagine a take-up that would be quite dramatic because patients are engaged. So you don't need to go through the normal channels that you normally would launch with focusing on Tier 1, Tier 2, Tier 3, key opinion leaders and then you get to primary care physicians because the patients would drive the narrative around wanting to be on a product like this.

And I would also say the other thing which excites us is that we think with petrelintide, if the profile that we have seen thus far comes true, it will also be a product which will allow patients to stay on therapy for longer. And if you start to think about capturing new patients, but also having them to stay on for longer, then that's where you can actually drive up volumes and ultimately value for this category, but also in the end, address -- truly address the obesity pandemic and all the disease that follows.

Right. No, it's super exciting. Super exciting. Maybe let's -- we talked a bit on mono. Let's maybe think about combo as well. As a reminder, you obviously have the ZYNERGY Phase II trial starting as well in combo with Roche. Can you maybe speak a little bit on aims with that trial, what you're looking to demonstrate and then translate that through link that back to the commentary you had before of decision between mono versus combo therapy and how you expect that will evolve over the longer term?

Absolutely. And when we did the partnership with Roche, of course, it was important for us to have shared economics not only on the petrelintide opportunity, but also on the combination. So we could really, in a consolidated and shared effort, build the franchise leadership around petrelintide that we are aiming for. So with the combination product, it's a unique opportunity to leverage the strength of each individual molecule.

But when you think about combination therapies in the future, you also have to acknowledge that these should be products that are provided to patients who can benefit from both modalities. And I just -- as one example, even in today's market, 15% of patients don't respond to a GLP-1. So you also -- you don't want to put such a patient on a combination product.

So when we envision what the combination product should do in the future, it's around providing additional weight loss or metabolic benefits for those patients who have already benefited from 1 of the 2 components that are within such a product. That would -- that's the logical positioning. That could be patients who live with obesity and type 2 diabetes. It could be patients who are -- who may be coming from a very high BMI status and thus ultimately requires the deepest weight loss.

Once they have started the journey, they may get on to a combination product. So it's really an opportunity to expand not only the amount of weight loss you can achieve, but also perhaps how you address certain comorbidities of obesity.

Okay. Great. And trial just starting to get up and running and maybe a little bit on what the aims are on that trial.

Yes. So it's a clear dose-finding study where we are trying to find the right balance between the GLP-1/GIP component, meaning CT-388 and then the amylin component with petrelintide because -- and it could ultimately also be different profiles for different patient segments. But for us, it's incredibly important to get the ratios right and a little bit in line with what we have talked about with petrelintide.

If you think about this market in the future, you need to have the right molecules, not just molecules. And in particular, when it comes to combinations, we need to move beyond just trying to seek the highest weight loss if it comes at the compromise of tolerability, very few would actually ever get to that in the real world. So we need to find the right balance where we also get the right amount of weight loss when you still consider tolerability.

Okay. Great. A little bit more on Roche as a partner. And I guess as a reminder, this was a $1.65 billion upfront partnership, over $5 billion in milestones and importantly, the profit share on both the mono and the combo as you mentioned. Can you speak a little bit around why Roche as a partner? What were the attributes there that really excited you as you stepped into that partnership and selected them?

It was a highly competitive process when we were partnering out with petrelintide. And what really excited us about Roche at that time was both Thomas and Teresa's very strong commitments when we spoke with them around how they wanted to be a top 3 player. They shared their plans around how they wanted to establish a strong manufacturing network and overall just where they wanted to take the company. And I must say that I'm extremely pleased to see that everything we discussed at that time has come true.

I mean I think people who follows LinkedIn can see how they are investing in manufacturing capacity. And also, I think they have started to be more public in their kind of commitment to how they want to lead in this space going forward. So among all the large pharma companies we spoke to, we just sent the strongest commitment to actually to come in and make a difference for patients in this new category, which I still think is a new category. Remember, we are 4 to 5 years into treatment of obesity and weight loss.

So while a lot of people may think it's these treatments has been around for a long time. It's really novel. We have one category more or less with the GLP-1 class. We have 3% to 5% of patients being treated today in the U.S. There's so much opportunity to come in and lead if you want to do things differently.

And that was what we heard from Roche that they wanted to come in and drive innovation in this space, not only when it comes to molecules, but also how you go to market, how you secure the most effective manufacturing. And that's what we see in the partnership.

Okay. Great. No, great partner. We'll see how Teresa addresses it over the coming weeks as well with their respective R&D Day. Let's turn to second asset within the portfolio, still on obesity versus the other areas. And clearly, a different partner with Boehringer and survodutide. Can you maybe frame that as an asset, how that is distinctive from the amylin where you're looking, where you and your partner see the greatest potential of that product?

Yes. So survodutide is a licensing agreement we made with Boehringer. So they are fully responsible for the clinical development and commercialization. So we just have high single to low double-digit royalties, which is a nice situation to be in, in particular, because survodutide, and we just saw the first data here from the Phase III program here at ADA this year. It looks to be a very, very strong GLP-1 glucagon molecule when you think about not only weight loss but also metabolic health.

What Boehringer showed at ADA was that while they achieved around between 16% to 17% weight loss in the Phase III program, most of that weight loss was attributed to losing weight in the losing fat, getting fat out of the liver and the intestinal fat which is normally seen as the bad fat, if you will, so it was predominantly liver and visceral fat that was lost. And they also showed data that there was only 10% muscle wasting or muscle loss, which is in contrast to the 20% to 30% we have seen from other GLP-1s.

So I think they have a molecule here with survodutide, which is really going beyond just weight loss and addressing the metabolic health that we're actually all trying to achieve with these weight losses. So we are super excited, and we know Boehringer is super excited about the prospects of survodutide. And as they say, you see obesity, think liver because a lot of the metabolic disturbances you have with living with obesity starts in the liver.

And if you can really get fat out, that's a major event. They also -- they will report the rest of the Phase III program this year in obesity. And then they have a large program in MASH and NASH, including end-stage liver disease that will read out in the coming years and will hopefully help further underscore the potential to actually -- to address some of the underlying organ defects that you see with long-standing obesity.

The other thing which we are pleased with the partnership is the continuous commitment to invest into the program. So earlier, I think, in August, they announced that they started a Phase III study in type 2 diabetes to really -- with the aim of expanding, I guess, the label universe for survodutide.

And sometimes in this world of obesity treatments, we forget that the GLP-1s are still generating more revenues within type 2 diabetes. So it's nice to see that continuous investment. They're investing in women's health. They're investing in heart failure. So they're doing additional studies to really support this product.

Okay. Great. So multiple indications and really then looking to derisk the pivotal program over the next year, right. And the MASH data that comes through the course of '27?

If you look at clinicaltrials.gov, that could be one guess. They will inform the market once the data is there.

Okay. Great. Let's pivot again. Let's turn to rare diseases. Clearly, a number of products that you have there, which are in late-stage development. Let's start on dasiglucagon, clearly in development in congenital hyperinsulinism. Can you frame that as an asset, the strategic value of where the product is and how you think about that asset over the longer term, particularly with the resubmission coming up?

Right. Yes. So congenital hyperinsulinism is a devastating disease in neonates and small children who are born with this genetic defect where they produce too much insulin and thus, they end up with low blood sugar and really high risk of brain damage. And in a lot of these children, which is a rare indication, but for a lot of those who are diagnosed, you cannot surgically remove the affected areas. So they live with this glycemic events and need to be on frequent IV sugar and what have you in order to not get into hypoglycemia.

So it's really a devastating disease. And we have a Phase III program now and patients who have been on treatment for several years, demonstrating that we can ease life for these patients. We can basically reduce the number of hypoglycemic events and allow perhaps families to sleep a little bit more through the night instead of having to wake up every 2 hours and feed their children.

So it's a program that we will resubmit to FDA here in the second half. We hope to have it approved next year. And in parallel with that, we are engaging in partnership discussions. While we do have a commercial ambition that is really focused on go-to-market with our petrelintide alongside Genentech, targeting a large consumer opportunity for the rare disease we -- our ambition is to establish a partnership with a dedicated rare disease company who can help us reach as many patients as possible, starting with the U.S., but we have a global effort on survodutide as well.

Okay. Understood. Similarly, with glepaglutide, your short bowel syndrome asset. Can you remind us all there where that stands? I believe the second Phase III trial, sorry, is now ongoing. And similar question, strategic value of the asset versus financial value as you bring this forward?

It's another rare disease asset where we have invested a lot, and we have a strong commitment to get improved therapies out to patients living with short bowel syndrome. We have just earlier in the year, started the second Phase III study to support regulatory approval in the U.S. based on feedback from FDA.

So that is up and running and recruiting. In parallel, last year, we submitted the file for EU -- potential EU approval, and we should hear back from EU this year for potential approval in the EU. And again, it's an asset where we want to find a partner. So once we have a little bit more progress in these aspects, it could be later this year, we will start partnership discussions and make sure that we are reaching as many patients as possible through a partner for short bowel syndrome and in particular, for glepaglutide. It is a market where today, I think with the short-acting GLP-1 that is available is north of $1 billion in sales.

It's a decent market where we think with glepaglutide is approved, it really provides a significant improvement over current therapies in that it's a very easy injection, and we have also been very pleased with the clinical profile of the product that we have seen thus far. So it's another asset where you can say it's not one which we -- where we would invest in bringing it to market ourselves, but we would seek a partnership, which, of course, could help us expand the reach and the value of the opportunity.

Okay. Great. I'll jump again. Let's go to your early -- and I'll come back to obesity and once we wrap up. But I guess, earlier research efforts started to move into inflammation with a compound going into the clinic. Before we touch on that, maybe just ambitions and how you think about those earlier-stage research efforts with a bit of a broadening of the pipeline?

We are hugely ambitious on the early pipeline. So we hope to have 5 products on the market by 30, but we also hope to have a pipeline of 10 clinical assets, which should arrive from our research effort. So we have really stepped up our research efforts in the past few years. And just to put it into perspective, in the coming 4 or 5 years, we're going to spend 5x as much on research alone as we did in the past 5 years.

Actually, we're going to invest around USD 800 million into research alone. We have a very strong group in Denmark, which is where we were founded. In a few weeks' time, we're actually going to open our Cambridge, Massachusetts research site, which will be equally sized -- and we have, I would say, probably 20 to 30 of the people who are going to work there already signed in. So we are ready to hopefully start the first experiment quite fast.

There, we're going to go beyond peptides, which is where we have historically been mostly active and into other modalities, really leveraging where we see ourselves having a competitive edge in the metabolic research. Not many companies have as much data and as much as deep understanding in metabolic pathways as Zealand.

So we will utilize that knowledge while we will collaborate with modality leaders, do more partnerships, just as we did with OTR last year on small molecules, we expect to do partnerships with other modality-based platform companies within the metabolic space to continue to invest. So after investments in the train side, it is our key second priority to invest into the pipeline to make sure we continue to innovate and have the products of the future as well.

Okay. And I guess the first thing coming out of that is the Kv1.3 blocker in going through the SAD, the MAD now starting to get going. And clearly, just given the mechanism, broad potential across a range of immune-mediated disorders. How do you think about that program, taking it forward yourself versus maybe a partner in due course? And also just indication selection, as I mentioned, broad range. Where do you think the biggest potential? And why do you want to take it?

It's really a super exciting asset, which has this pipeline in a product potentially. You can -- you have the preclinical evidence for almost at least all the autoimmune diseases I can name. So of course, it's going to be important to select which one you're going for and in which kind of order we -- earlier this year, we initiated a Phase Ib/IIa study, a smaller study in patients living with psoriasis just to see if we can get the first biological evidence.

Now we have seen -- we have already seen engagement on the biological pathways we are targeting in our early exposure. So we can see we have receptor engagement. We can see we are affecting the immune pathways that we are hoping to see, but could we also pick up an early biological response in patients with psoriasis. We will soon also start another smaller study in another indication.

But ultimately, it's also a program where we would envision to have it in a partnership with a more established player in the autoimmune space because it is complicated studies. And it's -- and again, if we want to invest in multiple parallel programs, it's a partnership that we are looking at. So one which is a little bit outside the focus of our other early efforts, but one which could really hold a huge potential in a broad range of autoimmune diseases. And yes.

Okay. Great. Let's turn them back and you started talking on it with metabolic Frontier 2030. You mentioned. It remind us ambitions there, really how broad you're thinking on taking the business and that big vision, and then we can go to partnerships. But first of all, the vision.

Yes. So we -- if you think about where we will be in 2030, it's, of course, our hope that we'll be launching our first product alongside Genentech into a very consumer-driven market. And so we are investing in building what we can describe as a fully integrated presence, including commercial presence to support such a launch.

So that reflects our ambition to actually come in and play -- to become a key player in the metabolic space, not only when it comes to early innovation and research and development, but also being out there addressing customers in the end. the problem that we are looking into when we think not about obesity, but all the consequences of how obese the world is becoming with all the metabolic diseases that follows simply requires new ways of going to market. It requires new innovation.

And we are here to actually take our part in addressing that need. We think we are uniquely set. We think it's actually also a unique moment in the history of addressing these kind of metabolic diseases because for the first time, we are in a situation where there's actually a huge alignment with what society needs and what each individual person is actually looking for.

I mean -- so we are getting into a situation where preventive medicine suddenly can become reality, something people have talked a lot about, but now we are at that time where preventive medicine can become a reality as long as you develop medicines that fits into the lives of people and you find ways of getting these medicines to people so they can actually stay on them.

And that is what excites us as a company. We think we are uniquely set up also with all the changes we see in the data, AI and platforms of how you can actually ultimately reach patients. It's a unique opportunity to actually go for a market like this. Historically, it would have been almost impossible to break into primary care as a newcomer because of the size of the organization you would need.

But these things are changing so much, so rapidly these years. And we think it speaks to our benefit that we actually can come in and innovate and participate in getting the products to the patients.

Okay. And that sounds like both with partners and internal, you had your partnership earlier this year. I guess why them as a partner? What did they bring as an organization to really fill in the vision that will help support the vision that you're bringing forward? And is this something that you're really looking for as you think about further partnerships?

I think -- and this is not only with regard to obesity, but the biggest barrier to success and to innovation is if you think that what you have is what will also make you strong in the future. And when you hear Teresa and talk about it, they talk about innovating, doing something novel, not trying to pretend that there is a primary care sales organization that worked in the '90s that will also be beautifully set up to deliver in this space in the future.

It's about innovating and doing things differently. And that's what I hear when I speak to Roche and Genentech that they are here to innovate and then a very strong commitment to lead as both expressed by Thomas and Teresa. And that's why they're such a strong partner for us because, of course, they have a global footprint.

So you can kind of tick box all those elements, but then the desire to innovate and deliver novel ways of -- and driving a deep sense of wanting to make a difference for these patients and help address the metabolic consequences of where we have gone as a society is what makes them a strong partner.

I think we fool ourselves if we think that what makes companies successful even in the past 5 years is also what will make them successful in the coming 5 years because of the changes that we are seeing, and we are here to tap into those.

Okay. Well, it will be a fun next few years. Let's probably go back to the other kind of big picture. The most important, I guess, catalysts as we go through the next 12 to 18 months that we should be looking for?

I mean we are, of course, super excited to get the Phase III program kicked off, so people can sense a little bit more reality, see the progress in recruitment and getting close to market with petrelintide. And then we have additional data from a smaller Phase II study with petrelintide in obese individuals living with type 2 diabetes that will read out later this year. We have the combo study that is kicking off. And then for survodutide, we have further Phase III data, including the CVOT study, the cardiovascular outcome study with survodutide that should read out later this year.

Then -- and of course, at one point, the MASH program, which is really what could significantly differentiate the survodutide asset compared to some of the other GLP-1s out there. Then there's the early activities, including Kv1.3. There's the rare disease programs, AMA decision on glepa getting the CHI resubmitted to FDA, potential partnerships. So there is, I would say, a very deep and rich set of news flow approaching us in not only in the next 3, 6, 9 months.

Okay. Great. Well, with that, I think we're coming up to time. So thanks for that. Thank you for being here. Hope you have a good rest of the conference, and thank you all.

Thanks.

Good day, and thank you for standing by. Welcome to the Zealand Pharma Interim Report H1 2026 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Eric Rojas, Vice President and Head of Investor Relations. Please go ahead.

Thank you, Heidi, and thank you, everyone, for joining us today to discuss Zealand Pharma's results for the first half of 2026. The related company announcement is available on our website at zealandpharma.com. As outlined on the slide, I would like to remind listeners that during today's call, we will be making forward-looking statements that are subject to risks and uncertainties. Turning to today's agenda. Joining me on this call is Adam Steensberg, President and Chief Executive Officer; David Kendall, Chief Medical Officer; and Henriette Wennicke, Chief Financial Officer. All speakers will be available for the Q&A session.

I'll now hand the call over to Adam.

Thank you, Eric, and welcome, everyone. In the first half of 2026, we delivered on the key objectives we set out at the start of the year and grew significant progress across our pipeline. I'm pleased to walk through those accomplishments today.

Starting with Petrelintide, we reported positive ZUPREME-1 results, demonstrating double-digit weight loss with a tolerability profile consistent with placebo. On the back of that data, we confirmed advancement into Phase III registrational trials initiating in the second half of this year, so full speed ahead. On Survodutide, our partner, Boehringer Ingelheim, reported positive SYNCHRONIZE-1 and SYNCHRONIZE-MASLD results. Delivering comparative weight loss and targeted liver fat reduction, pointing to the potential for sustained improvements in metabolic health. What is compelling is that survodutide targets the fat that actually drives poor metabolic health. And I believe that, that is an increasingly important value proposition as this category matures.

BI also solidified their commitment and excitement around survodutide by announcing an expansion of the development program with 4 new and additional Phase IIIb trials initiating in 2026. On the early pipeline, we have initiated a Phase Ib clinical trial in plaque psoriasis, with ZP9830 and a first-in-human clinical trial with our GIP agonist ZP6590. So real momentum in building out the next wave of innovation. In May, we initiated a USD 200 million share buyback program, a statement for our strong commitment to returning capital to shareholders when we have the flexibility to do so. And finally, as announced yesterday, we monetized our royalty rights to a nonstrategic asset through the USD 100 million agreement with Royalty Pharma for rusfertide, which will be redeployed back into our strategic priorities and long-term growth initiatives. This has been a very strong half year and execution across our business, and we remain focused on advancing our programs to get these medicines to patients as fast as we can.

Before I hand over the call to David, I want to briefly mention what we witnessed at the American Diabetes Association meeting in June this year. The messages on key unmet medical needs in chronic weight management was clear: tolerability, treatment persistence and patient experience. ADA opened with a symposium on amylin that spoke directly to these gaps. And what struck me the most was not the data, it was the framing. The speakers or key opinion leaders in the obesity space laid out a hypothetical treatment paradigm for chronic weight management. This felt like a real shift in how the field is starting to think about treatment sequencing. And I think it maps closely to how we see the role of petrelintide.

For the majority of patients, the proposal was to start with a long-acting amylin as a first-line therapy. The logic here is simple. Why start with a very cumbersome treatment when a more benign one can deliver the weight loss most patients are actually after. For the patients with higher BMI and/or complications at GLP-1 with established evidence or higher efficacy dual or triple agonist could be the option. Then if those paths fell short of the patient's needs, escalate to combination therapy or bariatric surgery. This narrative is now being proposed by the broader scientific community as a logical way to think about chronic weight management. What I find validating is that this is exactly the value proposition we have been building for petrelintide, a benign, highly tolerable therapy delivering double-digit weight loss for patients starting their weight loss journey with the option to add or escalate if need of more.

With that, I will turn over the call to our Chief Medical Officer, David Kendall, to walk through the progress across our pipeline. David?

Thank you, Adam. I will start with an overview of our pipeline. The first half of 2026 has been incredibly exciting and was one of the busiest 6-month stretches in our company's history. We shared initial Phase I data for our novel Kv1.3 ion channel blocker, reported Phase II results for petrelintide and as Adam mentioned, presented these data at the American Diabetes Association's Scientific Sessions. And our partners at Boehringer Ingelheim presented results from 2 Phase III studies with survodutide. Beyond these readouts, we continue to advance our pipeline in other important ways. We confirm plans for initiation of a registrational Phase III program for petrelintide as monotherapy, and we will initiate the Phase II ZYNERGY trial evaluating the petrelintide and enicepatide combination.

As Adam also mentioned, we advanced our early-stage portfolio, including both the novel Kv1.3 ion channel blocker and our GIP agonist. Furthermore, for our rare disease programs, the Phase III EASE -5 trial for glepaglutide in short bowel syndrome continues to progress well, and we successfully completed the EASE-2 and EASE-3 extension trials, which will support the long-term efficacy and safety of glepaglutide. We look forward to sharing these data at scientific congresses in 2027. We have delivered a remarkable string of clinical milestones in the past 6 months, a real testament to the incredibly committed and talented teams we have at Zealand Pharma.

Let's now turn to our Phase II ZUPREME-1 results, which we firmly believe support the unique potential of petrelintide as a future first choice therapy for people living with obesity. Petrelintide delivered double-digit weight loss with no apparent plateau over 42 weeks of treatment in a study population that was generally balanced between women and men. What stands out in these data is not solely the clinically meaningful weight reduction, it is the tolerability profile observed. More than 3/4 of the gastrointestinal events reported with petrelintide were mild, were transient in nature and occurred predominantly during dose escalation. More importantly, up to 98% of participants successfully escalated to their target maintenance dose.

When looking at the adverse event rates, in particular, the reports of diarrhea, constipation and vomiting, they are strikingly similar rates in those treated with petrelintide as compared to those receiving placebo treatment, supporting a GI tolerability profile that is comparable to placebo. Together, these data point to the potential of petrelintide to fill a critical gap in chronic weight management, namely a highly tolerable therapy that delivers the weight reduction that the majority of those seeking weight management desire with exceptional tolerability and the potential to support long-term adherence.

With these data in hand, we and Roche have made the decision to advance petrelintide monotherapy into a Phase III registrational program on track to initiate later this year. We look forward to sharing more details around that program once those studies begin. We are also on track to report top line results for the Phase II ZUPREME-2 study with petrelintide in participants with overweight or obesity and coexisting type 2 diabetes in the second half of this year. ZUPREME-2 has enrolled approximately 200 adults with a balanced gender representation comparing 3 doses of petrelintide with placebo over 28 weeks of treatment. The primary endpoint is percentage change in body weight from baseline, while key secondary endpoints include change from baseline in hemoglobin A1c and changes in cardiovascular risk markers, including fasting lipids.

We are also expanding our petrelintide franchise with the initiation of the Phase II ZYNERGY trial, evaluating petrelintide in combination with enicepatide. Roche's potential best-in-class GLP-1/GIP dual receptor dual agonist. ZYNERGY is a comprehensive dose-finding study designed to identify an optimized ratio of petrelintide and enicepatide. The study includes 6 arms, 3 different dose regimens of the petrelintide/enicepatide combination along with petrelintide monotherapy, enicepatide monotherapy and placebo treatment groups. Participants will receive petrelintide and enicepatide as separate injections, allowing us to explore multiple combinations before committing to a fixed dose single cartridge co-formulated combination in Phase III. This study will enroll adults with obesity or overweight and at least one weight-related comorbidity with the primary endpoint of percentage change in body weight from baseline to week 40.

As we have seen in separate Phase II studies, petrelintide's impressive tolerability profile paired with enicepatide's strong efficacy makes this combination a compelling and natural next step in the development of our portfolio. We believe it has the potential to deliver both substantial weight loss and improvements in cardiovascular risk markers while maintaining a competitive tolerability profile for patients who will benefit from additional weight loss efficacy.

Turning to survodutide. Our partner, Boehringer Ingelheim, reported detailed results from 2 Phase III trials at the American Diabetes Association Scientific Sessions this year, and I would like to spend a moment on these exciting results. The 76-week SYNCHRONIZE-1 trial in participants living with overweight or obesity met its primary endpoint with survodutide delivering up to 16.6% weight loss from baseline compared to 3.2% with placebo. What we would like to further highlight today is data from the prespecified MRI substudy that looks beyond the top line number and assesses body composition following weight loss, a view of specifically what kind of weight is actually being lost.

Relative to baseline, survodutide achieved up to a 34% reduction in visceral fat, the metabolically harmful fat that sits around the organs and drives cardiometabolic risk alongside a 63% reduction in liver fat content. Lean mass loss accounted for no more than 11.3% of the total tissue mass change at the highest dose. This is a body composition profile we believe supports sustained meaningful improvements in metabolic health. This is a differentiation point we believe will become increasingly important as the field moves beyond weight loss alone as the benchmark and focuses on overall improvements in metabolic health status.

The 48-week SYNCHRONIZE-MASLD trial in participants living with overweight or obesity and metabolic dysfunction-associated steatotic liver disease or MASLD with evidence of inflammation and/or fibrosis also met both of its primary endpoints. Liver fat normalization was achieved by 6 out of 10 participants treated with survodutide for 48 weeks with an associated mean weight loss of up to 12%. On tolerability, what we're seeing is broadly consistent with what is expected across GLP-1-based therapies. It is worth providing some additional context here as the SYNCHRONIZE program used a stricter titration protocol than is typical in clinical practice or in many other clinical trials with limited flexibility for slower up titration, dose adjustment or temporary interruption of study drug.

In a number of cases, participants were required per protocol to discontinue rather than adjust treatment. We and our partner, Boehringer Ingelheim, believe this contributed to both the GI event and discontinuation rates observed. We were also particularly excited to see Boehringer Ingelheim expand the survodutide program with 4 Phase III studies, including ELEVATE-LIVER, assessing preservation of cardiac structure and function in people with MASLD or early MASH. The newer programs, including the LIVERAGE study, incorporate more flexible patient-centered titration strategies to better reflect real-world use and support tolerability.

Altogether, this reflects the breadth of opportunity for survodutide across the cardiometabolic and liver disease spectrum, a focus beyond brute force weight loss and to overall metabolic health. Lastly, I want to mention that SYNCHRONIZE-2 and SYNCHRONIZE-CVOT, the long-term cardiovascular outcome trial represent key upcoming readouts, both expected this year. We look forward to those readouts as we continue to believe survodutide is well positioned as a highly differentiated option addressing obesity and its most serious metabolic consequences.

Turning now to our early-stage immunology candidate, ZP9830, our novel Kv1.3 ion channel blocker. Kv1.3 is a potassium ion channel selectively upregulated on effector memory T cells, the cells that drive much of the tissue damage in autoimmune and inflammatory diseases through the release of pro-inflammatory cytokines. Blocking Kv1.3 may dampen specific pathogenic immune activity while preserving the protective function of the broader immune system. That selectivity is what makes ZP9830 a genuine pipeline and a product opportunity across a broad range of cell-mediated autoimmune diseases.

Building on the positive Phase Ia single ascending dose results, we have now initiated a Phase Ib trial in approximately 30 participants with plaque psoriasis. This 8-week trial will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of ZP9830 with treatment-emergent adverse events as the primary endpoint. We look forward to progressing this candidate through Phase Ib and to report top line results from the ongoing multiple ascending dose trial part of the Phase I trial later this year. The Zealand teams are both energized and excited with the clinical development progress we've made thus far in 2026, and I look forward to providing additional updates going forward.

And with that, I'll turn the call over to our Chief Financial Officer, Henriette Wennicke, who will review our financial results for the first 6 months of 2026. Henriette?

Thanks, David, and hello, everyone. I'll start by focusing on the strength of our balance sheet. We ended the first 6 months of 2026 with a significant cash position of DKK 14.5 billion. As a reminder, while we have recognized the revenue from the Phase III initiation development milestone of DKK 3.7 billion, we will only receive the payment from us later this year when we actually start the study.

We continue to focus on active balance sheet management. This is evidenced by the launch of the USD 200 million share buyback program in Q2 and the announcement yesterday of the USD 100 million royalty monetization of a noncore asset via the agreement with Royalty Pharma rusfertide. I'm very pleased with this agreement, which converts a future potential royalty stream into immediate capital. And we will continue to leverage our strong financial position to invest into future growth opportunities in line with our strategic priorities. Beyond our near-term commitment with the existing clinical pipeline, this means expanding our capabilities to build a leading pipeline for the long term, drawing on our deep expertise in metabolic health and peptide innovation and complementing this with external innovation through partnerships that allow us to expand into other modalities, just like the partnership with OTR Therapeutics on small molecules.

Moving to the income statement for the first 6 months of the year. Revenue was DKK 4.5 billion, driven by recognition of the Phase III initiation development milestones of DKK 3.7 billion and the first anniversary payment of DKK 798 million from the collaboration and license agreement with Roche. Operating expenses totaled DKK 1.2 billion. The vast majority of that was dedicated to research and development, reflecting continued investment in the petrelintide franchise, including preparation for the Phase III program with petrelintide's monotherapy and the ZYNERGY Phase II combination trial that David described earlier on. Expenses also reflect increased investments into our research program, clinical advancements of early-stage assets as well as the ongoing Phase III with glepaglutide.

Net financial items amounted to a positive DKK 292 million for the period, reflecting exchange rate adjustments on our USD-denominated holdings and interest income from our investments in marketable securities and cash equivalents. As a result, profit for the first 6 months of 2026 was DKK 3.5 billion.

Now let's briefly move on to the outlook for the full year. There are no changes to our financial guidance of DKK 4.5 billion in collaboration revenue for 2026. And we continue to expect operating expenses in the range of DKK 2.7 billion to DKK 3.3 billion, mainly driven by R&D activities. And with respect to the royalty sale agreement with Royalty Pharma for rusfertide just announced yesterday, we will receive USD 50 million in cash in Q3 and the remaining USD 50 million at the first anniversary of closing of the agreement. I would like to highlight that the anniversary payment is not linked to anything else than time.

And with that, I will turn the call back to Adam for concluding remarks.

Thank you, Henriette. Leveraging our momentum, we look forward to several important milestones and catalysts ahead in 2026. These include data from additional key trials in the SYNCHRONIZE program with survodutide, continued clinical advancement of petrelintide franchise and the progress across our early-stage programs.

With that, thank you all for your attention. I will now turn over the call to the operator, and we'll be happy to address your questions.

[Operator Instructions] We will take our first question. The first question comes from Hakon Hemme Bro-Jorgensen from Danske Bank.

On the combination product of petrelintide and enicepatide can you clarify your dose-ranging approach? Is petrelintide held constant around its maximally effective dose, while enicepatide dose altercation varies or are both components varied? And secondly, on the Kv1.3 channel blocker, how should we expect the future progression of this molecule to unfold? Will you run multiple Phase I indications in parallel or wait for more data before deciding where to focus?

Thank you Hakon. On the combination study, which, of course, we are extremely excited to get going and progress as we understand how important this could be for the future patient care. As we have discussed a few times before, the profile of a combination between an amylin and GLP-1 GIP actually holds the potential to address several different patient segments, including those living with the highest degree of obesity could also be patients who live with both obesity and type 2 diabetes and other situations.

And the specific combinations and which molecules we titrate and the specific titration ranges is something we will probably have to keep a little bit proprietary for some time as we build a very competitive profile for this combination product for the future. But as we have mentioned a few times, we could consider quite a number of different patient needs to be addressed by this combination product. And we're extremely excited about getting it going and progressing it together with Roche.

On Kv1.3, it's very clear, as David also mentioned, it has this pipeline in a product potential because Kv1.3 in these T effector memory cells are so central to the immune reaction in autoimmune diseases, but actually also in certain inflammation seen in metabolic diseases, we would definitely envision a broader program as we get later into development, but it's too early to comment on which indications we specifically will pursue beyond psoriasis. Thank you, Hakon.

And the question comes from the line of Mohit Bansal from Wells Fargo Securities.

So I have a couple of questions, one on survo and then one on petrelintide . So on survo the key question when we talk to doctors is that glucagon agonism does have a benefit in like liver fat reduction and all that. However, the question is, would you be able to show a differentiation against the GLP-1 or GLP-GIP based on the traditional MASH endpoint because they are more histology-related endpoints. Or you may have to come up with some unique endpoints or an outcome trials like Lilly is doing something of that sort that you may have to do to prove that this is GLP/GIP plus kind of drug.

Secondly, on petrelintide, so one key theme, especially looking at the data for obesity was that doctors love the fact that you could actually titrate only once and then you could get to a tirzepatide like weight loss. So for petre, given the safety profile is pretty good here, do you see a possibility on differentiation on the dose titration part, which would be very appealing to the primary care doctors.

Thank you for your question. And I will just touch upon the first -- the second question on petrelintide and then hand over to David on survodutide. But on petrelintide and titration, I think it's actually an important thing to think about that when we look into how petrelintide is being dosed, we actually see this more as dose escalation. We have just gotten so used to talk about dose titration when we think about the GLP-1s because they are so intolerable molecules, the GLP-1s that you have to carefully titrate them, you go up in dose, then you find out that patients can't tolerate it and you step down in dose, then you try again a few weeks later and so on and so forth. That's a very, very cumbersome journey to get to the effective doses that delivers the weight losses that people like to talk about.

With petrelintide as David mentioned, people can follow the dose escalation, meaning that you don't need to titrate up and down. So it's a very simple stepwise approach as you see with many general medicine in other categories. And if you think about our Phase II study, you also saw quite significant weight loss at the lower doses. So I think as a field, when we start to talk about amylins, we need to get used to talk about dose escalation rather than titration. It's 2 very different situations between the amylins and the GLP-1s.

So David, will you talk about survo and the glucagon component for MASH resolution.

Happy to, Adam, and thanks for the question. I think you hit on one of the key points, which is the glucagon agonism that's added to the survodutide molecule. Clearly, we have a belief and our Boehringer Ingelheim partners have a belief that the glucagon signal and its ability to alter specifically how free fatty acid is trafficked and metabolized in the liver is distinct from the pure incretin mechanism or GLP-1 agonism. I think one has to look no further than the Phase II data that were reported now 2 years ago at the liver meetings in Europe, where the improvements in fibrosis and resolution of MASH with survodutide, at least based on those Phase II data are what we would consider best-in-class in terms of potential. That does not mean that other mechanisms, GLP-1 agonism alone with semaglutide, GLP-1 GIP agonism with tirzepatide will have an effect, presumably much of that driven through reductions in body weight specifically.

But we and our BI partners firmly believe that, that glucagon signal has a critically important role in what is the primary insult that is driving the trafficking of fat into the liver, in this case, modifying that through the glucagon signal. The preliminary results from SYNCHRONIZE-MASLD also showed that 6 and 10 have resolution of liver fat, albeit in a lower-risk population. So I think those are 2 very important data points that suggest that while weight reducing therapies alone are very effective, that adding this glucagon signal may carry very important additional effects at specifically targeting not just MASLD but MASH, the F2, F3 and ultimately F4 population. So obviously, more to come with the LIVERAGE program, but exciting data to date, we believe, supporting this unique mechanism.

Your next question comes from Alana Shamzi from Jefferies.

Firstly, on amylin therapies, interested to hear if you hear of any illegal or unapproved use of amylin, including petrelintide in the same way that's been seen for drugs such as retatrutide? And then secondly, on GIP, could you walk us through how you're thinking about the development strategy from here? Specifically, what do you see as the most attractive commercial positioning for GIP-based therapy? And what could combination trials look like?

Thank you for your questions. I'll just address the first one and then hand over the question on GIP to David. We have not heard specific illegal use of compounded or imported use of petrelintide. Of course, it's something we monitor closely as we have seen these things with other products. So it's something we have to monitor closely going forward.

David, will you take.

Yes. Yes. Yes. Happy to, Adam. And as regards amylin, it's worth noting that pramlintide approved symlin has been available indicated as an adjunct to insulin therapy, but we do know of both data published with pramlintide in the weight-producing space and some use as an adjunct to weight management, not illegal use, just use of a licensed compound. Your question on GIP and its potential in the metabolic health space, I think there is much to learn about GIP agonism. We see reports each day on both agonist antagonist approaches. But clearly, GIP through its myriad effects on both beta cell function islet cell function, potentially on bone health and muscle mass clearly has with the dual agonist molecules shown great promise. What is less well understood is how can this be combined with other classes of therapies, in particular, nonincretin therapies such as petrelintide.

So clearly, having an effective GIP agonist compound that is safe and well tolerated. That's what the Phase I trial will assess for us. That can and likely will be used in multiple combinations. This is another molecule as is the history of Zealand that we believe can be readily co-formulated and administered with a number of other metabolically active peptides, not limited to the incretin hormones, but as an adjunct to a number of peptide hormone therapies. So right now, this is step 1, just as others have developed on these stand-alone molecules that will allow some freedom in formulation and dose selection as opposed to being tied into a fixed dual agonist molecule. Much more to come, in future earnings calls and with data becoming available. Thanks.

Your next question comes from the line of Rajan Sharma from Goldman Sachs.

I've got a couple. So firstly, just on the petrelintide, enicepatide combination. Could you just outline your target product profile there? We've also seen some data for Lilly's eloralintide and tirzepatide combination in the EASD abstracts. Is that a level of efficacy that you think is achievable with petre combination? And could you maybe just talk about potential other areas of differentiation there? And then second question, just on the royalty agreement that you announced last night. Could you just maybe talk about the rationale for the timing there, looking at the balance sheet and your previous communication, it doesn't feel like there is an obvious need for capital immediately. So just wanted to understand what the rationale was for doing that deal and doing it now.

Thank you for your question, Rajan. I'll take the first one and hand over the second question to Henriette. On the petrelintide, enicepatide combination, I would say there are opportunities to address multiple patient needs with such a combination. And rather than just pursuing the weight loss olympics, which I think I've been calling a few times that we should stop to care about, we should think about what are the true future patient needs. If you think about a more mature chronic therapy market, most patients will likely start on a monotherapy and then only step into combination therapies if their needs are not solved by a monotherapy. The combination of an amylin and a GIP in our minds, looks to be fantastic for those patients who need more. So that could be a patient who started on enicepatide and wanted more and then you add a combination or it could be the other way around, as I explained and as many physicians discussed at ADA this year that you start on petrelintide, for instance, what we think is the most tolerable approach to achieve a weight loss.

And if you then find out you need more, then you step up to a combination between the 2 products. Where the combination, of course, looks extremely attractive with the data that are available, broadly speaking, from amylin and GLP-1 GIP combinations is also in patients living with obesity and type 2 diabetes because it seems like we can address both the weight loss and the glycemic deficiencies in a strong way. So I would say -- when we think about how to develop combination therapies for the future and not the current market, it's extremely important to think about what is the profile needed and not just try to run for the highest number, in particular, not if you then achieve very high dropout rates or a lot of GI side effects when you achieve those numbers.

So I think you need to have a more balanced view when you view these data readouts in the future, at least how we think about designing these studies is about what is the future patient needs, what are the profiles of such combination products that could make them highly successful in a future, more complex treatment world rather than just running after specific numbers. So I hope this addressed partly your question.

And then I'll hand over to you, Henriette.

Thanks, Adam, and thanks for the question Rajan. So you can say this royalty stream, of course, very passive. I think rusfertide as a product and an asset in our pipeline was maybe forgotten a bit by some. This was a good opportunity, and we saw a good appetite to actually get this deal done at this time. I think it's an opportunity for us to take this cash and redeploy it into some other activities and opportunities we have in the pipeline. And of course, this was a very passive ownership we had on this product and other strategic assets that doesn't really fit, you can say, our future ambitions and the vision. So we will redeploy this cash and put it into future opportunities.

Your next question comes from Suzanne van Voorthuizen from Van Lanschot Kempen.

This is Anna on for Susan. So could you elaborate on your view on the wider landscape in weight loss with now or available on the anticipated launches of petrelintide and enicepatide how you expect the treatment paradigm to change with increasingly more options to the needs for efficacy and safety and convenience? And where do you believe that petrelintide will sit?

Thank you for those questions. I'll start and maybe David will add some color to some of my comments. On the segment and the GLP-1 -- all GLP-1s, of course, as we are seeing right now, they have opened up the market and at least according to the manufacturers of these medicines, they are very much getting new patients on board who have not been candidates for their injectable GLP-1s. What we still need to see is, of course, how people manage to stay on these therapies will it truly change how we have seen the GLP-1s being used, where we know after 3 months, we have 30% who have dropped off and after a year, only 20% are still on. And I really have to remind us all that obesity is a chronic disease, and it should be considered a chronic treatment.

So this thing that we get on and get off is probably not the way we would address obesity for the future. And that's why we are so focused on developing medicines that can give patients the weight loss that the majority of patients are looking for, which is a double-digit number. If you ask patients, broadly speaking, 80% in our surveys at least suggest that they would be looking for weight loss below 20%. What is important is that we are only, I would say, 4 to 5 years into the treatment of what we consider the biggest health care challenge of our time, obesity and all the metabolic consequences of living with obesity. So it is a very dynamic market. And as we will see more tools and in particular, differentiated tools getting to the market, it will, of course, also be more complex treatment algorithms.

One thing where we see -- I think we'll see a major shift is that instead of just looking at specific patients and saying this treatment is for that patient or this treatment is for that patient, we will start to consider treatment of obesity as a weight loss journey, meaning you start on one product and then you see where you get on that one. And if you don't achieve your goals or if you can't tolerate it, you get on another product and then you see where that gets you to or you get on combination products. That's how we treat other chronic diseases. And that's the complexity that we are trying to develop our portfolio for.

And this is also coming back to why we are so excited about the profile of petrelintide because we think it's the logical starting point for most patients ultimately when they start a weight loss journey. And then only if they need more weight loss, you will start to consider other more cumbersome modalities or combination therapies. So a more mature market, you should view patients as being on a journey towards achieving their goals and not just as this product fits this patient forever. So it will be more complex. We think we have the pipeline to actually address key aspects of the need of the future, and it will be exciting.

Thank you. David, do you have further?

Yes. Adam, I'll add a couple of points, and I will reemphasize, Anna, that these are therapies for a lifetime for that weight loss journey that Adam described. We are still early in this journey and the currently available therapies are really limited to a single incretin-based approach. And much of the clinical development has been in those with what I'll call more substantial or advanced perhaps end-stage obesity with serious complications like cardiovascular risk, liver disease. The orals are still a minority of the prescriptions as we see the data. Weekly injectables are quite readily adopted given both the efficacy, it is that dose escalation, de-escalation and complexity.

To Adam's point, I think historically, we have seen in chronic disease that treatment options and their availability with different characteristics, different user profiles don't say for this patient, choose X, but actually as Adam described, allow us to impart upon a weight loss journey in serving those individuals who live with overweight obesity. I will provide some historical context because I was around and working at a small company, Amylin Pharmaceutical, when exenatide was launched and the world looked at us and said, well, we have insulin, why would we need alternatives to insulin in the diabetes space. And subsequent to that time, GLP-1s were adopted more broadly, DPP-4 inhibitors, SGLT2 inhibitors. We came to a place where options became really the norm to consider in the management of the chronic disease of type 2 diabetes.

In this case, that patient experience, initiating therapy that you can readily or simply dose escalate to an effective dose. And I remind listeners that even the 1 and 2.5 milligram doses of petrelintide reported in ZUPREME-1 had significant near double-digit weight loss. So we are not talking about ineffective therapies that in fact, across the board, that tolerability, we think, can serve an incredibly important need as more and more patients in more and more settings, not just specialty settings, embark upon that weight loss journey. So there will be room to evolve this market over the next 5 to 10 years, just as we've seen, as Adam mentioned, with other chronic diseases.

Your next question comes from the line of Andy Hsieh from William Blair.

So at ADA, we heard several investigators discussing the outperformance of placebo arm patients. And I'm just curious if you and Roche have thought about ways to potentially mitigate this kind of recent phenomenon. We also have a second question about 9830, the Kv1.3 inhibitor. You mentioned about the potential for a pipeline within a compound. And I'm curious about the upcoming Phase Ib trial. Do you have -- or will you have any PD biomarkers available for that trial to really support that assertion that we can look forward to?

Thank you for your questions, Andy. I will hand them over to David, both on the placebo responder rates in obesity studies, but also on Kv1.3.

Yes. Thanks, Andy, and thanks, Adam. Placebo response is obviously, I think, something we all think about, but in well-executed trials where you provide additional support to the individuals who participate in your trials, I think it is now quite well understood that in general, a 2% to 3% body weight reduction on average across trials can be expected. I think there are critically important things that will allow us to better understand that. Remember, placebo-controlled trials are not part of clinical practice, meaning that change from baseline when you are on active drug with the same lifestyle counseling support interventions is really for us and I think for clinicians, a key endpoint. Placebo correction is obviously important for regulatory approval.

I think 2 things can shed additional light on that. One is the degree to which you have to support patients who achieve that placebo-associated weight reduction. The second is in trials that have open-label extension when patients treated with placebo then switch to active drug, how significant is the clinical response. Similarly, longer trials that is required to have 52 weeks on steady-state dosing also allow you to see the lack of sustainability of many of the placebo-treated groups. So I think all of those are taken as one part of the business. We don't want to enroll patients and leave them unsupported in the population that should receive placebo. That is obviously an important part of the regulatory pathway.

The 9830 question as regards the Phase Ib approach in psoriasis. Psoriasis has a number of approaches that are both approved and in active investigation, but it is an important, as I'll describe it, sentinel disease where you have skin lesions, plaque size, PASI scores, et cetera, that can be utilized even over short term to get a glimpse, if not an early indication of the pharmacodynamic response.

That said, is this the only pathway down which we'll go? Absolutely not, as Adam alluded to earlier, having the opportunity to address other inflammatory diseases, other diseases where -- or disease states where inflammation may play an important role in associated comorbidities such as MASH, such as cardiovascular and peripheral vascular disease. So the pipeline in the product really relates to what we see as the opportunity of the T cell and T effector memory cell mediated or driven disease states, the psoriasis study being the first sentinel look at the potential to impact not just markers of inflammation, but clinical measures like plaque size and PASI score.

Your next question comes from Martin Brenoe from Nordea.

I just have 2 questions, shifting gears a little bit here. But maybe just coming back to your previous commentary about the external opportunities that you have as part of your strategic priorities. Can you maybe just put a few words on how this is tracking? What kind of assets are you primarily looking for? And where do you see the biggest gaps in your pipeline that you might not be able to close organically?

And second to that, on the early pipeline, can you just help me understand what your top priority is? We will get multiple Phase I, Phase II initiations. Can you just elaborate a little bit on that? And should we expect inflammation as a category to become a strategic indication for Zealand Pharma on the medium term here would be my question. And then just final question, sorry for the many questions here. But when we look at other therapies, I get the commentary that it's not a great part of the overall category today, but with the trajectory we're seeing that most likely will have a pretty decent size of the total market over the medium term. So just wondering how you see Zealand Pharma tapping into that opportunity.

Thank you for your questions. And if I'll just start with number one, the strategic priorities when we think about external opportunities, I think you should really think a little bit along what we also announced last year in December with OTR, where it's a collaboration with more of a platform company who can help us tap into modalities where we are not as established ourselves yet. So this was a small molecule drug discovery collaboration where we then apply our strong metabolic know-how and then take the products, of course, forward. So similarly, when we are looking into the focus for our external opportunities right now are in the early stages as we expand the modalities that we are going to work on beyond peptides. So that is the clear focus right now. As you can see, we are quite busy in the clinical part of the pipeline.

How we think about developing the pipeline, it's really that overarching theme of metabolic health. So beyond obesity, of course, beyond weight loss, but really how do we help people have a longer health span, not just a lifespan, but living healthy longer. And a component, as David also alluded to, of course, a strong component within that metabolic disturbances we see associated with obesity and the metabolic challenge situation that many find themselves in today is, of course, inflammation. So you could see inflammatory targets being part of Zealand's innovation. But when it's more specifically towards specific indications that are autoimmune diseases that are established, that's where you should expect us to, at one point before we get to the market, have partnerships in place. So we have dedicated companies to work on those pathways. Kv1.3 is a good example because it's a pipeline in a product. Of course, there will be certain areas where we would not take the lead ourselves ultimately, but have a partner doing so. So that would be the strategy for that.

On the oral therapies, we do see a significant opportunity with oral therapies, in particular, once we move beyond the GLP-1s because an oral GLP-1 doesn't address the biggest issue with the GLP-1s, which is the side effects that many people fail to tolerate them. But of course, as we think about this market in 10, 15, 20 years from now, we also expect orals to play an increasingly important part. And that's one good example is why we engaged in a partnership with OTR. We have other opportunities. So we are really thinking about the future. But if you think about it, an injectable convenient injection once a week is actually, as we have seen with the success, not only in obesity, but also in diabetes with the GLP-1 despite their quite cumbersome use, a quite attractive profile.

Your next question comes from Kerry Holford from Berenberg.

Petrelintide in terms of timing, Adam, you stated it was now full speed ahead in your intro. And I think we all agree speed to market is important. Just intrigued to hear the latest on this because obviously, we saw the headline Phase II back in March. We don't see any Phase III trials yet listed on clinicaltrials.gov. But we do see the details for the Phase II combo, which is scheduled to start in September. So is it fair to assume that Phase III mono will start after Phase II? And what else are you now waiting on in conjunction with Roche to move into and actually start the Phase III mono?

Question from a financial point of view also following that Royalty Pharma agreement. interested to hear whether you're looking at any other royalty agreements that you may have internally, which could be capitalized and redeployed in this way. And then if I can squeeze a final one in on survodutide. The body composition data are clearly interesting. But of course, the debate ADA was on tolerability. To your earlier point, are you able to tell us whether any of the new Phase IIIs that are planned will allow for slower dose titration to improve the AE profile and discontinuation rate?

Thank you for your question. So I'll take the first and the last and then hand over the middle question to you, Henriette. On timing of petrelintide mono, I can assure you it's full speed ahead, and I cannot comment on if it's before or after we will start the combo study, but I can assure you that it's full speed ahead as both us and we understand the importance of getting to market as early as possible with this potentially very important first choice medicine.

On survodutide, I think it's fair to expect that the titration scheme has been changed for the new Phase IIIb studies that have been the 4 studies that have been initiated this year also because Boehringer have already been out stating that for the LIVERAGE program, so the program targeting MASH, they have actually a different titration scheme. And you also heard if you participated at the ADA that the presenters there described that it does lead to a different experience on these drugs and less at least perceived side effects. That was what we heard at least. So yes, we would assume the titration to be more reflecting what is being used in LIVERAGE and there, they have indicated that the titration is different.

And really, again, highlighting that Boehringer have initiated a Phase IIIb study to inform how to dose this product in the real world. So our clear assumption is that it will have a tolerability profile, which is comparable to the other GLP-1s once you allow more flexibility in the dosing. And that's why we are so excited, at least we also see Boehringer's excitement around the program. Henriette?

Thanks, Adam. So of course, what we do always is to look at our balance sheet and see how we optimize and also how we deploy capital. And you can say this was an example of active, you can say, capital allocation. Of course, all our assets and all our agreements are listed in our annual report. So it should not be a surprise. But as always, as you know, we look for opportunities both to get cash in and cash out at the right time. And this, I think, was a good example of that.

Your next question comes from the line of Mathijs Geerts Danau from KBC Securities.

I had one question on the Kv1.3 inhibitor. Could that also be co-formulated with your other peptide drugs in obesity-related indications?

Thank you. That's a very interesting question, and it's definitely something we'll be looking into because the combination of both addressing metabolic disturbances and the underlying inflammatory components of metabolic diseases is highly interesting. So good question, and we'll probably address it in more details at future calls and conferences.

We'll take one more question.

Your final question comes from the line of Prakhar Agrawal from Evercore.

Congrats on all the progress. Maybe firstly, on ZUPREME-2, if Adam and David, if you can set expectations for ZUPREME-2 on weight loss, HbA1c and safety tolerability given what we saw in ZUPREME-1? And anything on the baseline, for example, men versus women split that we should be aware for ZUPREME-2? That's my first question. Second question, on the petri plus Roche's GLP-1/GIP agonist combo, one clarification. If you can elaborate on the form factor. Is this a single-chamber device or something else? And then last question, maybe just broadly on the Kv1.3 channel blocker in psoriasis. Given what we are seeing with some of the orals in this space in psoriasis, where do you think this MOA can differentiate, especially with -- in the context of oral TYK2s and oral IL-23 that are showing biologic-like efficacy, anything that you think that Kv1.3 could do better?

Thank you, Prakhar. I'll just answer your questions. On ZUPREME-2, I would say it's a shorter study. Remember that. It will read out here in the second half. We will be looking to see, of course, both weight loss, but also glycemic control and other parameters, how they read out. One of the key features of amylin in general, and that's, of course, also why we're exciting about this program is that it looks like amylin is as effective in driving weight loss in obese individuals living with type 2 diabetes as it is in those who do not have type 2 diabetes. So that's some of the aspects we will be looking for in this study. And of course, also understanding better how petrelintide affects the glycemic situation for these patients.

But again, I have to remind you that this study is not informing our Phase III initiation, but it's a study we very much look forward to see the results and really also if we can expect to see similar weight loss in patients with type 2 diabetes as in those who do not have diabetes. Remember, with GLP-1s, often you see around 30% less effect for weight loss in patients with type 2 diabetes. On the combination of the 2 products, I forgot what you asked about. But on Kv1.3 -- sorry, but let me just answer on Kv1.3 first on psoriasis. This is a small Phase Ib/IIa study to look for PD markers in the disease state and psoriasis is only one potential indication we are pursuing. You should expect us to pursue multiple indications in parallel as we mature this program if it's successful here in the early stages. Could you just repeat your second question because, yes.

Yes. It's on the form factor and the device and it is like a single chamber device that you're using?

I think David mentioned this in his prepared remarks that we are applying 2 different cartridges in this study in order to inform the single cartridge use in the Phase III -- anticipated Phase III program, where it should be a single container.

This concludes today's question-and-answer session. I'll now hand back to Adam Steensberg for closing remarks.

Thank you for attending and for all your questions today. We look forward to future announcements and updates and to connecting in the coming weeks and months. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good afternoon, everyone. Thanks for joining us. My name is Rajan Sharma, European pharma and biotech analyst here at Goldman Sachs. Very pleased to have Zealand Pharma with us and Adam Steensberg, CEO. Adam, thank you. Thanks for joining. I know that you've been on the road with ADA. So thanks for adding on this to the trip.

Pleased to be here.

Lots to get through. And obviously, we're coming off the back of ADA. So maybe that's a good place to start. There are a few updates there, both with survodutide and petrelintide. Could you maybe just start with survodutide because that was kind of the more -- or the newer update that we got over the weekend and just provide your thoughts on the data.

Absolutely. And as you said, I just went almost a week around at ADA, and it was really, you can say, positive experience coming out of ADA, kicking off Friday with a symposium on amylin and really starting to change the conversations from how we get to the maximum tolerated doses more towards how do you get to the minimum effective doses when you think about treating obesity.

So there's a quite significant change in the ecosystem right now that we start to see more modalities approaching the market and specifically with Boehringer being the CEO, Sid, and I was, of course, extremely pleased to see the strong presence they had at the conference, probably being one of the biggest sponsors and having this very strong presence around obesity and think liver.

And as you also said, they presented data Sunday, which really speaks to the strength of survodutide being a liver, fat and visual fat targeted therapies, which also showed signs of preserving muscles to a larger extent than what we have seen before with other molecules. So I was actually very pleased with the profile and also with seeing how the Boehringer management team, their excitement around it.

When we think about the top line data that was released on the -- both on weight loss and tolerability, I was also a little bit surprised to see that somewhat higher level of vomiting and discontinuation than what I had expected from the study. But at the session, we learned that Boehringer had applied a very strict titration protocol where they did not allow people in the trial to kind of personalize the titration and they did also not allow for deescalation once you have reached the higher doses.

So we know that from any other trial that if you don't allow for flexibility in the titration, then people have side effects on the GLP-1. So that was a little bit of a surprise to me that, that was a study design that was chosen. Investigators indicated that, that was based on some regulatory interactions.

What I would say, however, and what gives me a lot of confidence going beyond those headline numbers is when I speak to the senior executives at Boehringer, and they are very, very confident that they can -- you can say, change this with a more personalized and modified titration scheme where you allow to go slower and also deescalate once need be. And they, as you could also see in the release from them, have actually initiated studies now to help inform how to titrate survodutide in a real-world setting including also new studies in women's health and heart failure and what have you. So a very, very committed team, but also a little bit surprised to see that they have been so strict about titration.

Yes. And just on that point on the titration, I remember at the presentation, the presenter noted that the flexibility was added quite late in the trial, and that's going to be kind of informing future programs. So are you aware in SYNCHRONIZE-2, for example, is the flexibility in the trial? So could that be a trial, which shows better tolerability and similarly with the LIVERAGE program, which will be important for NASH?

Yes. So we don't have the insights. It was implemented into these studies once Boehringer started to discover that they had issues with dropout rates. And apparently, when you listen to the investigators, it had a meaningful impact. For some of these studies, it was perhaps too late to have an impact what the investigators indicated, I think, at the conference was that the LIVERAGE studies, which we started later, I think they were running with the flexible titration schedule from the start.

And there, they felt that the issues with tolerability have been addressed. So I mean -- and of course, I don't have all the detailed data that Boehringer team have it, and they feel extremely comfortable around being able to address this. And that gives me a lot of confidence as the molecule move forward, really being a molecule that targets, I think the biggest, you can say, desire for when you engage in a weight loss that is you should not focus about who can get the highest weight loss, but who can get the most metabolic benefits out of a reasonable weight loss.

Okay. And just on the piece, and you mentioned around sort of liver fat and visceral fat and even body composition. To what extent is that important to both physicians and patients? Because I know, again, at the conference, there was some debate around the whole body composition piece and the extent to which that is important in clinical practice. So what's your take there?

I think it's easy to think about that for the physicians, it's extremely important that you lose the right amount of fat because as a physician, you know that it's the visceral fat, it's the fat in the liver that cause all the negative health consequences of living with obesity strong say driver for a physician to target that weight loss towards bad fat, if you will, and protect somewhat, especially the muscles, but actually also subcutaneous fat.

One thing if you think about people living with obesity who start on a weight loss journey, we know for a long time, there's a big concern around losing muscles when you embark on a weight loss journey. And here, we saw data, I would say, which have -- which showed only about 10% of the weight loss was driven by muscle, which is a very different number than the 30% we have seen with other molecules. So that could speak directly to, you can say, the patients really wanting to protect their muscles when they engage in a weight loss journey.

The other thing which I think will also play into the patient experience is that we see a lot of patients stopping taking the higher doses of the currently available GLP-1s because they don't want to lose too much facial fat and subcutaneous fat. And that's again, with survodutide, where it's targeted visceral and liver fat, I think we actually have a product that will speak directly to being able to have a modest weight loss, lose the right fat, the bad fat and protect your facial fat for instance, so you don't get that, you can say, expression where you start to feel that look even older.

Yes. And obviously, as a company, you know the GLP-1 space pretty well as well, given your history there. And when you look at the survodutide data and that sort of elevated discontinuations and nausea, do you think that's driven by the GLP-1 component of survodutide? Or is that additional sort of AEs being driven by the glucagon component?

I think it's driven by GLP-1. And I think there's not a single GLP-1 out there or in development who -- which would not deliver the same amount of GI side effects and dropouts if you were as strict as Boehringer initially were in these studies. We know that these drugs are being personalized.

Also in real world, I mean, there are very few physicians who would prescribe a currently approved GLP-1 according to label because they know [indiscernible] you can say reasonable, both from a side effect profile, but also if you look about -- think about that you don't want to lose weight too fast. So we are -- from the real world, we are starting to learn to dose much, much more slow with these molecules. And that is what Boehringer is now addressing in an upcoming Phase III study to really inform how to use and how to titrate these products in the real world.

Yes. Okay. Maybe thinking a little bit more positively on survo, the MASLD data, I thought was pretty impressive. Could you again just kind of provide your perspective there and help us put that into context relative to the other GLP-1s?

Yes. But I -- this -- I think I started saying that, that is really what impressed me. And remember, they achieved these data even in -- during the constraints of the study that we just discussed. So that makes it even more impressive. We saw livers that went from 30% fat content to 2% fat content in the presentation. And this is really the holy grail of trying to promote metabolic health and help people living with obesity having a more -- a better metabolic condition.

And if you then think about that Boehringer is also investing in likely the largest studies ever conducted in MASLD. So we have LIVERAGE 1 and 2, which address both 2 and 3, but also cirrhotic patients. That gives Boehringer a very, very strong value proposition for the -- for survodutide being. If you're an obese individual, there's a 65% chance that you also have excessive fat in your liver. And there's a chance if you live with that condition for a long time, it will develop into later stage end-stage liver diseases.

So why not treat the liver also knowing today that most patients are not interested in that very high weight loss. So if you're a person who looks for a 12% to 15% weight loss and you can target that weight loss to liver health, liver fat, that's a strong value proposition.

Okay. And then if you think about utilization, and obviously, that's up to Boehringer in terms of the commercialization as opposed to yourselves, but you will need to think about commercializing petrelintide. So how would you sort of think about the potential population that survodutide might be relevant for in obesity as opposed to in NASH?

Yes. But it's relevant for patients who can tolerate a GLP-1. And it's, of course, when you're a prescriber, it's relevant for patients where you want to really target that liver-specific weight loss, which could translate into very, very significant metabolic benefits because the liver is actually where a lot of the risk markers for cardiovascular disease arrives that comes from COT lipids et cetera. That is from the liver. So you may actually consider a product like survodutide could ultimately provide more metabolic benefit. And it also address atopic fat in other organs and thus helping organs even more than the direct effects of a weight loss.

So I think it's really a product that speaks directly into the metabolic health, those who seek metabolic health more than just weight loss. And the narrative that we have been promoting for quite some years and I've called to stop the weight loss in [indiscernible] because the observation in the real world is that patients don't care about that highest weight loss number.

We have, for a long time as an industry, been pushing towards that biotic surgery weight loss, not realizing that most patients are not in for it and very few actually are offered biotic surgery historically. Patients seems to be looking for that 10% to 15% weight loss. And if survo can deliver that, but generate significant more metabolic health, that's a very sharp value proposition. And that gives me a lot of confidence in Boehringer also pushing that narrative forward as one of the highly differentiated GLP-1 options out there.

Yes. One of the other things I thought was interesting about that study was the fact that up to 15% of patients on the placebo arm were actually receiving a GLP-1 therapy and got access. So there's probably a good segue into petre as well. How do you think about controlling that in a clinical trial? And is that just a challenge that the industry faces from here?

I think it's likely the highest number we have seen thus far, but I think it's things we need to get used to deal with in clinical trial readouts in the future because there's a lot of patients number one, who have already been exposed to therapy and thus, you can say, have had initial weight losses, and therefore, you may not be able to expect the same degree of weight loss in the future study environment.

The other thing is when people find out that they are on placebo, which is quite easy when you're in a GLP-1 study, then you have patients who then turn to use GLP-1s. And it was a high number in this study, which also drew up the placebo effect for the study. But I think we need to be used to kind of find ways to look at the data despite the fact of these differences and how many patients decide to utilize the GLP-1.

It very much depends on also which sites you go to. It's clear that it's a larger phenomenon in the U.S. because you have easier access to GLP-1s than in, for instance, Europe. and other places of access to alternative channels, if you will. So it's something we, as an industry, will have to deal with. It's something we will have to discuss with FDA how to handle. And of course, when we ultimately view data, we need to take those differences into account.

Okay. And at some point, do you expect that the standard way of running an obesity trial will be to use a GLP-1 or another approved medication in the control arm?

I mean that remains to be seen. But remember, if you add GLP-1 as a control arm, then you will not be blinded anymore because people will know what they aren't because of the side effects of GLP-1s. So it's not easy to just -- there's not a one fix here. It's going to be a multitude of different things. But of course, ultimately, head-to-head studies will be important to inform how to use these medications as we start to have more tools.

We have to remind ourselves that today, we only have kind of 2 very similar tools, which I would normally describe as a HAMR and one which is a little bit bigger and then someone is trying to develop a sedgehammer. Once we start to have a full toolbox, of course, in a more mature market, we will start to see more head-to-head studies.

Yes. Okay. And last one on survodutide and I assume the sedgehammer is potentially retatrutide that you're talking about. How do you think survodutide compares in a world where retatrutide may also be on the market, given it has a glucagon component and could have a liver benefit as well?

Yes. But that, of course, remains to be seen how the 2 molecules play out when we start to see the clinical data. I think survodutide, as Boehringer is arguing and as we have been arguing for a long time, it has specifically been designed to address liver health, liver fat, not with the maximum weight loss in mind.

So with the relative balance of an appropriate weight loss, which they released, we saw these fantastic data in liver -- getting fat out of the liver. So the relative balance between the GLP-1 and glucagon component has to be shown how that you can say, at different dose levels contribute to a healthy liver for the different molecules. We are very, very, you can say, happy with the profile, the balance between weight loss and metabolic improvements that we see with survodutide and that Boehringer reported.

Okay. Maybe we should move on to petrelintide. I'm conscious that we've already got through quite a lot of time. What were the key updates that you would highlight for petrelintide at ADA? Obviously, we've already seen the top line data. What were the incremental new learnings in your view?

I mean there's no question that ADA this year was kicked off with an ADA sponsored symposium and amylin where the presenters presented amylin as a logical new first-line therapy as they would argue why would you not start with the most benign treatment and only go to more cumbersome treatments if that first modality doesn't deliver what it's looking for.

And specifically at that session, they also presented the different amylin analogs. And when petrelintide was mentioned with the double-digit weight loss and placebo-like tolerability, all of them said, this is a natural first choice therapy for a patient who starts a weight loss journey. And one of the presenters even kind of presented a hypothetical future treatment paradigm where amylin would be really the primary care product and the GLP-1s would be reserved for the more complicated obese patients, which is actually speaking very much to how we have seen the field and how we have been developing petrelintide, not trying to go for the highest possible weight loss compromising on tolerability, but really going for that weight loss that we believe most patients are looking for 10% to 15% and then a placebo-like tolerability profile. And that is what we saw at ADA.

And when you -- that the conversations not only in the symposium, but at the congress in general, it was about tolerability. We need to find medicines and ways whereby patients can stay on therapy. So we don't have these cycles all the time on treatment, off treatment. That doesn't promote a lot of health if people get off treatment all the time. We need to develop tools that patients can stay on.

But I would also say what -- and I think it's going to be a quite we can say, influential ADA when people look back at this one because it's really -- my sense is that the obesity field that at least has matured quite a lot in just compared to last year where we start to think about it like what has happened in other chronic therapy areas.

Once you always start to treat the most difficult-to-treat patients. But as we mature, we start to think about obesity prevention, why is it we should wait until you have a body mass index of 45, why not start earlier?

And the other thing is, why don't we start with the most benign therapy that has a high likelihood of giving you the weight dose you're looking for, just like petrelintide and then only after that go to more cumbersome treatment. So that was a lot of the themes that we heard at ADA and petrelintide just speaks directly into that value proposition.

Yes. I guess to be sort of a definitive first-line therapy, part of that is also going to be outcomes-based, right? So is that a view that you share that you would need whether it's cardiovascular or otherwise that you need to demonstrate that there is a benefit beyond the weight loss to be able to justify that first-line use?

Absolutely over time. And we just have to remind ourselves that the reason that we as an industry are in this space is, of course, to promote health. So ultimately, we also need to show that in outcome studies. And there, we have more data for the GLP-1 class. So -- but what I would say is that if you think in the life of a normal prescriber, they have -- there are 3 main drivers for prescriptions, data, heart and hassle.

Data is about what is the weight loss you can deliver. And here, we think with petrelintide, we can actually deliver the weight loss that the majority of patients are looking for.

Heart that is you have to believe you do something well for the patients. And when we look into the risk markers for cardiovascular disease and other organ diseases, they all go in the right direction. So at least there's a lot of belief that you can do something good until we deliver the proof in an outcome study.

And hassle, with the tolerability profile that we have of petrelintide, we can remove the hassle that people are more and more aware of with the GLP-1s. It's a super cumbersome situation to prescribe GLP-1s because you have to engage with the patients, deescalate personalized every patient journey that takes a lot of time in the clinics. And the minute we can offer something where it's an easy prescription where you don't hear back from the patients until a few months later and they can follow the prescription. We think that's going to be a major change.

In our Phase II study, we had 98% of the patients who could follow the escalation steps without having to modify it that you could not do with a GLP-1. So the change could come very, very fast in the minds of both patients, but also prescribers this first line of therapy.

Yes. You mentioned the Phase III data. Can we talk a little bit around that? So I guess it's looking at the stock reaction, it's fair to say that the market is a little bit disappointed by the level of weight loss that petrelintide showed in that trial. Has that data set changed your view and your conviction? And I think you talked previously to sort of 15% to 20% weight loss long term. Do you think that's still achievable given what we've seen in Phase II?

The product that we are aiming to deliver now in Phase III is a product that delivers double-digit weight loss and with a placebo-like tolerability. And what really impressed us with the Phase II data was that the tolerability profile was even better than what we saw in Phase I because we have -- we are using escalation every 4 weeks instead of every 2 weeks. So -- and that is really what is important here that is to deliver the most tolerable approach to deliver this double-digit weight loss.

And I would argue, just as a lot of the key opinion leaders at ADA argue that for any patient, it's a logical way to start your weight loss journey to start on an amylin in particular with [indiscernible] because it looks so benign. And if you're among the high responders, most patients will likely get to the weight loss target that they have. If you're in the middle range, some will get to the weight loss target they have. Others would have to add something.

And if you're in the lower range, you should change the different modality. So I'm not going to pursue the highest number. I'm going to pursue the product, which I think will be the natural starting point for any patient. And then as importantly, a product which patients can decide to stay on because it's really the biggest issue is that people stop taking the GLP-1s today. And so we don't get to persistency.

It's also the way we have less than 20% on treatment after a year, which is a huge dilemma because then we don't achieve the health that we are looking for. If I have a product that is tolerable, that doesn't impact the way people want to live their lives, I believe they will decide to stay on that therapy, and for a company also, of course, it's the opportunity to unlock the value in this market if we manage to get patients to stay on therapy rather than just using it for a few months.

Yes. Okay. Can we talk about the Phase III as well in terms of what -- I mean, expectations for the trial design? And I think you haven't necessarily publicly committed to higher doses for petrelintide in Phase III and looking at the tolerability profile that you talked to may justify that. So could you just help us understand your thinking there?

Yes. So we are, together with Roche, like fully focused on getting this Phase III studies. These studies started here in the second half. So it's full on. We are -- with both companies, really, really putting a lot of efforts into speed up and have a keen focus on getting to market as fast as possible. It's clear with -- as we move into Phase III, you should probably expect to see a different gender balance. So we have more females in the study, which should, of course, provide higher numbers and also a study of a longer duration will add to that.

When it comes to doses, we have not been, you can say, specific on the doses that we're going to forward take into Phase III, but we have presented the maximum effective dose, which was in the midrange. And I would say you should not expect us to utilize doses that are beyond what we tested in Phase II because our data suggests that we will not get additional benefits out of that.

On the other hand, what the data also suggests is even if we dose very high, we don't see a change in the side effect profile, which gives us a very high confidence as we move forward that we will not pick up some strange signals in Phase III. So it's with a high degree of confidence we move forward.

The profile of the drug is one which we believe will give double-digit weight loss and a placebo-like tolerability and really speak to that first-line therapy where any patient will start the journey.

Yes. Okay. And then you also have the combination with CT-388 and I think there is an AXL name for that one now. How should we think about that fitting in with petrelintide monotherapy?

That was actually -- you're right, we have -- when we partnered up with [indiscernible], we made sure that we had equal financials and also equal development and commercialization, say, on the -- both the monotherapy with petrelintide, but also the combination and we're going to push the combination into Phase II here this summer and which is a rather large study of more than 400 patients to really explore what are the right ratios between amylin and GLP-1/GIP, petrelintide and CT-388. It's -- and that those -- you can say the outcome of those -- of that study is, of course, going to inform how we're going to dose it in Phase III in a fixed dose single container system.

What I would highlight and another highlight for me at least at this ADA was also that it was presented Phase II data from CT-388, which as we have kind of also assessed in our diligence when we partnered up, suggest that it's a very, very good GLP-1/GIP.

So from a combination point of view, of course, it adds a lot of hope for us to be able to deliver something very special here.

On the point of sort of the combination, Lilly were obviously quite vocal in their kind of confidence in Eloralintide at ADA as well and talked to kind of having potentially the biggest development in their company with multiple combinations.

So how do you think about competitiveness of petrelintide firstly as a monotherapy relative to Eloralintide? And then obviously, the combination given that they've already started or they're ahead in development with the tirzepatide combination?

For the monotherapy, we feel extremely comfortable because of all the things we have discussed here, it's not about winning the numbers games. It's about delivering a product that can give patients the weight loss they're looking for in the most benign way and that we think that profile is what we see with petrelintide.

We're actually super happy to see that Lilly is also moving forward with a monotherapy because then there can be 2 companies who are going to build a new category. It's not a small task to build a new category. And we personally believe that amylin is going to become a larger category for weight management because of that first line and that opportunity to actually have people to stay on therapy.

When it comes to combination therapies, I actually also think we have the 2 strongest combinations who would not like to combine the most tolerable amylin product with the most potentially efficacious GLP-1/GIP product. So as we approach development of the combination product, we have to be very smart about what we do here as people probably are aware of that an obese individual who also have type 2 diabetes, that could be a natural place for an amylin GLP-1 because GLP-1 is very strong in HbA1c, amylin less so. Amylin is very strong on weight loss in diabetes patients, GLP-1 less so. So that's a natural opportunity that people are aware of.

The other thing when you think about combination therapies going forward, it's good practice for medical doctors to only combine things that work. And we already know for the GLP-1s that are 15% of patients who don't get any benefit. So you don't want them in your combination study. So we need to be very smart as we start to think about what is the right product profile and who are the patients who're going to develop the combination if it's a focus on highest weight loss. It also has to be patients who actually want to have a 30% weight loss that you enroll in your studies and not general people living with obesity because most are going for that 10% to 15%.

So this is where you will see a lot of change in the clinical trial conduct in the coming years and in the marketplace as we start to have choices, we're going to move beyond that. Let's dose to the maximum tolerated dose. That is something you normally would do in oncology, not in chronic diseases towards minimum effective doses and then combinations that can help people individualize their weight loss journeys.

Okay. And then on time lines, so the combination Phase III starting this summer, the monotherapy Phase III starting second half of the year. What is sort of time lines for readouts of those trials? And then ultimately, what is your base case for launch?

Yes. So we have not committed to that. And in the honor of the partnership, I will not be more, you can say, clear on time lines, except to say that we are, as companies, hyper focused on speed to market and then, of course, continue to invest to expand the label.

Okay. And how do you execute around that in terms of hyper focus on speed to market? Is there anything that you can do in the Phase III? Is it rapid recruitment? Or is it sort of...

It's, of course, making sure, number one, and it's, of course, focusing on recruitment, but still making sure you get the right patients and enroll from the right centers. And then it's focused on getting to market with enough to get to market and then expand the label from there. So -- and yes.

Okay. And you haven't given us a time line for launch, but when you launch in the market, what are your expectations for pricing within obesity?

It's too early to come because it's so dynamic as we all have witnessed in the past period. I'm not [indiscernible] as some have described it, I've seen companies trying price points where patients are ready to contribute to paying. So we have almost half of the people being on treatment today that pay themselves. So you kind of try to put your price where. And that's back to -- if you're out of pocket, it's back to what is the value that the patient feels that they get out. So that's value-based pricing, just as you would do in consumer goods.

When it comes to the traditional channels, it's again back to value, but that's, of course, more on what value do society see and so on. So we need to see the dynamics of the market. And then I just, again, have to say, as you launch a new category, it will be -- that will carry its own pricing dynamics compared to existing categories. That's what we always see in other disease areas as well. So I cannot comment and be more specific on pricing, but I think the key opportunity to unlock the value on where petrelintide will really host the potential to unlock the value is to get patients to stay on therapy because then you also capture more value from each patient.

Okay. And then the ZUPREME-2 data set should be expected second half of this year, right? What are your expectations for what we should see there? Or what is the profile that you're hoping to see?

The general notion from, I think, everyone who works on amylin is that amylin may provide the same degree of weight loss in patients in obese individuals who live with type 2 diabetes as in those who don't have type 2 diabetes.

With GLP-1s in general, you see 30% less weight loss in patients living with type 2 diabetes. So of course, I look forward to see if the profile of the weight loss is similar to what we observed in patients who did not have diabetes.

Okay. And of course, I guess, the tolerability will -- you expect still a placebo-like...

I would hope, yes.

Just maybe in the last few minutes, just thinking about some of the commercials on the obesity side of things. We've obviously seen a very strong launch from the first oral GLP-1. How do you think about relevance of the injectable opportunity in the context of that launch?

Yes. But it's clear to me at least that oral GLP-1s do not address the biggest short experience of having lost appetite. That is what we hear from patients is the biggest issue. And -- but [indiscernible] doing and I guess what we're seeing right now is it may be expanding the number of patients who decide to get on a weight loss medication.

With a focus on a novel category as we are doing with petrelintide, it's actually an opportunity for us because there will be more patients who have been exposed to a GLP-1 and have experienced those side effects that most actually decide it's not for them because we have more patients who have tried a GLP-1 and decided never again than we have patients on a GLP-1.

So if anything, it will just expand the number of patients who have been exposed to a GLP-1 and can come and claim to their health care providers, I tried it. I don't want to do another GLP-1. I want to try this novel modality when petrelintide hopefully launch into the marketplace.

Okay. And do you have a kind of internal estimate or expectation as to what the split may be between injectables and orals long term in obesity?

No. It's too early to say, and it's this fine compromise the dilemma around, yes, oral sounds simple, but we also know that compliance is very bad on orals in general versus an injectable every week. Once you've taken the first shot, actually, many people find it more convenient to be an injectable. So it's very, very difficult to predict where this market will go with all the things that are changes.

I have no question that will be in place also for the oral and for the injectables. And let's remember, we are so early into the treatment. We are 4 years into treatment of what I consider the biggest health care challenge of our time, and we're treating so few patients. So there will be plenty of room for growth for a lot of different opportunities.

Okay. And then maybe just to touch on capital allocation. You obviously have very healthy financials post the deal with Roche. And you did announce a buyback with earnings earlier this year. Could you just talk through the rationale for the buyback and the timing?

Absolutely. And we have a clear set of priorities when it comes to our capital allocation. Number 1 is petrelintide and maximizing the opportunity, investing as much as we can into petrelintide monotherapy, but also the combination product with CT-388 and secure the strongest launch possible.

Number 2 is to expand our research focus. We're actually going to spend 5x as much in research in the coming 5 years as we did in the prior 5 years, so USD 800 million. That is our second priority, including expanding our research footprint into Boston, Massachusetts. And then we had excess capital and decided to pay some back to investors in our share buyback program.

Okay. I guess the fact that you think you have extra capital, does that mean that the petrelintide development program is pretty much underpinned by the cash that you have?

We have a clear path to profitability. That was a firm point for me when we did this deal. I didn't want to be in a situation where I could not fund my half of the party.

Okay. And then maybe in the last second, anything in the broader pipeline that you would highlight beyond -- maybe even beyond obesity that may be underappreciated.

But we have 2 rare disease assets, one which we're going to resubmit to FDA later this year, could be on the market next year and then another one, which is currently enrolling in Phase III. So those 2 programs could, of course, add significant value as we mature. They're not going to be the key focus for the company.

The early pipeline, how we mature that one, including a Phase I asset in a broad autoimmune opportunity. These are some of the new value opportunities that we love to talk more about in the future as well.

Okay. Brilliant. We look forward to hearing that. I think we're just at time. So thanks very much, Adam.

Thank you.

Good day, and thank you for standing by. Welcome to the Zealand Pharma Results for Q1 2026 Conference Call. [Operator Instructions] Please be advised that this conference is being recorded.

I would now like to hand the conference over to your speaker today, Eric Rojas, Vice President and Head of Investor Relations. Please go ahead.

Thank you, operator, and thank you to everyone for joining us today to discuss Zealand Pharma's results for the first quarter of 2026. This is Eric Rojas, and I recently joined Zealand Pharma as Vice President and Head of Investor Relations. I'm pleased to be with the team today in Denmark to get the conference call started and look forward to working with all of you. The related company announcement for Q1 2026 is available on our website at zealandpharma.com.

As outlined on the slide, I would like to remind listeners that during today's call, we will be making forward-looking statements that are subject to risks and uncertainties. Turning to today's agenda. Joining me on this call is Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, Chief Financial Officer; and David Kendall, Chief Medical Officer. All speakers will be available for the Q&A session.

I will now hand the call over to Adam.

Thank you, Eric, and welcome, everyone. 2026 so far have been marked by a defining milestones for Zealand Pharma. At our Capital Markets Day in December, we announced our ambition to become a leader in obesity and metabolic health and made several commitments with the launch of our strategy, Metabolic Frontier 2030. I'm super pleased to say that we are on track and executing against our strategy.

And what a start to 2026, it has been. Beginning with petrelintide, we reported positive top line results from the Phase II ZUPREME-1 trial that reinforced our conviction in its potential as a first choice treatment option for chronic weight management. The data showed a clear alternative to GLP-1-based therapies for weight reduction and long-term maintenance, setting a new standard for what to expect from a weight management journey. Building on these compelling results, we have now also confirmed advancement into Phase III registrational trials, which are planned for initiation in the second half of this year. This is a major step forward for the program for Zealand Pharma and for our collaboration with Roche.

On survodutide, Boehringer Ingelheim reported positive Phase III results from the SYNCHRONIZE-1 trial, delivering competitive weight loss and meaningful metabolic improvements, supporting the potential of survodutide as a differentiated therapy for people living with overweight and obesity. In our early pipeline, Phase I data with our Kv1.3 Channel Blocker showed its potential as a very promising product candidate with potential to address multiple [ Audio Gap ] an agreement with the Danish Center for AI Innovation to access one of the world's leading AI supercomputers. These are investments in our ability to move faster and smarter as we build the next chapter for Zealand Pharma.

Finally, marked by our strong balance sheet, we are now initiating a share buyback program as we continue to fund our strategic priorities and long-term growth initiatives to build Zealand Pharma into a leader in obesity and metabolic health.

Our collaboration with Roche continues to deliver. Just last week, I visited our Genentech partners in San Francisco for a great and productive workshop. Both teams are now focused on the execution of the upcoming Phase III trials for petrelintide monotherapy and the Phase II trial for the petrelintide/enicepatide combination product.

Zealand and Roche will co-develop and co-commercialize petrelintide and petrelintide-based combination products. This means that we capture the long-term value by sharing profits with Roche on a 50-50 basis in the U.S. and Europe on both monotherapy and potential combination products. Zealand will receive $250 million at the first 2 anniversaries of the collaboration. These are not contingent on any specific milestones other than time, meaning that we will receive the first $125 million here in the second quarter of 2026.

In terms of the total development milestones of $1.2 billion, $575 million are linked to the initiation of the Phase IIIa trials with petrelintide monotherapy, which we expect to start in the second half of this year, as I mentioned before.

We are steadily on track to execute our strategy to establish leadership in obesity and metabolic health. Our Metabolic Frontier 2030 strategy has 2 main focus areas. The first is redefining the near-term future of weight management, guided by our 2 late-stage candidates in petrelintide and survodutide, both supported by world-class partners in Roche and Boehringer Ingelheim.

The second is focused on expanding our capabilities to build a leading pipeline beyond these near-term opportunities. We are leveraging our deep expertise in metabolic health, enhancing our capabilities through our new Cambridge Research Hub and complementing this with external innovation via partnerships such as those with OTR Therapeutics around small molecules and the Danish Center for AI Innovation.

These are strategic investments to advance our ability to discover and develop the next generation of leading metabolic medicines, all aimed at delivering sustained leadership in metabolic health and achieving the 3 goals outlined in our Metabolic Frontier 2030 strategy.

If you look at what we have accomplished in just the first few months of '26, it tells a clear story, a new research hub, AI partnerships, strong Phase II data for petrelintide, followed by a formal endorsement of Phase III advancement and the first Phase III results with survodutide. And in addition to these meaningful and defining milestones, we have a number of important catalysts still ahead of us in 2026 and remain firmly on track to deliver on all of them.

And with that, I will now turn over the call to our Chief Medical Officer, David Kendall, to discuss our R&D pipeline. David?

Thank you, Adam. As always, I will begin with an overview of our pipeline. With the potential for 5 product launches by 2030, Zealand Pharma stands at a remarkable inflection point. Today, I would like to focus my remarks on the continued advancement of our 2 leading programs in obesity, petrelintide and survodutide.

We were very pleased to report positive results from the ZUPREME-1 trial earlier this year, reaffirming the potential of petrelintide in chronic weight management and as a first choice therapy for millions of people living with overweight and obesity. As reported in the top line results from ZUPREME-1, petrelintide delivered double-digit weight reduction after 42 weeks of treatment with a pristine and exceptional safety and tolerability profile. In this study, rates of gastrointestinal adverse events were generally at or below those reported with placebo treatment.

Importantly, no participants treated in -- with petrelintide in dose Group 3, the maximally effective dose, discontinued the trial due to gastrointestinal adverse events and approximately 70% of participants reported no gastrointestinal adverse events during the course of the trial, further highlighting the exceptional tolerability profile of petrelintide.

Taken together, the data demonstrate the potential of petrelintide to address significant unmet needs in chronic weight management by providing a highly tolerable treatment option that supports long-term treatment adherence and achieves double-digit weight loss, obtaining weight reduction consistent with what the majority of those seeking weight management desire. We look forward to sharing additional data from the ZUPREME-1 trial at the upcoming American Diabetes Association Scientific Sessions in June, and we'll be advancing petrelintide into Phase III trials with that initiation planned for the second half of this year.

Switching gears to survodutide, a potential best-in-class glucagon GLP-1 receptor dual agonist with the potential to play an important role in the treatment of obesity and metabolic disease, in particular, metabolic dysfunction associated liver disease. We were very encouraged by the recent positive top line results reported by Boehringer Ingelheim from the 76-week Phase III SYNCHRONIZE-1 trial evaluating the safety and efficacy of survodutide in people with overweight or obesity without type 2 diabetes. SYNCHRONIZE-1 enrolled a population of 725 participants with 59% females with a mean baseline BMI of 38 kilograms per meter squared and a mean body weight of 109 kilograms.

The trial met both of the co-primary endpoints. Survodutide delivered a competitive weight reduction of up to 16.6% from baseline after 76 weeks of treatment while also demonstrating meaningful metabolic improvements. Survodutide also delivered a significant and clinically meaningful reduction in weight circumference, which is a clinical marker closely linked to reductions in visceral fat and cardiometabolic risk.

Additionally, initial analyses indicate that body weight reduction with survodutide was predominantly driven by loss of fat tissue with lean mass contributing only a small proportion of total weight loss. We are extremely excited with these findings, which taken together demonstrate the potential of survodutide to broadly improve metabolic health by providing meaningful benefits beyond weight reduction alone. We look very much forward to the American Diabetes Association Scientific Sessions in June, where Boehringer Ingelheim will present the full data from the SYNCHRONIZE-1 trial.

Beyond the SYNCHRONIZE-1 data to be presented at the American Diabetes Association Scientific Sessions, Boehringer Ingelheim will also present full results from the Phase III SYNCHRONIZE MASLD trial, which is investigating the efficacy and safety of survodutide in people with overweight or obesity and confirmed or presumed metabolic dysfunction-associated steatohepatitis, or MASH.

Additionally, the Phase III SYNCHRONIZE program with survodutide in obesity includes 4 other clinical trials. We expect additional readouts from the broader Phase III obesity program throughout 2026, including from the SYNCHRONIZE cardiovascular outcomes trial. Together, these data are expected to support the first regulatory submissions for survodutide for the treatment of overweight and obesity. If successful, Boehringer Ingelheim would be the third company to market in the U.S. and Europe in this new era of incretin-based therapies for chronic weight management.

We are also very excited by the ongoing execution of the Phase III LIVERAGE program evaluating survodutide in people with established MASH. This program includes 2 trials assessing safety and efficacy in patients with moderate to advanced fibrosis as well as in those with established cirrhosis. Given the high unmet medical need and limited treatment options for this population, supported by the groundbreaking Phase II data for survodutide in MASH, we believe survodutide have the potential to become a leading therapy for people living with overweight or obesity and coexisting MASH.

With that, thank you very much for your attention. I would now like to turn the call over to our Chief Financial Officer, Henriette Wennicke, who will review our financial results for the first 3 months of 2026. Henriette?

Thanks, David, and hello, everyone. Let's start with the income statement. Revenue in the first 3 months of 2026 was DKK 34 million, driven by the collaborations and license agreement with Roche. Net operating expenses totaled DKK 573 million. 82% of that was dedicated to research and development, mainly driven by the Phase II ZUPREME program with petrelintide, preparation for Phase III and also investment into the research portfolio.

The S&M expenses are driven by pre-commercial activities associated with mainly petrelintide, while G&A expenses of DKK 82 million reflect continued organization scaling, IT infrastructure and facility investments.

Net financial items in the first 3 months of 2026 of DKK 145 million are mainly driven by interest income from excess liquidity invested in marketable securities and cash equivalents and exchange rate adjustments.

We ended the first quarter of 2026 with a solid cash position of DKK 14.5 billion, which is expected to be further enhanced by DKK 4.5 billion milestone payments from Roche in 2026.

Our strong capital preparedness enabled us to execute on all our key strategic priorities, maximize the value of petrelintide, intensify our efforts in our early-stage research pipeline and leverage external innovation to enhance our R&D capabilities. We are well on track to execute and deliver on our Metabolic Frontier 2030 strategy, which we presented late last year at our Capital Markets Day.

At the same time, following the recent positive developments in our leading obesity programs, we are leveraging flexibility in our solid financial position and strengthened outlook to return capital back to our shareholders. As announced this morning, we have initiated a share buyback program of USD 200 million, corresponding to DKK 1.3 billion. I am extremely pleased that a company of our nature is able to distribute capital back to shareholders without scaling back what Zealand does best, research and development within metabolic health and with a continued appetite for organic and inorganic investments.

And now to the outlook for the year. The financial guidance for net operating expenses in 2026 is unchanged and is expected to be in the range of DKK 2.7 billion to DKK 3.3 billion, mainly driven by research and development activities.

In addition, we are providing collaboration revenue guidance of DKK 4.5 billion for the full year following the confirmation of Phase IIIa progression for petrelintide monotherapy. We will receive from Roche a USD 125 million anniversary payment in Q2 and a USD 575 million development milestone in the second half of 2026 when Phase IIIa is initiated. The collaboration revenue amounting to DKK 4.5 billion was booked into our accounts in early May.

And with that, I will turn the call back to Adam for concluding remarks.

Thank you, Henriette. Leveraging our momentum, we have a number of important catalysts potentially shaping long-term value creation still ahead of us in 2026. These include data from all the key trials in the SYNCHRONIZE program with survodutide and clinical advancement of petrelintide, including both the monotherapy and the combination with enicepatide.

I will now turn over the call to the operator, and we'll be happy to address your questions.

[Operator Instructions] We will take our first question -- the question comes from the line of Kirsty Ross-Stewart from BNP Paribas.

So maybe first one, just on the upcoming Phase III petrelintide trial. I think the FDA guidance requires 1 year of treatment on maximal dose in a Phase III trial. So given you're expecting to reach the maximal dose in 3 steps, are you planning on running a 60-week trial and being able to kind of narrow the gap versus Lilly who's got an additional titration step versus you? And are there any other trial acceleration efforts that you're looking at using to kind of bring up that launch time line?

And then maybe secondly, on the more broad obesity market. I mean, I think it's fair to say that the orals are exceeding initial market share expectations. I think it's nearly 15% of kind of U.S. script volumes already going to the orals. So just interested on your view on the importance of developing an oral asset and perhaps maybe Utpal can comment on kind of the priorities for the pipeline efforts, how far the list is developing in oral and what, if anything, is above that on the priority list?

Thank you, Kirsty. I'll just provide a few comments and maybe hand over to David for a few other comments. It's, of course, too early for us to comment on the specifics of the Phase III program. David may provide a few more insights, but what I can reassure you that we are doing a lot of things to accelerate the program together with our partner, Roche, as we are very aware of the importance of speed to market. When you are building a new category as we aim to do with petrelintide and so we have a lot of efforts on that one.

When it comes to the oral therapies, as we also announced at our Capital Markets Day, we are now collaborating with external parties on small molecules, and we have efforts to also explore the opportunities, broadly speaking, for all therapies when it comes to Amylin. As a company, we're actually more excited about that opportunity into the future. So it's, of course, something we are investing in. We are also excited to see how the oral GLP-1s are taking off now. And of course, we need a few more months to see how they -- if they are and how they're going to shape the market going forward.

But it's an important thing to remember that most patients after a certain time will be off treatment with the GLP-1-based therapy. So if anything, it will actually just, you can say, expand the number of patients who have been exposed to a GLP-1 and also live through some of the difficulties on a GLP-1 and thus expand the market opportunity for a novel category as we are developing with petrelintide.

David, do you want to put a little bit more flavor on the petrelintide Phase III program?

Happy to, Kirsty, and thank you for the comments. As to duration, you're right about the regulatory requirements for 1 year of exposure at the IIb marketed treatment dose. And obviously, there, it's a balance between achieving that as rapidly as possible. One thing that helps you expedite execution of Phase III is fewer dose escalation steps. On the other hand, you want adequate duration to ensure that you've reached the maximal weight lowering effects. And as we've seen more broadly in the weight management space, trials beyond 60 weeks out to 78 weeks are the common practice.

But to your second comment about triggers for speed, obviously, the sooner you can get to maintenance or the -- to be marketed treatment dose, the more rapidly you get last patient last visit. But that will be balanced not solely by the regulatory requirements, but also looking to achieve the final nadir in weight reduction that's possible. And again, those time intervals I quoted are the ones that are under consideration for our Phase III program.

To add to Adam's comment, Kirsty, on orals, obviously, one of these efforts is our announced partnership with OTR on which we're working with a number of potential oral assets. Given the uptake, certainly, we see the opportunity. It is also our mind, however, that having efficacy and tolerability that mimic as closely as possible to what is achieved with the peptide therapies, noting that if, for example, an oral amylin is achieved, we would expect a comparable efficacy and continued or even greater safety and tolerability profile. So work underway on all fronts for potential oral assets as well.

Your next question comes from the line of Rajan Sharma from Goldman Sachs.

I've got one on survodutide and one on petrelintide. Maybe just starting with petrelintide. So you haven't previously committed to higher doses in the Phase III despite the good tolerability that we've seen. So could you just provide your latest thoughts around this now that you've had time to reflect on that ZUPREME-1 data set? Is it reasonable to assume that you will go to higher doses in Phase III? And if not, why not?

And then secondly, on survodutide, what are you looking for in the SYNCHRONIZE-MASLD data presentation at ADA, which might give you incremental confidence in survodutide's profile, both in MASH and obesity? And what do you think will be an acceptable discontinuation rate?

Thank you, Rajan. Maybe just to start with survodutide. I think we, of course, look very much forward to see the presentation of the full data on the specifics on losing fat versus muscle that was highlighted in a qualitative statement in the Boehringer Ingelheim release. I think you cannot underestimate the value, not only from the prescriber perspective and the health, you can say, that you can generate by mostly losing liver and visceral fat and then preserving muscles. But I think it's also something that will speak directly to the patients if you have a product that can actually target the weight loss to the abdominal visceral and liver fat and protect the muscles to some degree. So that is, of course, a very important data set also hopefully supported by the readout from the MASLD study. So it is a very important part of the presentation at ADA, I would view also from a patient perspective.

But David, over to you.

And one additional comment, Rajan, on the survodutide data. I think this is very simply a clinical assessment without biopsy to determine the suspected presence of liver disease, something that will obviously be quite common in clinic as a former practitioner, seeing a significant number of patients with diabetes coexisting overweight and obesity and abnormal liver function studies. This will be the first glimpse, if you will, into the potential without pursuing liver biopsy, which is required in the LIVERAGE program and is the endpoint for indication seeking in that LIVERAGE program, but I think will be a great bellwether of the potential of the LIVERAGE program to deliver and provide clinicians the confidence that should they see patients who meet those clinical criteria, survodutide can and likely will be a preferred alternative.

To the petrelintide question and higher dose, I think as you well know, Phase II clinical trials are dose-ranging trials where we were able to see significant reductions in body weight at each of the top 3 doses in exposure, dose Group 3, 4 and 5. It is unusual that one reaches a therapeutic efficacy plateau without limitations from tolerability.

So in contrast to many of the incretin-based therapies where dose-limiting may occur due to either tolerability issues or in the case of GLP-1-based therapies, increase in heart rate, we were able to achieve max efficacy at dose Group 3 as was shown in the top line results. But the other 2 higher doses showed no greater abnormalities in either tolerability or new safety signals, which gives us great confidence in the safety margin with what was the maximally effective dose falling at that midrange or dose Group 3. So you could anticipate that if that is the maximally effective dose, that's the dose that will be taken into Phase III.

We now also have nearly 150 or more individuals who are exposed to even higher doses with comparable safety and tolerability gives us great confidence in the safety margins of what is likely to be the maximally effective dose. So expect that and details, obviously, on the full data set will be available during the presentations at the American Diabetes Associations Scientific sessions.

We will take our next question, and the question comes from the line of Andy Hsieh from William Blair.

This is Kelsey Lucerne on for Andy Hsieh. So we've seen companies in the field conducting studies to better position for the maintenance market done through independent Phase III trials like the ATTAIN-MAINTAIN or MARITIME-Switch study or incorporating maintenance regimens into an open-label extension portion. So as you prepare to launch the Phase III program for petrelintide, what's your strategy to generate maintenance data to maximize the asset value?

Thank you for your questions. And I agree that it's, of course, extremely important, particularly when you're developing a category like petrelintide and amylin that you're focusing on maintenance because this is the big dilemma in the current market that most patients fail to stay on the GLP-1s and thus never will get to explore the health benefits of the weight loss and the benefits of getting to these therapies. So we have a keen focus, of course, with petrelintide an opportunity now to develop a medicine that can be used not only as a weight loss agent, but actually a chronic therapy as they should be used in this category.

It's too early for us to comment on the specific trial elements of our studies in more details. But rest assured, once they get up and running, you will all get the insights into the program. It's a very ambitious program, and it's, again, if the intent we have with this molecule is to, as David and I also shared in our prepared remarks, is to develop petrelintide as a first choice medicine.

If you consider a patient who think about going on a weight loss journey and an interaction with a health care prescriber, if you look into other chronic therapy areas, most patients will always be exposed to the most tolerable approach that has a good chance of getting the patient to go. And that is our ambition with petrelintide to make it a first choice therapy that can help most patients getting to the goal they're looking for. And then, of course, as important, we need to make sure that patients also stay on therapy so they don't lose the benefits of that weight loss. So we will focus on both parameters in our program and look forward to provide further updates as we get these trials up running.

Your next question comes from the line of Benjamin Jackson from Jefferies.

Just a couple for me. The first on ZUPREME-2 in the second half of this year, is there anything you're watching for there that perhaps could surprise you and change the way that you think about the development program at all? Obviously, historically, GLP-1s have shown 35% or so less weight loss in the overlapping cohort of type 2 diabetics and obese. Do you expect to see the same thing here with amylin? Or is there a chance that it's a little bit different?

Then secondly, on ZUPREME-1, is there anything in the trial design now that you've had time to reflect on it that perhaps would suggest that something within the trial design itself limited that efficacy and caused that plateau at the top doses rather than the actual kinetics of the molecule itself?

And then if I can squeeze in a third, I think I know the answer, but I'll try it anyway. Do you have any sense whether your partner, Boehringer, intends to provide more indications around their commercial strategy for survo at ADA or when we could perhaps get a little bit more clarity on that? Obviously, less of incentive to talk to the market about that. But any thoughts around those 3 would be super useful.

Thanks for the question. And just to address your last question first, we cannot comment further on Boehringer's plans, but we, of course, notice significant excitement in the releases and the statements around both the opportunity to treat the patients with overweight and obesity and patients living with MASLD. But it is up for Boehringer to comment more specifically on the plans and when they expect to be on the market. But we are at least extremely excited and look forward to the symposium at ADA that Boehringer will host and share more data from the program. So more on that. I'm sorry, we cannot provide more clarity to that at this moment. David?

Yes. Happy, Benjamin, to comment on ZUPREME-2. A couple of specifics to your question. Certainly, the effect on body weight is the primary endpoint for ZUPREME-2 in these individuals with overweight and obesity with coexisting type 2 diabetes. While we expect an effect on hemoglobin A1c reductions in glucose, it is well known that amylin agonists are generally less potent in terms of overall glucose lowering, but do have a significant glucose lowering effect.

Petrelintide, in fact, the only approved amylin was approved only as an adjunct to insulin therapy for glucose lowering. But the unique mechanism of action of amylin being a non-insulin stimulatory signal, only exerting much of its effect on blood sugar through postprandial glucose control in part by effects on gastric emptying with short-acting agents and a clear effect on suppressing glucagon, we would -- we will look closely on whether there is greater preservation of the weight-reducing effect in the type 2 diabetes population that is close to or comparable to that seen in the non-diabetes population.

To your point, GLP-1s with their potent insulin stimulatory signal, insulin as a storage hormone, abrogates some, in fact, a significant portion of the weight lowering effect of GLP-1-based therapies in those with type 2 diabetes. So a preservation of that effect or at least a smaller loss of any of the effectiveness in the type 2 diabetes population.

Why is that important? Clinically, if an individual with well-controlled diabetes is truly on a weight-reducing journey or a weight loss journey, then having a therapy that can achieve comparable effects, whether there is or is not abnormalities in glucose tolerance will be an important insight. Obviously, because of the regulatory requirements to include diabetes patients in your Phase III programs, understanding that a similar dose response and dose effect can be observed is similarly important. So preservation of that weight effect would be the primary one we will be looking closely at and obviously, it would be confirmed then in the Phase III trials.

In terms of ZUPREME-1, as we've alluded to in previous discussions following the release of those top line data, there are a number of trial constructs, which will be put in place, which in great part, are done to achieve a study population that most closely reflects the future potential clinical population, which is a preponderance of females, up to 75% females and females seek weight-reducing therapies much more commonly. The other things that are learned in this and any trial is site selection and persistence on therapy, meaning the true treatment est demand in terms of overall result, and that will be working on not just recruitment, but recruitment, retention and then persistence on therapy. So those will be some of the key things we focus on in Phase III that are learnings from ZUPREME-1.

The other thing that many have noticed is Phase II trials where doses are escalated more rapidly tend to give you a deeper initial weight loss curve but sacrifice tolerability significantly regardless of the therapy. So we are not in a position where we're going to push the speed of dose escalation because the very clean tolerability profile is something we wish to preserve, still expecting a clear double-digit weight loss with the appropriate population studied.

We will take our next question, and the question comes from the line of Alexandria Hammond from Wolfe Research.

I guess as you think about the Phase II readout for petrelintide and CT-388 combo, is there a specific efficacy threshold that, that combo needs to clear to justify moving into the Phase III? And how does tolerability kind of factor into that bar? Is there a scenario where a modest efficacy gain over a monotherapy is sufficient for that if it can kind of preserve petrelintide's placebo-like tolerability profile?

Thank you for your question. And thank you for bringing up also the combination where we will start the Phase II study in this quarter. And we are highly excited about the opportunity to not only develop petrelintide as a monotherapy as a first choice therapy for the many who are looking for that double-digit weight loss and a very benign safety profile with the combination product, I think we are -- we actually believe we have a number of opportunities to look into other segments of patients. Of course, there are still the patients who need the highest weight loss, those who would historically be candidate for biotic surgery, for instance, there's also people living in obesity and type 2 diabetes at the same time, as David just alluded to, a combination of GLP-1 and amylin could actually be a very interesting opportunity for such patients.

So I would say the Phase II design that we -- and the study that we are initiating now has been designed so we can actually get several answers for what is the right profile of the drug and targeting those specific needs. I would say we don't have specific thresholds. We will, as we did with petrelintide, look for the profile of the drug and match that towards specific patient needs in that broader portfolio of opportunities that we are developing towards the patients who live with obesity and comorbidities at the same time.

Your next question comes from the line of Nusrath Hussain from UBS.

On behalf of Xian from UBS. I have 2 questions, if I may. First, with Phase III-MASLD data for survodutide coming at ADA and the ongoing Phase III-MASH trials across F2, F3 and F4, could you outline the major differences between patients that you enroll for MASLD and MASH trials? How much read across do you expect from MASLD to MASH? And are there any biomarkers, subgroup analysis or secondary endpoints for MASLD that could be informative for fibrosis improvement, especially in F4 MASH?

And then secondly, you've announced a $200 million share buyback at a time where we would expect R&D and SG&A to increase as petre and other earlier-stage programs progress. So could you comment on your current view of the survodutide royalty stream? Have we now seen the full obesity tolerability data set? And if so, does the recent survo data change your expectations for that royalty stream?

And then lastly, did confidence in future survo-driven cash flows play a role in the decision to initiate the buyback at this point?

Thank you for your question. And maybe I'll just address the survo program. Remember, it's Boehringer Ingelheim, who are running the program, and we are entitled to high single to low double-digit royalties and outstanding milestones of around EUR 350 million. And we cannot comment on the specifics for neither the data that Boehringer is going to present at ADA here in June, but we know that they do expect to present data from the obesity MASLD data.

We also know, and I think that's been clear for a very long time that they are extremely committed into the MASLD program with LIVERAGE-1 and 2, where they are enrolling close to 3,500 patients, both F2 and F4. So it's 2 programs, one in obesity and one in MASLD that they are highly committed to.

And as I also alluded to in my prepared remarks, with this coming out of this quarter where we have had Phase II data for petrelintide and the decision to move into Phase III, which provides clarity on the near-term milestones from that program. But as important, the Phase III readout from survodutide has created a lot of clarity on our future revenue streams and derisked, you can say, our operations and adding to a very strong financial position.

Henriette, maybe you want to comment a little bit more on that situation?

Yes. Thank you, Adam, and thank you for the question. You're absolutely right. We launched the share buyback program. And as Adam alluded to, we've just had 2 major derisking events for our leading obesity programs. This, of course, give us increased flexibility in our outlook, but also confidence in our outlook for the years to come. And that has allowed us to launch the programs. We are not compromising on the development programs. We have all the research investments.

So we have, in the past, commented that we will increase our research efforts fivefold in the next coming 5 years compared to the last 5 years. And that will continue. And that will both be with organic and inorganic investments across the board. So the deal we did before Christmas with OTR, you will likely see more deals coming up in the period to come. So I think you should see this in -- as our confidence has increased over the last period and our financial flexibility have also increased.

Your next question comes from the line of Suzanne van Voorthuizen from Van Lanschot Kempen.

This is [ Romy ] on for Suzanne. I have 2 questions. The first, knowing now the progress of petrelintide to start Phase III in the second half of the year. I was just wondering where ultimately you see petrelintide fitting into the general obesity market and more specifically within the amylin class based on the data we have to date?

And secondly, I think you already mentioned this in the previous answer, but can you confirm your weight loss expectations for petre for the Phase III study? Yes, that's my question.

Thank you for your question. And I think when we at least look at the future obesity market and when we -- based on our market research, we do with patients and other stakeholders in the market, it's important to consider that obesity is a chronic disease. And for an individual patient, it's very often a journey when you start a weight loss program towards an objective of losing some weight.

If you look into other chronic diseases where there are multiple choices of medicines in diabetes, in hypertension, in lipid-lowering space, most often patients will be started on the most tolerable approach. And then after a few months, they will have an interaction with the healthcare provider to discuss if they are on the right trajectory to achieve the goals that they have, have their goals changed or are they not moving with the speed that they are considering. And if they are not, then you can start to have a conversation should we add or change something. But that is -- and then you would often go to the more cumbersome, perhaps even slightly more effective tools, but you don't start patients with the most cumbersome tool just because it can provide a slightly more average weight loss.

So this is why we are -- you can say the way we view this is that -- and why we keep saying this first choice, this is the logical first choice, the profile of petrelintide is what we have called the sweet spot that you can deliver double-digit weight loss with a tolerability profile, which in Phase II with the maximum effective dose was similar to placebo when we look into GI effects.

The other thing which we think is you need to appreciate also as we get into a market with a new category, it's not just about effect and tolerability, it's also the experience that you have being on a drug. And as David has mentioned many times, amylin works in a very distinct way from the GLP-1s by making people feel full faster. It doesn't affect your appetite to the extent that the GLP-1 will do. It helps you feel full faster once you start eating. And we think it will add to the overall better experience of being on an amylin and thus, again, serve that need as a first choice.

And I would -- to further build on this, if you are a patient who have spent, let's say, 30 years becoming morbidly obese or having a very high BMI, you don't need to solve that in 2 or 3 months. This is a journey that should be solved over a longer period. So -- but still, it's a natural place to start with a product profile like petrelintide.

If you then need more, that's where you turn to a combination product as we are doing with CT-388 and petrelintide. And that's the logical approach to treating patients in a more mature market. And that's why we continue to say that we are super excited with the profile that we saw because we actually observed petrelintide to be even better tolerated than what we have seen in the Phase I studies in a large cohort of patients, also having exposed patients to higher doses, which will not be carried forward into Phase III, but with a lot of safety around it.

So when we move into Phase III, we do expect to see, as David also alluded to earlier, higher weight loss numbers as we expect to enroll more female patients, run the study for longer and address a few of the other trial-specific elements of the Phase II study. So we are very confident that we get a profile of a drug that address exactly what patients are looking for. And when you do market research, you will also hear that 1 out of 5 patients are looking for a weight loss of less than 10% and 4 out of 5 patients are looking for a weight loss of less than 20%.

The average weight loss that patients experience on tirzepatide today in the real world is around 12%. It's not the 22% or even higher numbers that people like to talk about. So we believe we have a product that speaks directly to what patient wants and the tolerability profile is of such a magnitude that it would be considered a first choice medicine if and when it gets to the market.

Your next question comes from the line of Charlie Haywood from Bank of America.

It's Charlie Haywood, Bank of America. First one is just on the petre weight loss curves that we're expecting to see at the upcoming conference. Any comments on the shape of that curve? And if once we've seen the data, there will be any debate on how we should think about sort of potential plateau after the 42-week period?

And then on the prior comment to dose ranging, obviously, the higher 3 doses showing very similar weight loss. Is there any meaningful difference in the weight loss curves between those 3 and the time it took to reach that 10% to 11% weight loss?

And the final question, just sort of higher level on obesity and potential petre pricing as a monotherapy. I think the market has obviously seen aggressive price cuts and is panning out to much more of a consumer-driven market. So given potentially price, i.e., $150 instead of oral could have been the driver of a material acceleration in volumes. How are you thinking of pricing evolution going forward from here? And do you still see petre potential premium pricing as an option in a consumer-driven market?

Thank you. And it's, of course, too early for us to comment on the specifics around pricing, except that, of course, ultimately, it will be value-based pricing. And I just, again, want to highlight this thing that from a society point of view and from a health perspective, you actually don't get a lot of value if patients don't stay on therapy because, yes, you may experience a weight loss, but if you're regaining that weight loss and also with less muscle, you may even be worse off.

So in order to get value out of these medicines, you need to make sure that patients can stay on therapy. And that's why we think it's incredibly important, the profile of petrelintide so far suggests that it's active product that people will be able to stay on to a larger extent than those where there are more side effects. So that is one important part when you look at this from a health perspective.

We also have to realize, as you brought up, that a lot of these prescriptions are patients paying themselves. And again, just broadly speaking about value-based pricing, what is the value of having a better weight loss experience? That is something we need to understand better, but we thoroughly believe that petrelintide can deliver a better weight loss experience than when you lose weight on a GLP-1.

So these are things that we'll continue to explore and discuss with our partners. But it gives us confidence, in particular, in this opportunity to actually address the maintenance setting and thus making sure that patients stay on therapy for longer. That is, of course, an important part to the overall value of the franchise. And it also speaks to the other comment about the volumes. If you manage to get patients to stay on therapy, of course, volumes will go up.

On the specific weight loss curves and plateau and the different doses, we -- that's to be discussed at the ADA meeting, of course, and we'll present more data and a more full data set at ADA. I just again have to remind people, as we also have -- David had highlighted that there were a number -- the balance between men and females in this study was quite dramatic, and there was actually a 6% difference in weight loss between the males and the females larger than what we had anticipated, but not uncommon to see differences between males and females. These are things that will be addressed in Phase III, and you will probably understand some of these features better at ADA.

[Operator Instructions] We will take our next question, and the question comes from the line of Mohit Bansal from Wells Fargo Securities.

This is [ Susan ] on for Mohit. As payers increasingly focus on real-world adherence and durability, what evidence do you think you need to demonstrate that better tolerability translates into improved persistence independent of pricing and out-of-pocket cost sensitivity?

And then a separate question on switching. What do we currently understand about switching patients between GLP-1s and amylin? Do you think that we need additional stuff to understand if additional titration or dose escalation is needed between switching between the different mechanisms of action?

Thank you for that question. And of course, as we launch petrelintide in the future, it will be incredibly important to collect real-world evidence for stay time for these medicines and use them as arguments for why you can actually provide additional value to society and demonstrating that patients actually stay on therapy for longer. So that will be, of course, an important argument in this.

And as David has also shown also in the prepared remarks today, I think when we talk about the escalation phase, it was 98% of patients in this study who managed to get to the top dose. So it's not -- we actually don't consider that you need to titrate the amylin as you do with the GLP-1. It's more about escalating. And if you look at the early data we released, even the lower doses, patients can expect quite significant weight loss. So it's a major difference here between the GLP-1s and the amylin at least with petrelintide that it feels that we believe that patients will be able to follow the escalation steps without having to individualize the titration for every patient, which will simplify the prescription in the real world compared to what we see with the GLP-1s today.

David, do you want to add further?

Yes. And I think Adam speaks to a very good point, Susan, and that's that the dose escalation and not titration to ensure that patients get to the most effective dose and stay on the most effective dose. We know with all of these centrally acting agents that, that dose escalation is an important part of the overall experience. Given that at dose Group 3, you would have a limited number of dose escalation steps, that means you get to the maximally effective dose not only in a high proportion of individuals, but at an earlier point in time.

As regards to your comment on switching, little is known. There were studies done many now decades ago with petrelintide and exenatide where switching did occur because these are 2 unique receptor families, receptor systems and GLP-1 and amylin-based therapies act through these different systems, it would be anticipated that if one switches from one to the other, it would be clinically appropriate to have a dose escalation scheme that pays homage to the newest therapy being introduced.

But obviously, that persistent studies, the things you alluded to in the real world will all be part of our consideration for a robust Phase IIIb program and beyond to better understand how can we make the experience for patients, those living with obesity, their providers, the pharmacists, all who are involved in this value chain to make this the best experience possible. And again, simplicity with tolerability is only part of that story.

Thank you. This concludes today's question-and-answer session. I'll now hand the call back to CEO, Adam Steensberg, for closing remarks.

Thank you all for attending and for your questions. We look forward to future announcements and updates and to connecting in the coming weeks and months.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Hey, good afternoon, everyone. I'm Yihan Li, Barclays European Biopharma Equity Research Analyst. Today, it is my pleasure to host Zealand Pharma, fireside chat with Adam Steensberg, the CEO of Zealand. So thank you for joining us today, and we are delighted to have you here to walk us through your story. So actually, to start with, I will hand it over to you, Adam, to have a brief introduction of Zealand and do some presentations.

Absolutely. A pleasure to be here. So Zealand Pharma, we are here to address what we believe is the biggest health care challenge of our time, and that's the obesity pandemic and all the diseases that follows the obesity pandemic, you can actually ascribe more than 220 diseases to the increase in obesity that we see these years, and we need to do something about this as a society.

So transforming the future of metabolic health, that is what Zealand is about. I will be making forward-looking statements today, as you probably expect. So if you think about our key priorities, then it's to redefine the near-term future of weight management, really focused on our 2 leading assets, petrelintide, which we have in partnership with Roche and then survodutide, which has been partnered out to Boehringer Ingelheim.

So these are the 2 leading programs where we, of course, spend a lot of efforts and also there will be tremendous focus on this year. But equally important for us is also to build the pipeline that follows these 2 promising opportunities for weight management. And here it's about leveraging our more than 25 years of history in peptide drug discovery and development, but also working in the metabolic space to really create a pipeline of more than 10 clinical candidates over the next 4 years.

And focusing also on tapping into some of the very big changes that we are seeing in the -- how we do research today and thereby committing to also getting to industry-leading cycle times from idea to clinic, partly by opening a new research site in Boston, which we expect to open this year, but also in engaging in more partnerships as just also announced, for instance, in December last year where we partnered up with OTR and small molecules for metabolic diseases.

All this and this journey is backed by a very strong financial and solid financial cash position. So we have around USD 2.3 billion in the bank. We expect $700 million more to come in this year. And that means that we have a foundation to actually pursue this ambition of transforming the future of metabolic health.

If we just take a step back and try to think about what it is we are trying to address when we think about the obesity pandemic and all the diseases that follows, then we are, I would argue, perhaps 4 years into having seen the launch of the first medicines that can actually help people lose the weight that they're looking for. So it's really, really early in the care of patients. And today, we are only targeting 3% to 5% -- or we only have actually 3% to 5% of the eligible population on treatment. So I think -- and I hope everybody agrees that we are in such early days to actually address this problem that we see.

It's also remarkable to think about that while we -- for other chronic diseases where I would argue most of them are less complex than obesity, we actually have up to 8 different tools, different modalities we can help address those situations. In obesity, we basically have one tool in the toolbox that's called GLP-1 based therapies.

And the other thing I really would like to underscore in this world where there's still a hyper focus on who gets the highest weight loss number. It's actually not what patient tells you if you ask them. Most patients are looking for a weight loss below 20%. So we might be excited when we see that a drug can give you 25% or 30% weight loss, but patients are looking for a weight loss in -- the majority of patients, at least below 20%.

And that also, I believe, is reflected to some degree with how the current GLP-1s are being used on the market today. So while we are used to high numbers in clinical studies from the GLP-1s, real-world evidence suggests that Wegovy provides around 8% average weight loss and tirzepatide around 12% average weight loss in how they are being utilized in the real world.

So there's been a hyper focus on the highest number, but that is not how these medicines are being used. And more importantly, if we are to address the consequence of the obesity pandemic, we need to go away from only having patients using these treatments on average for 4 months with less -- around 20% still being on treatment for a year. We need to make this a chronic therapy area where patients stay on therapy.

And today, we know that half of the patients that drops off a GLP-1 today is because of GI side effects. So we need to develop tools that can help people stay on therapy and not only when they await those Olympics because then you don't get to the true health benefits. And as importantly, for us as an industry, you actually don't unlock the value in the market if you don't get to chronic therapy because volume is what will drive the value in the future and not prices.

So with petrelintide, we are extremely excited about the profile of petrelintide, and we really believe it has the potential to redefine the weight management experience. And really with the data that we released last week in our Phase II study for us underscores this potential that petrelintide can serve as a foundational first choice treatment option, setting really a new standard for what patients can expect when they embark on a weight loss journey.

We demonstrated in a Phase II trial design, which was not optimized for maximum efficacy, double-digit weight loss and then a placebo-like tolerability profile when it comes to gastrointestinal AEs with not a single patient vomiting. And we just, again, would like to underscore the best medicines are actually the medicines that patient takes.

And I would also challenge people to think about if you have a product that can get you to the weight loss that you would like and you can achieve that without going through the hassle with a lot of GI side effects, a lot of difficult titration regime, stepping up and stepping down. If you can achieve that without all these things, would you choose that? Or would you choose a product that is more effective, but have all these hassles, and know what I would choose.

So we are extremely pleased with the data. And we think, as I said before, that petrelintide has this potential to really redefine the weight management experience. Also with the data, they will further now highlighting this opportunity for the combination product that we are also pursuing together with Roche on the combination with petrelintide and CT-388, where we now have a very tolerable base in petrelintide, where we can add some CT-388 to for those patients who need more weight loss or potentially those patients who need the highest weight loss.

So the profile of this combination product have given us even more excitement also around what we can achieve there. And the partnership we have with Roche is a true partnership where we have profit sharing, but also co-development and co-commercialization rights and Zealand will use those rights to establish our commercial infrastructure in the U.S. and thus also a launch pad for future medicines as we think about our future pipeline.

Now shifting gears to the partnership we have with Roche with Boehringer Ingelheim, which is on survodutide. This is a product that we licensed to Boehringer some years back, and they are responsible for all development and commercial efforts. We just have high single to low double-digit royalties on sales. What Boehringer said at Obesity Week last year was, See Obesity, Think Liver. And I think they were referring to the fact that a vast majority of obesity individuals also have fatty liver disease and up to 35% of obese individuals, they actually have MASH, so signs of diseased liver.

And the opportunity with survodutide is to not only leverage the biology of the GLP-1, but also tap into glucagon. And glucagon -- the prime pharmacology of glucagon is to actually get nutritions out of the liver and thus fat out of the liver.

So we think we are looking here at a highly differentiated product that can come out and not only speak to the GLP-1 benefits of reducing your appetite, but also speaking directly into liver health and potentially increased energy expenditure and with positive effects on other organs beyond the liver because if you reinstall the liver as the metabolic master switch, in theory, that should have very positive effects on other diseases such as heart disease and kidney disease.

So Boehringer will report the full Phase III program in obesity this year on survodutide, and we would hope to see them on the market already next year, which would mean that Boehringer would be the first large pharma company who will get into this space, treating obesity.

So that leads me to my concluding slide and just highlighting that we are entering the most catalyst-rich year in Zealand's history. We have further data from the ZUPREME program in patients with type 2 diabetes. We plan -- we expect to start the Phase III study with the monotherapy and also start a Phase II study with the combination therapy for petrelintide this year and then the full program on survodutide, then we will expand our research activities by establishing our Boston research hub and also expect news coming from some of our earlier pipeline programs this year.

That's awesome, like very clear and very helpful. I guess we will start from your amylin asset petrelintide. Just wanted to dig a little bit deeper in terms of your ZUPREME-1 data. So I think a key debate is it is like the dose response dynamic in this trial.

Do you think like the third dose cohort somewhat showed the best efficacy. And if we really look at the titration schedule, actually this third dosing cohort reaching the highest dose at week 12 versus dose 4 and dose 5 actually reaching at week 16. So just curious like to which extent do you think this difference in titration timing or exposure actually could have influenced the efficacy outcome across cohorts? And what gives you the confidence just based on the totality of the data, actually the third dose is the optimal dose that you will be able to move forward to Phase III?

We are quite confident that we have shown, you can say, under this study condition, the maximum potential of petrelintide and that is the mid-dose and that we don't get additional weight loss by pushing the doses higher. Remember, in this study, we used a dose escalation every 4 weeks, which was in contrast to what we did in the 16-week study where we dose escalated every 2 weeks.

What that led to was a quite significant improvement in tolerability, and we were already excited about the tolerability profile after the 16 weeks data. And now we have an even more tolerable approach, and we still managed to achieve double-digit weight loss in an unoptimized study condition.

So we really consider this the sweet spot. I also, again, would like you to refer you back to what I said before on what is the weight loss that people experience on tirzepatide in a real-world setting today, that's 12%. And still you have 50% of patients who stop taking these medicines due to GI side effects. We achieved double-digit weight loss here with not a single patient vomiting. And for me, that is a sweet spot to be in.

Yes, that's very helpful. And another question, I guess, people were asking is really the patient heterogeneity. So we see much more weight loss of female versus male, and also there's some inconsistency between U.S. versus European countries. So I guess like based on this data or like experiences, how would you design your Phase III population outside mix going forward?

Yes. I mean we have known for a long time that there are differences in how much weight men versus females lose in these studies and basically on drug. And again, there are differences between men and women. So that is expected for certain reasons. But we had a higher difference than anticipated with up to 6% more weight loss in women on a placebo-adjusted basis. And we also saw this phenomenon that there was actually 3% more weight loss in the European patients compared to the U.S. patients.

A lot of that difference was actually driven by some centers, which preferred -- which performed, you can say, significant below expectations, especially in the male population. So there are some, you can say, operational aspects we have to look into making sure that we don't include similar sites in our Phase III trial, which contributed to that, you can say, finding. And I think it's something we will, of course, make sure to avoid in our Phase III study.

So that alone, looking into those underperforming sites would get us into where we had perhaps expected to be with 1% more weight loss. And then, of course, as we think about the Phase III trial, we would also anticipate having around 70% females where we have, as you mentioned, significantly more weight loss. So all that gives us the confidence that in a future Phase III trial, which is, of course, optimized to show the maximum potential of the drug under the conditions is being administered, we will get into the weight loss, which we consider the sweet spot for future weight management.

And coming back to what I said in the start, I don't think the battlefield in the future is going to be who gets to the highest number. The battlefield is going to be how can you provide the weight loss that patients are looking for in the most pleasant way.

Yes. Yes, actually, to your point, like the pleasant way, so like the treatment persistence. So notably, your data for efficacy estimates versus treatment estimates, it seems like the delta is relatively small compared to incretins or like your peers. So do you think actually it can be a potential differentiator for petrelintide versus incretins agents.

100% because this is -- the thing is that in real world, in particular, but also in clinical studies, people have difficulties following the titration schemes for the GLP-1s. And there's we're getting used to these huge differences between efficacy estimate and treatment estimates, which I think reflects how difficult it is to actually get on these drugs and get up.

With our study, there was a very, very small difference between these two numbers. And as importantly, when we look behind the data and see if patients were able to escalate according to plan, it's basically all patients who can follow the plan. And that's again, back to simplicity. If you ask a key opinion leader, they would argue they can get any patient to the top dose on the GLP-1, but it's not easy.

And people want to live easy lives, so that's why I keep coming back to in the future, the battlefield is not going to be about who gets the highest number, it's about who can offer a treatment that delivers the weight loss that the individual patient is looking for in the most benign way. And that's where we think the data set we released with petrelintide sets a completely new standard for how you can get into double-digit weight loss with a very benign tolerability profile.

Cool. Just curious for the full data, can you disclose like which conference we are looking for or actually it's still under progress?

Yes, it's still under progress. We are still progressing on that one, but I can reassure you that we are eager to get the data out and discuss them more broadly. So we are pushing on all fronts there.

Awesome. I think another part of petrelintide is really your collaboration with Roche. So just like based on your data so far, just curious, the latest thoughts or like communication between you and Roche, are you on the same page that you will initiate the Phase IIIa trial -- monotherapy trial in the second half of this year?

You can say we have since the start of this year, communicated that we expect to start the study in the second half. And based on the communication that I've had with my collaborators at Roche and at multiple levels of the organization, that remains to be the expectations. Of course, formal decision-making only will be taken once you have had end of Phase II meeting, once you have had the full data sets evaluated and so on.

But I would say when we look at the data, as I also said in the initial prepared remarks, the tolerability profile is even stronger than what we have seen in the 16-week study. We got into double-digit weight loss, and I would say it provides an even more clear positioning as an alternative to what the weight loss experience is in the GLP-1. So we just see an even stronger foundation for this medicine and also as a first choice.

And stepping into combo potential. So what would success look like for this combination therapy relative to your monotherapy? Like any expectation?

Yes, but that's -- it's a very good question. And we are going to very soon start in this first half start of Phase II study to really explore the optimal combination of petrelintide and CT-388. By the way, we think CT-388 looks to be a great GLP-1, GLP. So we are pleased to have that as a combination partner in our collaboration.

And Again, for us, it's -- ultimately, of course, we'll need to see the Phase II readout, how it reads out, but it could be a product for those who need higher weight loss than what petrelintide can deliver on its own or for those who are really looking for the highest weight loss, which there's also a subgroup of patients that we'll be looking for. Or it could be one which speaks more to people living with both obesity and type 2 diabetes where the combinations of an amylin and a GLP-1 also looks really great. So there's actually a number of opportunities you can discuss with us for where to position or maybe we'll go forward.

And just curious, like any updates on the co-formulation of the combo therapy?

Updates in which way?

Like co-formulation?

Yes. But that is the clear opportunity that this will be a co-formulated product. That was -- I can reassure you that was a deep part of the diligence when we entered the partnership.

Great. Just switch gears a little bit to survodutide, of course. So the SYNCHRONIZE-1 data will be in this half. So just curious like what kind of data release should we expect for something like press release first and then full presentation, I guess, at the ADA conference?

Yes. So we expect data to be top line and then also be presented throughout the year for both the SYNCHRONIZE-1 and SYNCHRONIZE-2, but actually also importantly, the cardiovascular outcome study, which is also reading out this year and studies in patients from Japan and China. So it's a full Phase III program that will read out, and we do expect top line and then follow with presentations. And you can already see now at the American Diabetes Association that there's a big symposium on survodutide, which we look very much forward to hear what our good colleagues at Boehringer have to say about that.

Awesome. I think like a prior concern for survodutide or potential concern is the tolerability profile based on the Phase II data. And we know for the Phase III, actually, you are testing a higher 6-milligram dose versus 4.8 milligram in Phase II. But at the same time, you have 4-week flexible titration versus 2-week titration in Phase II. So wondering how should we think of the GI tox profile? And how confident are you actually Phase III can have better determination rate, better GI tox that's comparable to your incretin peers?

Yes. We definitely expect that survodutide will come out with a good number on the weight loss and also that Boehringer have shown that you can manage the GI side effects just as with any other incretin by applying more flexible titration and not pushing people to dose escalate according to schedule. I think as we have said for many -- for a long time, if people took the time and look back at how Phase II studies read out for tirzepatide and Wegovy, you would see the same signals in Phase II, which magically disappears in Phase III because you apply antiemetic medication because you do much more flexible dosing. So of course, we also expect that Boehringer have done this in this Phase III study.

Looking forward to that. Another thing, as you mentioned, the mantra, See obesity, Think liver, Treat the Heart. So -- and also like we know the MASH data and also the CVOT data will also be out this year. So just curious like how would -- for example, MASH data kind of accelerate the potential launch in MASH and also for CVOT, how survodutide could treat the preferred -- like as a preferred therapy for the high-risk comorbidity patients like your thought there?

No, but it's -- I think it's an area which the community in general has overlooked a little bit. But the fact is that the liver, if you can improve liver health, if you can get fat out of the liver and make the liver more insulin sensitive more than what you can just expect from a weight loss, then suddenly, you are reinstalling what I would describe as the metabolic switch that can also help other organs.

After all, when you eat a burger, the first organ that will meet that burger is the liver. So -- and that liver, if that can better handle that nutrition, your -- the rest of the body will be better at also handling the situation we live in with abundances of food and what have you. So I believe that not only liver could improve in this setting, but if you are in a situation where you also have to release less insulin, for instance, so you don't build up as much adipose tissue, which insulin actually does.

If you don't have as many inflammatory markers or -- you also get your lipids in better control, which you should do when you have a better hepatic function, then ultimately, that could spill over and actually cause the heart and the kidney and other organs to also benefit as a secondary phenomenon due to the improved liver health that we would expect to see with this product.

So I look very much forward to the full data disclosure. And of course, in MASH, which is the biggest underserved need still in obesity, there's a huge opportunity for Boehringer to not only lead in obesity with this new mechanism, but also come in and become a groundbreaking new therapy for patients, not only with F2 and F3, but also the F4, so cirrhotic patients where they're running a large study. So -- yes.

Awesome. I think that's right on time. Thank you so much for joining us, and thank you, everyone, for listening. It is our pleasure to have you.

Thank you.

Welcome to the Zealand Pharma Top Line Data From Phase II ZUPREME-1 Trial Webcast and Conference Call. Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your first speaker today, Adam Lange, Vice President of Investor Relations. Please go ahead.

Thank you, operator. Welcome, everyone. We are excited to have you joining us today to discuss the positive top line results from the Phase II ZUPREME-1 trial of our amylin analog petrelintide. Petrelintide is being developed under our co-development and co-commercialization partnership with Roche. You can find the related company announcement on our website at zealandpharma.com.

Turning to Slide 2, which outlines the agenda for today. Joining me to present and discuss the data are Adam Steensberg, President and Chief Executive Officer; and David Kendall, Chief Medical Officer. Our Chief Financial Officer, Henriette Wennicke, is also on the call today for the Q&A session that will follow after the presentation.

As described on Slide 2, as always, I would like to remind listeners that today's presentation and discussion will include forward-looking statements that are subject to risks and uncertainties. With that, please turn to Slide 4. I would like to hand over the call now to our CEO, Adam Steensberg. Go ahead, Adam.

Thank you, Adam, and thanks, everyone, for joining the call. We are very pleased to report the top line results of placebo-like tolerability and safety with double-digit weight loss for petrelintide in this Phase II trial. These data brings us a significant step forward in addressing the gap in treatment options for the millions of people living with overweight and obesity.

Did we anticipate to see 1% or 2% more weight loss in the trial? Yes. Does it change anything? Not at all. And we do expect to address this in the Phase III trial design and thus demonstrating petrelintide's potential to ultimately deliver mid-teens percent weight loss. These results, therefore, reinforce our conviction in the potential of petrelintide as a future foundational first-choice treatment option and a clear alternative to GLP-1-based therapies for weight loss and, importantly, weight maintenance.

Turning to Slide 5. Obesity remains 1 of the greatest health care challenges of our time with high and growing prevalence, while treatment penetration is only 3% to 5% in the United States today. In other chronic disease areas, there's a broad range of therapeutic options that can be tailored to individual needs. In obesity, we are still in the very early stages, relying on 1 single therapeutic category. And while the GLP-1-based therapies have clearly advanced the field, they have not yet delivered what ultimately matters the most, long-term treatment persistence, durable weight maintenance, and ultimately sustained improvements in health outcomes for the most people living with obesity.

As an industry, we have placed significant emphasis on the magnitude and the speed of weight loss. However, this focus does not reflect the goals of most people living with overweight and obesity. Data tells us that current GLP-1 users only aim to lose up to 20% of their body weight, with 1 in 5 targeting 10% weight loss and about 60% aiming for weight loss between 10% and 20%. In the real world, only a minority of patients escalate to the highest approved GLP-1 doses.

This may reflect several factors, including tolerability challenges and variability in treatment experiences. Real-world data shows that treatment persistence with GLP-1-based therapies remain a major challenge, with about 30% of GLP-1 users stopping treatment within the first month; by 1 year, nearly 80% have discontinued treatment. And remember, this is in today's world where there are no alternative treatments available. There are a number of reasons why people discontinue GLP-1-based therapies. But with petrelintide, we are addressing the #1 reason for negative treatment experiences and discontinuation, gastrointestinal effects such as nausea, vomiting, constipation, and diarrhea.

Moving to Slide 6. Today's data further strengthens our conviction that petrelintide can play a leading role in addressing this treatment gap. What we are seeing is sustained double-digit weight loss with expectations of greater efficacy in upcoming Phase III trials, which will be designed to show the full potential of petrelintide while maintaining the excellent tolerability profile. Importantly, the observed tolerability and safety profile is what we believe will set petrelintide apart and ultimately will set a new standard for people's expected weight management experience.

And with that, let's move to Slide 7 as I turn over the call to our Chief Medical Officer, David Kendall, who will walk us through the results. David?

Thank you, Adam, and again, thanks to all of you for joining us. I am very pleased to share additional details on the top line results of the Phase II ZUPREME-1 trial and also share our collective excitement to bring these data forward and continue to progress petrelintide through development.

The top line data shared today build on the consistent and very encouraging clinical results for petrelintide, demonstrating double-digit weight reduction paired with an exceptional safety and tolerability profile, reaffirming both the potential of petrelintide's role in chronic weight management, and bringing a new foundational therapy forward for those living with overweight and obesity.

Moving to Slide 8. Importantly, amylin-based therapies offer a number of unique physiologic and potential pharmacologic effects when compared to incretin-based therapies. As Adam noted, there is a clear and growing need to leverage novel classes of treatment in weight management and approach this complex metabolic disease of obesity in new and better ways. Amylin therapy offers a fundamentally different approach by enhancing satiety and by restoring leptin sensitivity. This capacity to leverage the body's natural sense of fullness is a meaningfully different effect when compared to GLP-1-based therapies, which primarily act by suppressing appetite.

On to Slide 9, which outlines the design of our Phase II ZUPREME-1 trial. In ZUPREME-1, petrelintide was evaluated in a randomized, double-blind, placebo-controlled Phase II dose-finding trial. The study evaluated and compared 5 different maintenance doses of petrelintide to placebo, with dose escalation executed every fourth week to achieve maintenance dose. The primary endpoint was the percentage change in body weight at week 28, and treatment continued through week 42, followed by a 9-week safety follow-up period.

Secondary and exploratory endpoints include body composition, assessed by magnetic resonance imaging, or MRI, and assessment of cardiovascular risk factors. Today's presentation focuses on top line results. Additional analyses will be shared as the full data set is finalized, and these data will be presented in publications and at upcoming scientific congresses.

Turning now to Slide 10 and the top line demographic characteristics in ZUPREME-1. As previously shared, ZUPREME-1 randomized 493 participants with a balanced distribution of men and women with a mean body weight of 107 kilograms and an average BMI of 37 kilograms per meter squared with a mean age of 47 years. Randomization maintained this balance across all treatment groups.

Moving to Slide 11 and the weight loss results across placebo and the 5 active treatment arms. Treatment for a total of 42 weeks resulted in significant weight loss across all doses of petrelintide, with mean weight loss ranging from 8.7% to 10.7% from baseline, and with no obvious weight loss plateau observed by week 42, supporting the potential for continued weight loss with extended treatment. Maximum efficacy with petrelintide was observed in dose group 3, and we are similarly encouraged by the weight loss efficacy seen even with the lowest treatment doses tested.

Moving now to Slide 12. The data from ZUPREME-1 are incredibly encouraging and provide us with critically important insights into the planned design for Phase III studies, studies that we firmly believe will demonstrate that longer-term treatment with petrelintide can achieve even greater weight loss, targeting mid-teen percentage reductions in body weight, while preserving the excellent tolerability profile.

Importantly, the treatment estimand results in this trial were consistent with the efficacy estimand results, likely driven by both a high retention rate and a high completion rate. Notably, and consistent with the results reported in our Phase I trial, nearly all trial participants receiving active petrelintide treatment achieved some body weight loss during the course of the trial.

It is also important to note that several trial-specific conditions likely impacted the efficacy outcomes reported. While greater proportions of women are known to enhance weight loss in clinical trials, the ZUPREME-1 trial focused on dose identification for Phase III and on assessing the potential for a significantly improved long-term treatment experience for all those living with overweight and obesity. In ZUPREME-1, female participants did, in fact, achieve a much greater weight reduction as compared to males, with women losing on average approximately 6 percentage points more weight than male participants on a placebo-adjusted basis with the maximally effective dose.

There was also a larger-than-expected geographic variation noted in the mean treatment response at maximal dose, with approximately 3 percentage point greater weight loss for participants from the EU versus U.S. study sites, with the weight loss observed in the EU study subjects achieving reductions more consistent with our predictions.

Let's turn to Slide 13 for a look at the details of the safety and tolerability profile observed in ZUPREME-1. Shown here are placebo-corrected rates of the GI adverse events that are both most commonly reported in studies of weight loss therapies and which are 1 of the main drivers of treatment discontinuation of incretin-based therapies in the real world.

Data reported today demonstrated petrelintide's placebo-like tolerability for the common GI adverse events of constipation, diarrhea, and vomiting. Notably, while predominantly mild nausea was reported with petrelintide therapy, overall rates were low, and reports of nausea were most common during dose initiation and escalation.

Most importantly, I wish to highlight that no episodes of vomiting were reported in any participant treated with the maximally effective dose of petrelintide. Additionally, approximately 70% of the participants on the maximally effective dose did not report any gastrointestinal adverse events during the course of the trial, further highlighting the superb tolerability profile of petrelintide treatment observed.

Overall, petrelintide treatment was judged to be safe and extremely well tolerated. No unexpected or novel safety signals were identified, and rates of alopecia, fatigue, and neuropsychiatric adverse events were very low or nonexistent. The study also demonstrated very low rates of injection site reactions with an incidence similar to placebo injections.

Slide 14 shows the treatment discontinuation rates for placebo, pooled petrelintide, and the maximally effective doses of petrelintide treatment. Again, it is noteworthy that treatment discontinuation was similar in those treated with active drug as compared to placebo, and that no participant who discontinued the maximally effective dose of petrelintide did so due to gastrointestinal adverse effects; once again, underscoring the tolerability and usability we observed with petrelintide.

Moving now to Slide 15 and a summary of these exciting and compelling results from ZUPREME-1. At Zealand Pharma and with our partner, Roche, today's data further strengthen our conviction that petrelintide can establish itself as the next true foundational approach to weight management. Petrelintide demonstrated sustained and clinically meaningful weight reduction at all doses with no obvious plateau in the pattern of weight loss.

The data also support a pristine and exceptional safety and tolerability profile for petrelintide with rates of adverse events generally similar to or lower than those observed with placebo. Equally important, there were no discontinuations due to gastrointestinal adverse events and no episodes of vomiting among those treated with the maximally effective dose.

Petrelintide treatment was also associated with favorable improvements in cardiovascular risk factors, including lowering of blood pressure, improvements in lipid profiles, no increase, and in fact, a 2-beat-per-minute decrease in heart rate, and reductions in markers of systemic inflammation.

We are extremely excited to continue to advance the petrelintide monotherapy with full ZUPREME-1 data to be presented in detail at an upcoming scientific meeting in 2026. We expect to initiate the Phase III program in the second half of 2026 with trial conditions optimized to achieve maximum clinical response while maintaining a highly differentiated and exceptional tolerability and experience profile while enhancing long-term treatment adherence.

With that, I would now like to move to Slide 16 and turn the call back over to Adam for closing remarks.

Thank you, David. Please turn to Slide 17. In conclusion, I want to emphasize that the combination of double-digit weight loss and the placebo-like tolerability profile places petrelintide in the ultimate sweet spot for the future treatment paradigm for chronic weight management. Petrelintide is not about chasing headlines for who can achieve the greatest weight loss number. It is about redefining the weight management experience and creating a future foundational and first choice medicine for the millions of people who live with overweight and obesity.

Let's turn to Slide 18. Before joining this call, I had a great conversation with Thomas Schinecker and Teresa Graham from Roche, where we acknowledge the importance of this significant milestone in our partnership. As you may know, next week marks the first anniversary of the partnership announcement, and today's news has only added to the strong commitment and collaboration between the 2 companies. We are excited about building our customer-focused commercial and medical affairs presence in the U.S. as we advance petrelintide and the petrelintide CT-388 combo through development and ultimately into the hands of patients.

Let's move to Slide 19. Today's news is only the first of many catalysts that we expect throughout the year, including initiation of the petrelintide Phase III program and the Phase II program with petrelintide in combination with CT-388 and importantly, the full Phase III data readout for survodutide in obesity.

And with that, I will now turn over the call to the operator and will be happy to address your questions.

And our first question today comes from the line of Andy Hsieh from William Blair.

So I have a question regarding the dose forward. So looking at across different dose groups, there are 5. It seems like the highest 3, there appears to be some sort of ceiling in terms of weight loss. And so on looking at the tolerability profile, it seems like, hey, that's suggesting you can add more on the dosing front. But then on the dose response, there seems to be a ceiling. So I'm just curious about your view on the interpretation of that. And also just forward in the Phase III setting, what are some possible doses that you're hoping to tease out?

Thank you for your question. And maybe, David, you will start by addressing it.

Yes. Andy, thanks for the question. I think an important part of understanding amylin pharmacology versus amylin biology, it's quite clear, our observations reflect yours, that at the 3 highest doses, we achieved very comparable efficacy, yet the tolerability profile, obviously, was quite favorable even at dose group 3. And ultimately, carrying doses forward, both through regulatory review but also to bring forth to patients, requires the optimum balance of safety and efficacy.

So whether we have reached the asymptote of the dose response curve, as has been observed with other therapies, in particular, pramlintide at its very high dose exposures in studies completed 20 years ago. I think it also speaks to the high bioavailability that we know exists with petrelintide, 80%-plus bioavailability likely allows us to maximally leverage the amylin receptor system for clinical effect. And obviously, we will look to take forward the dose that optimizes efficacy and maintains the tolerability profile that we spoke so much about.

And your next question comes from the line of Thomas Bowers from SEB.

So maybe I just want to follow up a little bit on the dose response. So do you believe you already have, that you could say, the maximal pharmacological effect of petrelintide? Also, keeping in mind that we know that Novo very recently shared on their conference call on cagrilintide that they actually see limited effect from dosing higher of cagri 2.4 milligram. So are we maybe seeing here this fear that you could see a [ darker ] ceiling effect here on the weight loss?

And then maybe just to follow up on that, in regards to your ambitions for the Phase III, you have previously stated 15% to 20% was the target. And I just wanted to confirm whether you said in your prepared remarks that you are now aiming for mid-teens in Phase III. Is that correct?

Thank you for your question, Thomas. And maybe I can start, and David, you can fill in. Thomas, I hope -- number one, I think it's really important to note, as David also highlighted in the prepared remarks, that in our study where we had a gender balance of 50-50, we actually observed that females achieved 6% more weight loss than males on a placebo-corrected basis, and also that we have observed lower-than-expected weight loss across some U.S. sites, which are, of course, all things we will address and account for in our Phase III design. So we, by no means, believe that we have exhausted or demonstrated the full potential of petrelintide when it comes to a weight loss potential.

And also, as was communicated by David, we have not seen a weight loss plateau. We expect to see also with continuous dosing that we see more effect. It's also really important to note when you -- if you want to compare across amylins, that as David also alluded to in the prior question, we have much higher bioavailability. So we are dosing extremely high, as we have also communicated before with the 9 -- with the top dose that we pursued in this study.

So I think it's fair to assume that David also said that we have probably demonstrated the maximum potential of amylin biology, but under some study conditions, which do not demonstrate the maximum potential of the product. And I would also like to highlight that there are other programs based on the same balanced approach that has demonstrated also efficacy in higher ranges. So we, by no means, think we have exhausted it. We think the study conditions is a major driver.

What excites us the most and what really this study was about was to find the doses to take into Phase III, and we believe we have those. And then importantly, we are seeing a tolerability and a safety profile, which is even more benign than what we have experienced in earlier studies. And no new -- actually no safety, you can say, findings, which is a major milestone as you progress into Phase III. David, do you want to add something?

Yes, Thomas, I think to echo what Adam said, in this study population, given the caveats that it is balanced for men and women, that we did see some unanticipated findings by geography. But I think it also underscores that with amylin biology and particularly amylin pharmacology, we are not as limited by GI tolerability issues to push milligram dosing. Similarly, we and others have not demonstrated any limitations on increase in heart rate, and I emphasized that in my prepared remarks.

o the challenges that come with, I will say, maximizing incretin-based therapies to much higher doses can be limited by adverse events and other, if you will, off-target effects like increasing heart rate. In this case, we identified that the 3 top doses, to your point, and Andy's, clearly had comparable efficacy, even in a population that was not entirely reflective of what will be the clinical population, which is predominantly female.

And we think in Phase III, optimizing for those conditions can give a clearer picture. But also go back to what Adam opened with, I think there is still intense focus on winning this weight loss numbers game, when, in fact, one of the greatest predictors of long-term outcomes will be persistence of the weight maintenance that individuals achieve. And with something that has placebo-like tolerability, I think the dose issues aside, that capacity to get to long-term persistence is what gives us the confidence that, yes, in fact, mid-teens efficacy is achievable.

Your next question comes from the line of Mohit Bansal from Wells Fargo.

Just 2 questions from my side, if I may. One, how do you see the potential of amylin in the light of these data more in terms of, is it going to be a monotherapy drug? Or do you think combo has a better potential in combination with CT-388? And then the second one is, so there's a little bit of change, if I'm sensing right, that earlier you were talking about 15% to 20% weight loss, but today you are talking about mid-teens. Am I sensing it right that your target profile is more like mid-teens now in the light of the data? Or this is what you -- is a fair target for an amylin-based therapy?

Thank you for your question, and I will start, and maybe David will add a little bit. So I would say, as we indicated also in the prepared remarks, we have actually increased our confidence in petrelintide as an alternative and a future foundational and first-choice therapy for the many people who live with overweight and obesity.

Remember, most people are not seeking weight losses above 20%. Most people are looking for weight loss below 20%. And we think with the profile that we have seen thus far, we can deliver the weight loss that most patients are looking for. And importantly, in a completely different experience where you don't have to be concerned about GI tolerability effects, physicians don't have to adjust doses based on individual experiences, you don't need maybe to consider getting off drug before you go for a birthday party.

So this is about turning the weight loss [ Olympics ] into chronic weight management. This is about delivering the weight loss that the majority of patients are looking for and changing the weight loss experience. And this is exactly what petrelintide as a monotherapy can do.

On the combination product, we remain also -- and you can say, of course, an important component of that combination product is the benign safety and tolerability profile of petrelintide. So our confidence in the combination with CT-388, also after Roche has announced some of the key data from that program has just also increased in the recent months.

So it's back to this opportunity to build petrelintide into the leading amylin franchise. And these data that we have seen today reinforces that potential, again, highlighting not only tolerability, but also the safety aspects where we have not seen anything that would suggest that the safety profile is placebo-like. So this is back to our firm belief that this is the way the obesity market is going. And David, maybe you want to add.

Yes. And, Mohit, I think very important questions. And to Adam's point, a reminder that our partnership with Roche is 50-50 on both the monotherapy and the combination. We believe both will have important roles to play. Obviously, preserving the, as I described, a pristine tolerability profile of amylin monotherapy will be part of the focus of putting that asset forward as a foundational therapy, but that does not preclude, as with many other chronic metabolic diseases, that the combination of therapies that best serves an individual patient will be desirable. And having that potential combination with our partner, Roche, to us makes great sense.

I think your other question regarding have we reached an asymptote with all amylin agonists. I'll give you my best perspective from days looking at pramlintide, a very short-acting agent now to cagri, elora, and petrelintide with data in the public domain. I think if one looks across those, not at the highest doses with higher rates of either discontinuation or challenging tolerability, using, for example, the 3-milligram dose of elora with a placebo-corrected treatment estimand of about 10.5%, not in the mid-teens to 20% that captured the headlines.

So I think this class of therapies, with petrelintide standing out, in our opinion, with the most favorable tolerability profile, can all readily achieve that mid-teens. If the right doses can be utilized, you're not limited by either formulation, injection site reactions, or the potential for antibody formation.

So I would apply the answer to that more broadly, to long-acting amylins in general based on the data available today. And again, we remain quite encouraged that the weight loss that the vast, vast majority of people desire, if it can be achieved as comfortably, as acceptably as possible with an asset like petrelintide, that will reshape the way we think about this.

And one last comment. If you go back to things like hypertension, even the management of type 2 diabetes, the game at first was to lower blood pressure as much as possible. You can do that with vasodilators that are fraught with adverse effects. We now have very well-tolerated classes of therapies that are used alone and in combination. And I think I see us in that same evolution in the weight management space.

Your next question today comes from the line of Kirsty Ross-Stewart from BNP Paribas.

So firstly, you've highlighted the difference in weight loss across women and men in the trial, but interested if you saw any differences in safety profile across men and women.

And then thinking through to Phase III trial design, you've alluded to plans to increase the proportion of women in the Phase III trial. So just interested in why you're taking that different approach that you've taken in Phase II? And what are the other key changes that you're thinking about as you go into Phase III or the learnings that you're taking from the Phase II data and in combination with data from competitor data sets as well?

Thank you. David, will you...

Yes. Very quickly, Kirsty, to your first question, no differences across males and females in terms of the safety tolerability profile, adverse effects, completer rates, all of the above. And in regard to the population anticipated to be enrolled in our Phase III program, I alluded to it already, one, to reflect the population as accurately as possible that seeks weight management today, but also understanding that the regulatory environment requires a certain proportion of exposure to all populations, men and women, various populations by geography, by comorbidities, et cetera. As we alluded to and we've maintained, in Phase II, we wanted to best understand dosing that could take us into Phase III, rather than to win some election or game in Phase II, realizing that it is Phase III that the regulatory authorities will ultimately use to judge safety and effectiveness.

We will now go to the next question. And your next question comes from the line of Carsten Lonborg Madsen from Danske Bank.

I only have 1 question left. I think in terms of looking here at the men versus women, there's so much focus on the weight loss you're seeing with the female population. But I'm actually more curious to understand why is it that males. in this study and in many other studies, get such a low weight loss and whether there could be something that's amylin-specific here, because it seems like you're moving down to something like 4% weight loss in males after 48 weeks. So that's really not a lot. And I'm wondering if you had an explanation for that.

David, please?

Yes. Thanks, Carsten. I think there are important physiologic reasons and pathophysiologic reasons that we understand regarding the differences in weight loss interventions, not just pharmacologic interventions, but lifestyle interventions. In general, women have greater degrees of adiposity at baseline. That is a physiologic fact. So greater adiposity likely accounts for a significantly greater potential impact of a weight intervening therapy.

I won't go so far as to judge the adherence compliance behaviors of men and women. I think that's outside the bounds of this. But both the greater adiposity that exists, more lean mass in men, even men who are obese or overweight, likely accounts for a significant proportion of that difference.

And then in terms of the Phase III trial, the things you're going to optimize, obviously, at this ratio you can optimize, but can you give more -- some other clear examples on other things you can optimize in the Phase III trial?

Yes, I'll take the rest of that. There are very important things beyond the split of men and women, including the proficiency of investigative sites. As a 17-year clinical investigator, it requires both commitment of the sites, their coordinators, and the individuals who are randomized to these trials to invest themselves in these longer-term Phase III trials, which all, as you know, extend beyond 1 year and potentially with open-label extensions.

So it will be site selection, geography, understanding the background environment in which these individuals are treated, will they have had a great deal of or very little exposure to potential weight-reducing interventions prior to enrollment in the trial. All those are considerations that we will and will need to put into this program to ensure that the regulatory authorities can fairly assess the safety and efficacy in the appropriate population.

So study sites, gender distribution, previous exposure to weight loss medications, and important comorbidities, and ultimately, ensuring adherence and persistence based not only on the characteristics of the intervention, but the investment of the study sites themselves in ensuring completion of the trial.

Your next question today comes from the line of Xian Deng from UBS.

So 2, please. So the first one, just wondering why do you think there is a difference in weight loss between European and U.S. participants? Is that lifestyle or you happen to have different demographics? And given that European participants actually have more weight loss, I'm just wondering how can you actually -- how do you plan to manage that at Phase III, given that FDA would require enough U.S. participants in the trial? So that's the first question.

The second one, just wondering, if I look at your Phase Ib results, you have 8% weight loss at the highest dose at week 16, and that was only 20% women, whereas now it's much longer study and you have 30% more women. And then the weight loss is 2% more, let's say, incremental. But just wondering, could you actually help us to reconcile the result of your Phase Ib and Phase II, please?

Thank you for your questions. And I'll start, and then, David, you can add. On the geographies, of course, we will make sure that we have a fair representation of both U.S. and European patients in the Phase III program. I think what we need to understand further when we analyze the data is the reasons why we saw significantly higher differences between the weight loss experienced in the European population and the U.S. population in this study.

And David alluded to some of the hypotheses which could have to do with prior GLP-1 experience and starting point for people's weight before getting into the study, et cetera. These are things that we'll continue to evaluate with our good partners at Roche and make sure that we build in systems, so we have not only the right sites, but also the right representation of patients in the Phase III program, which gives us a lot of confidence that alone can enhance it.

And then you're right, on the Phase Ib study in 16 weeks where we had only 20% females, we reported 8.6% weight loss in that study condition. We actually applied the dose escalation every 2 weeks. We also had different starting doses. The tolerability profile that we have observed in this Phase II study is improved even further compared to what we already saw as a very tolerable approach. So of course, again, ultimately, as we design our Phase III study in dialog with Roche, we will take into account all these parameters as we design for the profile of the drug we expect best meets the needs of the patients.

But as we have alluded to several times today, the world is in a much deeper need of a very tolerable approach, which can help people actually stay in therapy rather than just having a short weight loss experience and then a weight regain the months after they stop therapy. So these are discussions that we will have with our partner as we design the Phase III program, including considerations for doses, of course, and the escalation.

Your next question today comes from the line of Yihan Li from Barclays.

Yihan from Barclays. So I have 2, please. So the first one, we just did a very quick calculation. So it seems like if we assume 80% of females in your trial, you could potentially reach something like 12.5% [ each week ] loss. It's still like relatively lower than I expected. So just curious, like, what is your most recent thought in terms of the competitive landscape, especially given there are multiple amylin programs expected to report data this year?

And the second one, I'm just wondering if we could know the weight loss at 28 weeks, please. So just wanted to have a better sense of your weight loss curve.

Thank you for your question. And we will present the full data at upcoming scientific conferences to provide further insights. We have shared the top line and also what we believe representing the main characteristics of the outcome of this study. When you look into the weight loss that we achieved also when accounting for the gender differences, we do believe we get into the zone of what you could expect from this, especially and, of course, in the light of the very tolerable profile, and David have in some of his comments alluded to cross-trial comparisons, but you have to not only look into the tolerability from a GI perspective, you have to evaluate other safety findings.

You also need to look in the difference between efficacy estimates and treatment estimates, where traditionally, we see huge drops in the actual efficacy numbers. And with our study, we did not. Again, speaking directly to this thing that we have applied a treatment and dosing algorithm that patients can actually tolerate and appreciate to be on. And that is where we feel extremely comfortable as we move into Phase III with this profile that it has this potential with petrelintide to set a completely new standard for what a weight loss and weight maintenance experience can be. David, do you want to add?

Yes. I think 2 points to emphasize further to what Adam said. To have essentially 98% of those on the maximally effective dose, both get to maximum dose and complete the trial of 42 weeks on that dose. I can't think of too many other circumstances in my experience where you see that sort of persistence.

So I think, one, when you look at the treatment and efficacy estimands, they are very, very similar in contrast to studies where you may lose 10%, 20%, 30% or more of individuals. And I think back to a question, I believe you raised, we did achieve the primary endpoint at week 28 in all treatment arms as well. We're sharing the 42-week data because we think that's most germane to guide us into the Phase III program.

Your next question for today comes from the line of Suzanne van Voorthuizen from Kempen.

This is Suzanne from Kempen. About this more benign weight loss journey, it perhaps takes just slightly longer to get to the stronger weight loss numbers seen with other drugs, but with a super clean tolerability profile. I'm wondering if your thoughts evolve on the body composition you expect to see with petre. Is there a reason to believe that a more benign journey could lead to a healthier muscle versus fat loss ratio? And then I have a small follow-up after that.

Thank you, Suzanne. And, David, maybe you can address that. The data is being analyzed, and we will, of course, release them later. We don't have them at hand yet.

Yes. And I'll add, Suzanne, we're excited to see the body comp readout, particularly because of the use of the MRI or AMRA assessment, which gives a much better look at lean versus fat mass, not just lean mass and estimates. To the other point, there are historical data, and this is independent of the means of achieving weight reduction, but very rapid weight loss, while it makes for great headlines, also in a variety of interventions, leads to the highest rates of recidivism or weight regain. And there are some data that actually suggest that very rapid weight loss is metabolically less advantageous than gradual and sustainable weight loss.

And these are studies done years ago at the Pennington Biomedical Research Center and elsewhere. So I'm not saying that losing weight is generally negative. I think in almost all circumstances, there are metabolic advantages. But we believe that it is the entire weight loss journey, both for the patient experience, but also potentially for these metabolic advantages. I think we're also excited to get a readout both on the individuals with or without prediabetes who take petrelintide and the ZUPREME-2 trial, where we still believe that given the mechanism of action, we can preserve the weight-reducing effects of this intervention in diabetes versus no diabetes, remembering that if one looks at the semaglutide label, the weight loss in the diabetes population is less than 10% in Phase III trials. So you abrogate a significant amount of the weight-reducing therapies of these very effective insulin-stimulatory incretin-based therapies, something we look forward to further elucidating both in Phase II and Phase III.

And maybe just a small follow-up. I noticed that Roche is PRing this petre data from the Genentech part of the group. So I just wanted to double-check if there has been any change to the partnership or the way that the partners operate within the collaboration.

No, there has not been. Remember, Roche Genentech operates as a separate -- as a combined entity, but running the U.S. activities out of Genentech.

And the next question comes from the line of Jacob Mekhael from KBC Securities.

Maybe just to circle back on the topic of dosing. Given the good safety profile that you have shown, do you think there is potential to potentially skip dose escalation like some of the competitors have done in order to maximize weight loss? And I have also a follow-up on the design of the Phase III or on the time lines of Phase III. I noticed that Roche was able to move very fast and start a Phase III program with CT-388 this quarter once they had their Phase II data. Given they were able to accelerate that very quickly, is there any possibility for them to do the same with petrelintide and accelerate those time lines as well?

Thank you for the questions. I would say, as we have communicated also in the start of the year, we have already worked diligently with our good colleagues at Roche to accelerate on all aspects of getting into Phase III. And we remain as excited and now with the data at hand, but we maintain our guidance that we expect that the Phase III could start in the second half of the year. So that's very clear.

The other thing that is very clear is that with the data at hand and the very benign tolerability profile we have seen, now we need to evaluate all the nuances of the study and make the last design decisions on the Phase III program, also considering how to -- if we should make some changes to some of the escalations to achieve more. But as we have highlighted several times, it will not -- we will not do anything that compromises the weight loss experience because we think this is what will actually define and set a new standard for the weight management experience from a patient perspective in the future.

If there is a way whereby you can achieve a meaningful weight loss in the future without having these GI side effects, why would you choose a product that gives you a few percent more weight loss, but with a terrible GI experience? That is the question I think we should all ask ourselves when we move forward.

Maybe if I can squeeze one more, given the last comment that you just made. Do you still see potential for petrelintide as a first-line therapy given the relative weight loss difference that we've seen? Or do you think it would be better suited as a maintenance therapy?

No. I think it's exceedingly well suited for both. And we still are extremely excited about the foundational first-choice opportunity for petrelintide. Because again, if you can achieve the weight loss you're looking for without having all these GI side effects, without having a very cumbersome titration where you have to step up and step down to get to goal. And then also knowing that there's -- most would stop taking that medicine within the first year, why would you not go for the more tolerable weight loss experience?

But having said that, the key to unlock the value in the obesity market and get beyond some of the disappointments around not having enough patients, that is weight maintenance. So that is where the value is. That is to get patients to stay on therapy. But why would you not also use a product like this for the weight loss, the initial weight loss, if it can deliver the weight loss you're looking for? So both parts are important, but the value for sure lies in making this becoming a chronic therapy area rather than the event-based treatments that we see is how most use the GLP-1s today.

And our final question comes from the line of Andy Hsieh from William Blair.

Just quoting what David said that petrelintide showed a pristine tolerability profile. Maybe this is a follow-up to the previous question. So from a market segmentation perspective, can you share with us maybe updated thoughts on the maintenance setting? And also, would it be operationally difficult or maybe characterize from an operation standpoint, how easy it is to tack on maybe another 52 weeks of maintenance, like what we saw with ATTAIN-MAINTAIN following the active weight loss phase for CT-388, for example?

Thanks a lot for that. And these are all very good questions, which we will address and which we are addressing with our partner, Roche, as we speak, and very strong considerations for the Phase III program. I think it's, again, really important to take a step back, as we also said in our prepared remarks and try to envision a world where there's alternatives to GLP-1s and where you have a lot of patients being the key decision maker in which therapies you would like to get on and also stay on because we are approaching now probably soon 50% also out of pocket and with also 60% of prescriptions actually being patient-initiated.

That's a world where we think that most patients would like to get on a product like petrelintide and see if they can get the weight loss that they're looking for without going through all the hassle you have to do for many patients, at least, if you are on a GLP-1. And we think that petrelintide, with the data that we have seen today, and as we expect to show in the upcoming Phase III trials, will deliver the weight loss that the vast majority of people living with obesity and overweight are looking for. So while the opportunity to unlock the value of the market is in maintenance, and we should have a keen focus on demonstrating that potential and value to the patients, I do not see why patients would not also choose a product like this to initiate the weight loss journey.

Thank you. That was our final question for today. I will now hand the call back for closing remarks.

Thank you all for attending and for your questions. We look forward to future announcements and updates and to connecting in the coming weeks and months. Thank you

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good day, and thank you for standing by. Welcome to the Zealand Pharma Results Full Year 2025 Conference Call. [Operator Instructions] Please be advised that, today's conference is being recorded.

I would now like to hand the conference over to your speaker today, Adam Lange, Vice President, Investor Relations. Please go ahead.

Thank you, operator, and thank you to everyone for joining us today to discuss Zealand Pharma's results for the full year 2025. The related company announcement is available on our website at zealandpharma.com.

As outlined on Slide 2, I would like to remind listeners that during today's call, we will be making forward-looking statements that are subject to risks and uncertainties.

Turning to Slide 3 and today's agenda. I have with me on the call the following members of Zealand Pharma's management team: Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, Chief Financial Officer; and David Kendall, Chief Medical Officer. All speakers will be available for the Q&A session.

Turning to Slide 4. I will now hand the call over to Adam Steensberg, President and Chief Executive Officer. Adam?

Thank you, Adam, and welcome, everyone. 2025 was a breakthrough year for Zealand Pharma, especially considering the landmark partnership petrelintide with Roche. As we enter 2026, we are moving into the most defining and catalyst risk year for Zealand Pharma's history, which includes Phase II petrelintide data and multiple key readouts from the Phase III program in obesity with survodutide.

Moving to Slide 5. Obesity represents one of the greatest health care challenges of our time, not only because of its high and growing prevalence, but because of the long-term consequences of living with the disease. The longer people live with obesity, the greater the burden and the higher the risk of serious complications.

Real-world data clearly shows that treatment persistence with GLP-1-based therapies remains a major challenge. To date, up to 12% of Americans have been exposed to a GLP-1-based therapy, yet only a small fraction remains in treatment. Approximately half of patients who discontinue GLP-1 therapies cite gastrointestinal adverse events as the primary reason.

As a result, the key to unlocking the full value of this market is to develop therapies that deliver weight loss that patients desire, but with a better treatment experience that support long-term use in a real world.

This leads me to Slide 6. In many other chronic diseases, physicians typically have access to a broad range of therapeutic options that can be tailored to the needs of the individual patients. In obesity, the treatment landscape remains comparatively narrow where we today rely on a single therapeutic category. While the GLP-1-based therapies clearly have advanced the field, they have not yet delivered what ultimately matters the most long-term treatment persistence, durable weight maintenance and sustained improvements in health outcomes. With petrelintide, we see the potential to expand and strengthen the treatment paradigm for weight management.

Moving to Slide 7. The partnership we announced last year with us has delivered on everything we had hoped for. And our teams are currently moving full steam ahead and focused on finalizing the design of the Phase III program that we expect to initiate later this year to position petrelintide as a future foundational and first choice therapy for people living with overweight and obesity.

I want to emphasize that, this is a true balanced partnership. This is reflected not only in the financial structure where we share profits in the U.S. and Europe, but also at the strategic level with shared development and commercialization rights for petrelintide and petrelintide-based combinations. This structure allows us to retain significant long-term value of the franchise while preserving the strategic rights needed to support our ambition over the long term.

Moving to Slide 8 from one strong partner to another. Boehringer Ingelheim is positioned to lead the next wave of GLP-1-based innovation with survodutide, and we are very excited about the potential of survodutide to emerge as the preferred therapy for a large population of people with obesity and MASH.

Liver disease is one of the most prevalent comorbidities associated with obesity. As Boehringer highlighted at Obesity Week last year, when you see obesity, think liver. And as one of our external speakers and the principal investigator in SYNCHRONIZE-1 noted at our Capital Markets Day, see obesity, think liver, treat the heart. This framing highlights the excitement for the upcoming Phase III obesity data with survodutide, including data from the cardiovascular outcome trial.

Switching gears to our research efforts on Slide 9. Our ambition extends beyond refining the near-term future of weight management. Over the coming period, we aim to build the most valuable metabolic health pipeline, supported by our competitive advantage with more than 25 years of expertise in peptides and metabolic health, proprietary know-how and high-quality in-house data. Combined with rapid advancements in AI and machine learning, this strong foundation position us to remain at the forefront of innovation.

While AI will improve efficiency across the industry, true differentiation comes from the quality and scale of proprietary data used to train these models. This is where we intend to focus our efforts. Our goal over the next 5 years is to advance more than 10 candidates into the clinic and set industry-leading cycle times from idea to the clinic. In a field historically characterized by long and complex development cycles, the pace of innovation is accelerating, and we intend to lead that.

With that, I will turn over to David.

Thank you, Adam. I will begin with an overview of our pipeline shown on Slide 10. Zealand Pharma is in a unique position today with the potential to achieve 5 product launches over the next 5 years. We are also embarking upon a data-rich period ahead with important results from many of our clinical programs. All told, this represents an incredibly exciting and highly compelling path forward for our company.

Let's turn to Slide 11 and the ZUPREME-1 trial with petrelintide. We look forward to reporting top line data from the Phase II ZUPREME-1 trial this quarter. This trial is evaluating the efficacy and safety of petrelintide in participants with overweight or obesity without coexisting type 2 diabetes. ZUPREME-1 is a dose-finding trial assessing 5 dose levels of petrelintide administered weekly versus placebo over 42 weeks of active treatment.

The trial includes monthly dose escalation over a period of up to 16 weeks, followed by maintenance doses of up to 9 milligrams. The study's primary endpoint assesses change in body weight at week 28. However, top line readout will also include important efficacy and safety measures at week 42.

As previously shared, ZUPREME-1 enrolled a population of 494 participants with a mean baseline BMI of approximately 37 kilograms per meter squared and includes a balanced distribution of females and males. This population differs meaningfully from those studied in our Phase I trials, and also from populations enrolled in recent Phase II and Phase III clinical trials of other amylin analogs.

Moving to Slide 12 for a reminder of our ongoing plans for petrelintide. Together with our partner, Roche, we are looking forward to leveraging insights from the ZUPREME-1 trial to inform the final design of a comprehensive and ambitious Phase III development program for petrelintide in weight management.

We expect to initiate the Phase IIIa registrational trials for petrelintide monotherapy later this year, which will be followed by a comprehensive Phase IIIb program designed to further expand and unlock the full value of petrelintide.

With Phase II data approaching, I would like to briefly revisit our target product profile for petrelintide. Our goal with petrelintide is to deliver the level of weight loss that the vast majority of people living with overweight and obesity are seeking, while also providing an improved patient experience to further enhance the use of petrelintide for long-term treatment.

Accordingly, a successful outcome for us would be data that reinforces our confidence in petrelintide's potential to achieve approximately 15% to 20% body weight reduction in longer-term Phase III trials, together with a safety and tolerability profile that represents a significantly better experience relative to incretin-based therapies, firmly establishing petrelintide as a foundational therapy for the management of overweight and obesity.

In parallel, we are excited about the opportunity to explore petrelintide as a backbone for future combination therapies. Petrelintide in combination with the dual GLP-1 GIP receptor agonist, CT-388, is the first combination being developed in our alliance with Roche. Zealand Pharma and Roche remain on track to initiate the Phase II trial of the petrelintideCT-388 combination in the first half of this year.

Now turning to Slide 13 and survodutide, a glucagon GLP-1 receptor dual agonist that we believe has the potential to play an important role in the next phase of innovation in obesity and metabolic disease.

In the first half of 2026, we look forward to the results from the 76-week SYNCHRONIZE-1 trial, which is evaluating the safety and efficacy of survodutide in people with overweight or obesity without type 2 diabetes. In the prior 46-week Phase II obesity trial, survodutide demonstrated very compelling and competitive weight loss of up to 19%.

Beyond SYNCHRONIZE-1, we expect additional readouts from the broader Phase III obesity program over the course of 2026. Together, these data are expected to support the first regulatory submissions for survodutide. We are also excited and extremely encouraged by the ongoing Phase III program evaluating survodutide in people with metabolic dysfunction-associated steatohepatitis or MASH. This program includes 2 trials assessing safety and efficacy in patients with moderate to advanced fibrosis as well as in those with cirrhosis.

Given the high unmet medical need and limited treatment options for this population, we believe survodutide has the potential to become a key therapeutic option for people living with overweight or obesity and coexisting MASH.

Let's now turn to Slide 14 and our novel Kv1.3 inhibitor. Yesterday, we announced positive top line results from the first-in-human randomized double-blind, placebo-controlled Phase I trial evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of ZP9830 following a single administration to healthy male subjects. ZP9830 was very well tolerated with no serious or severe AEs or dose-limiting safety findings at any of the dose levels tested.

PK parameters increased in a dose proportional manner across the investigated dose range, in line with predictions based on preclinical data. We are very pleased with the results of this trial that are very well aligned with our expectations, reinforcing our confidence in our Kv1.3 channel blocker as a very promising drug candidate with the potential to target multiple autoimmune and inflammatory diseases. We look forward to reporting top line results from the multiple ascending dose portion of this trial and progress ZP9830 into Phase Ib/IIa development in the second half of 2026.

With that, thank you very much for your attention. I would now like to turn the call over to our Chief Financial Officer, Henriette Wennicke, who will review our financial results for 2025. Henriette?

Thanks, David, and hello, everyone. Let's turn to Slide 15 and the income statement. Revenue for the full year of 2025 was DKK 9.2 billion, driven by the initial upfront payment received under the collaboration and license agreement with Roche. The net operating expenses, excluding other operating items, totaled DKK 2.1 billion in 2025 and was within the guidance range of DKK 2 billion to DKK 2.3 billion. 76% of the net operating expenses in 2025 were dedicated to research and development, mainly driven by the clinical advancement of the petrelintide program, including the 2 Phase II trials and the preparation for Phase III.

The S&M expenses are driven by the pre-commercial activities associated with mainly petrelintide, while G&A expenses reflect a strengthening of organizational capabilities, investments in IT infrastructure and legal expenses related to the patent portfolio. This resulted in a net positive result of DKK 6.5 billion for the year.

Let's move to Slide 16 and the financial position. We ended the year of 2025 with a strong cash position of DKK 15.1 billion. Our cash position was strengthened during the year by the initial upfront payment of DKK 9.2 billion from Roche, partly offset by the operating expenses during the period. Our strong capital preparedness enabled us to meet all obligations under the collaboration with Roche for petrelintide, including the comprehensive Phase III program. It will also allow us to intensify our efforts in building a leading metabolic health pipeline and deliver on our Metabolic Frontier 2030 strategy.

Let's turn to Slide 17 and the outlook for the year. For 2026, we guide for net operating expenses to be in the range of DKK 2.7 billion to DKK 3.3 billion, mainly driven by research and development activities. On the development side, key cost drivers include the expected initiation of a Phase IIIa program with petrelintide monotherapy and the initiation of a Phase II trial, the petrelintide CT-388 combination.

In addition, strengthening our research engine is critical to realizing our vision of building a leading metabolic pipeline and the guidance, therefore, also reflects a step-up in research costs. Overall, the anticipated OpEx spend reflects the momentum we have built into 2026 and position Zealand Pharma to leverage the future growth opportunities.

And even though, we only provide guidance on operating expenses, I would like to take the opportunity to remind you that Zealand Pharma is eligible for potential milestone payments for Roche of USD 700 million in 2026. This includes an anniversary payment of USD 125 million and a potential development milestone payment of USD 575 million, which is subject to initiation of a Phase IIIa program with petrelintide monotherapy.

Finally, let's move to Slide 18 and our sustainability efforts. As a biotech company, we place the health and well-being of patients at the center of everything we do. And our ability to ensure advance our pipeline and ultimately serve patients rest on our people. We are extremely proud that while we increased our headcount by 41% in 2025, we maintained a very high engagement -- employee engagement score of 8.9 on a 10-point scale. And at the same time, we maintained our employee turnover rate at just 7.8%.

We believe this is a testament to our unique company culture and our continued dedication to fostering an engaging and enriching workplace. This makes us confident that we have built a sustainable organization setup capable of supporting our long-term aspirations. We are also committed to taking responsibility for the environmental impact of our operations.

In 2025, we committed to the science-based targets initiative and joined the UN Global Compact. In 2026, we will continue our work to transition our company and collaborate closely with our business partner to mitigate climate change.

And with that, I will move to Slide 19 and turn the call back to Adam for closing remarks.

Thank you, Henriette. Building on the momentum we created in 2025, we have entered the most catalyst-rich year in Zealand Pharma's history with defining data readouts expected for both of our leading obesity programs, petrelintide and survodutide.

As we execute on our Metabolic Frontier 2030 strategy, we are also highly energized to open our new research site in Boston this year and to pursue additional partnerships that further strengthen and expand our pipeline.

I will now turn over the call to the operator, and we will be happy to address your questions.

[Operator Instructions] We will take our first question, and the question comes from the line of Hakon Hemme from Danske Bank.

In regards to the upcoming Phase II readout on petrelintide Phase II, the ZUPREME-1, what level of details are you able to share with us on the day of the announcement? Apart from the weight loss, will you include data on petrelintide's tolerability profile in the announcement?

Thank you, Hakon, for that question. So we can confirm that the data are anticipated this quarter, which, of course, means also in the coming weeks, and we are highly anticipating being able to share the data broadly. We will, as we always do when we share top line results, provide a balanced presentation of the data while also reserving data that can be presented at scientific conferences later in the year. So you should expect a balanced view, which will discuss both top line efficacy and safety tolerability.

We will take our next question. Your next question comes from the line of Rajan Sharma from Goldman Sachs.

I just wanted to get your latest perspectives on competitive dynamics in the obesity market following the first oral launch. I know, you've always been clear in the view that injectables will be the largest segment of the market. Has anything changed given the launch trajectory of or Wegovy? And then maybe just to add on that, where do you expect net price to be in obesity by the time petrelintide launches?

Thank you for your question, Rajan. And I think it's -- we have not -- our minds around the oral versus injectables have not changed due to the recent launches. It's very important, and we remain you can say, focused on the fact that all GLP-1s that are launching right now do not address the biggest -- what we consider the biggest issues with the GLP-1s, which is tolerability.

As we discussed in the prepared remarks, we have 50% of the patients who stop taking these medicines is due to adverse events related to the gastrointestinal tract. So while we do expect the all options to expand the GLP-1 market, we do not think it will -- it's actually addressing the main issue around the current therapies that are around. And that's why we are so excited about being able to lead in a novel category, which we think have the potential to provide patients, as David discussed, the weight loss they are looking for, but a more pleasant weight loss experience. And it's really back to the thing which we have also advocated for, for a long time.

Instead of having such a keen focus on prices as an industry, we need to move the focus into how we help patients stay on therapy. The key to unlock the value of the obesity market is to make sure that obesity medications are used as chronic therapies rather than event-based weight loss agents. And that's where we think petrelintide and the amylin category has the potential to unlock the market value for obesity.

When it comes to prices and which, of course, has a lot of focus right now in the current competitive environment also with having had compounders around, it's again some dynamics that we have talked about for a long time. And the uniqueness about the obesity market is we have the more classical market where we have payers and insurance companies and then we have the self-paid market. And you need to address both.

Of course, when you launch with a new category, which may provide a much more pleasant weight loss experience, there will be novel dynamics also with regard to pricing. So while the GLP-1 dynamics will affect entrant into that market, we do anticipate that novel themes will play out when you launch novel categories, just as we have seen in other therapeutic areas. So -- but it's too early to provide any specifics on the net pricing when we launch petrelintide.

We will take our next question. The next question comes from the line of Kirsty Rosergewart from BNP Paribas. Kirsty Ross-Stewart from BNP Paribas.

Kirsty Ross-Stewart from BNP Paribas. So regarding the Phase IIIb development for petrelintide, can you just expand a little bit on the types of opportunities you're hoping to unlock with the broader clinical trial program? And how much of the total opportunity do you believe is represented by the monotherapy? Is that kind of the majority part? Is that what we should be thinking as the main part? Or just are you seeing this as a small portion and just the tip of the iceberg? And just related to that, can you remind us on the financial obligations from you and Roche regarding the future Phase IIIb development?

Thank you for your question. I'll just start with a few remarks and then hand over to David. So as -- as you know, our -- the focus for the team right now is to accelerate time lines to a potential launch of petrelintide and in parallel, invest deeply in making sure that petrelintide will become a foundational and first choice therapy and thus also having the data foundation to support that positioning. And we will have -- we'll share all costs with our partner us in those efforts. It's clearly the monotherapy that have our key focus right now.

But as David also discussed, the combinations now starting with CT-388 is also carrying investments as we progress these programs. And we will hope to see more combinations really utilizing petrelintide's potentially as a foundational therapy. But perhaps, David, you can comment a little bit more on the Phase III considerations and why we have strong believe that it can become a foundational therapy.

Yes. Thanks, Adam, and thanks, Kirsty. As noted, the Phase IIIb program beyond a rapid acceleration of the Phase IIIa program to ensure the earliest possible submission and potential approval. You can imagine that it is obviously the outcomes that matter most to patients and their providers that will be the focus, not only of the weight loss studies in Phase IIIa, but focusing on those complications, which we know are readily tied to weight reduction, such as obstructive sleep apnea, osteoarthritis and osteoarthritis pain, noting that amylin agonists may have the unique potential to favorably alter bone metabolism and impact pain markers as has already been shown with the GLP-1 agonist reduced weight has its benefits and going beyond that.

But beyond those, I think attention to preserving muscle mass, maintaining functional status, focusing on the population that seeks weight-reducing therapies the most, specifically women and women's health implications. And finally, a very important impact of those coexistent comorbid conditions, cardiovascular outcomes being primary, looking at the impact on liver disease and other metabolic dysfunction associated comorbidities.

As Adam noted, the focus initially is on monotherapy, establishing amylin-based therapies and petrelintide in particular, as a foundational therapy, but understanding that in complex metabolic diseases such as lipid disorders, hypertension, type 2 diabetes, we have learned that the complexity of these diseases often requires multifaceted approaches to therapy. So combinations with incretin-based therapies and other modalities as being investigated by us and others, we believe will become the cornerstone of the optimal treatment for obesity and its related conditions.

To reemphasize what Adam stated, petrelintide as monotherapy, which we firmly believe can be foundational, but also substantially improve the patient experience will be the focus of Phase IIIa with the extension in Phase IIIb to unlock the full potential of this asset.

And just maybe a comment from me, Kirsty, as well on the financial obligation. So yes, we will share costs both on Phase IIIa but also Phase III 50-50 with Roche. As I mentioned in my remarks, we will receive USD 575 million in connection with the Phase III initiation, and we will also receive USD 575 million in connection with Phase IIIb initiation from us.

We will take our next question. Your next question comes from the line of Andy Hsieh from William Blair.

Congratulations on a stellar 2025. Adam, I appreciate that you're moving the field away from the weight loss Olympics, as you coined the phrase. Just to gauge expectations ZUPREME-1, semaglutide and tirzepatide showed an additional 2% and 3% weight loss from 42 weeks to study end. So objectively, should we subtract that 2% to 3% from your TPP goal just to account for the timing difference and gender mix for the imminent readout?

And also, if you don't mind, maybe a macro question on what Lilly has done recently. We wanted to recategorize as a biologic. So if they're successful, do you think that, that might set a precedent for all the peptides out there, including petrelintide?

Thank you for your question, Andy. And I would say when you -- and of course, everybody compares across studies. When we have designed our ZUPREME-1 study, we have had one key focus, and that is to generate the most robust data set to allow us for the most robust decision-making to move into Phase III. So we have not enhanced the study with a disproportional high amount of women or high BMI. And we've also decided to look at the data point of week 42 instead of week 48 as others would do in order to have the most robust data set for Phase III decisions.

So when we then -- as David also shared in his prepared remarks, think about what are the weight loss that we anticipate to see -- we would expect in that study under these study conditions that translate into a 15% to 20% weight loss in a Phase III study setup. That's how we will look at the data. And I would say, historically, when you look into male-to-female ratio, if you take a study that is enriched with only females versus males, you could probably expect what, 5% more weight loss in the female-only cohort.

If you then also enhance the BMI and the study duration, then you would see even higher differences. So we are looking for a data set that when we do our internal modeling will allow us to get this 15% to 20% weight loss. And the reason that we have called to end the weight loss Olympic is just the plain fact that patients are not interested -- most patients are not interested in a weight loss above 20%. So why is it that we, as an industry and a community keeps talking about those numbers as if they were so important.

You can do these surveys among patients, and you will get the same answer across any survey that we have seen thus far. And that's why I call for the end. As I also said, and as we discussed also in one of the prior questions, the key to unlock the value in this market is to develop therapies that provides patients with the weight loss they're looking for and as importantly, therapies that they can stay on instead of therapies where they only take them for 3 to 6 months and then stop taking them.

The big dilemma we have with people don't stay on therapy is that most will likely regain the weight and thus never get to the health benefits. So both from a patient, a society perspective, but also from a company value perspective, the focus has to be on treatments that deliver the weight loss that the most patients are looking for, 15% to 20% and then importantly, medicines they can stay on. And that's why I'm calling to the weight loss Olympic, focus on medicines that deliver what the patients want, and you will unlock the value in this market.

On your other question, with regard to efforts to move from a small molecule designation to a biologic. I'm sure that industry is looking into different ways to enhance, you can say, the positioning of their drugs. And I will not share our specific efforts to protect the value of our programs. But rest assured that we also have that -- those efforts as key focus.

We will take our next question. Your next question comes from the line of Yihan Li from Barclays.

Yihan from Barclays. So I guess I wanted to switch gear a little bit to survodutide and also MASH. So for MASH, based on our recent KOL checks, I believe the off-label use of including MASH appears increasingly common. So for example, our physicians would still use tirzepatide in MASH, if possible, even though we know it is not formally approved by regulators. So I'm just curious from your market research, are you observing something similar in terms of this physician behavior?

And also more broadly, like assuming survodutide will be launched in 2027, and we understood you might be more offense on this partnership, but also wondering anything you could share regarding its commercial strategy across obesity and MASH?

Thank you for your question. And it's important to note that it is Boehringer Ingelheim, who is solely responsible for the development and the commercialization of survodutide. We will just get milestones and then high single to low double-digit royalties. The profile that we have seen thus far from the clinical data released by Boehringer for survodutide gives us a lot of confidence in the molecule, both with regards to weight loss, but also in MASH.

On the weight loss parameters, as we have discussed before, we think the weight loss levels and the weight loss experience is going to be quite comparable to what we have seen with some of the market-leading GLP-1s on the market today. We look forward to seeing the Phase III data. When it comes to the MASH data, the Phase II MASH data that we have seen and is also expressed by Boehringer at the time when the data was released, we see them as breakthrough data. These are unprecedented levels of improvements.

And I think that's also reflected in the fact that Boehringer have decided to invest in the largest ever Phase III program for MASH, not only addressing F2 and F3, but also F4 patients, which gives unique opportunities to broaden the potential label if approved beyond into the most severe cases of MASH, but also with the scope of the program could provide very early indications of clinical and not just biomarker improvements.

With regard to what you mentioned as off-label use, if I heard you right, of the GLP-1s, I would say please remember that the majority of MASH patients are obese in the first place. And thus, of course, it's a logical choice to use the existing medicines to help patients achieve some weight loss as many MASH patients suffer from both obesity and other complications than MASH. So that is only a natural consequence. What we believe is that once you have a product that can make a significant larger effect on the disease status, we should expect to see a very attractive take-up also exemplified by the enrollment into the Phase III program and Phase II program for survodutide. So we have a high confidence in the program. We have a high confidence in Boehringer's ability to execute. They are one of the strongest large pharma players in the cardiovascular metabolic space, and we look forward to see the data coming out this year, including the cardiovascular outcome data in obesity.

We will take our next question. The question comes from Xian Deng from UBS.

Xian from UBS. So 2, please. The first one is on ZUPREME-1. So really appreciate you emphasized -- reiterated the importance of tolerability. So just wondering, looking into ZUPREME-1, just wondering what sort of profile do you -- would you actually consider as really your target profile in terms of tolerability? Would you say -- let's say, do you think it's actually possible to achieve, let's say, placebo level similar to placebo level of vomiting and constipation. So any color on that, that would be great.

So the second one is sort of a general question. So a few days ago, so Eli Lilly showed some quite interesting data combining tirzepatide and Taltz in psoriasis, which actually showed better skin clearance than Taltz alone. Of course, that's in psoriasis patients that are also obese. But just wondering if you have any thoughts on that? And would you consider, for example, in the future, collaborating with some other autoimmune players on something similar as well?

Thank you for your question. I'll just start by putting some thoughts on your second question and then hand over to David to follow up and also address your first question. I think maybe you also saw that yesterday, we also announced a Phase I data readout with our Kv1.3 ion channel drug, which is a broad autoimmune anti-inflammatory target, which has potential across a number of inflammatory conditions. And thus, we see that as a potential pipeline in a product. And -- there's another notion out there that in relation to the obesity pandemic, you actually see quite significant increases in the prevalence of some chronic autoimmune and inflammatory conditions, which had otherwise been seen as being rather stable.

So we see a strong link between the obesity pandemic and the rising prevalence of some of these conditions. And it's clear that if you name things like psoriasis or even IBD, there are some strong links with the obesity pandemic. So we are highly energized by our own Kv1.3 data and the opportunity to perhaps link metabolism and inflammation in the future. But David, maybe you want to elaborate.

Yes. And again, thanks for your questions. On the issue of tolerability, noting that tolerability is really a collection of factors. We focus, obviously, a great deal on the GI adverse events that have been made so central, particularly to incretin-based therapies. And while our Phase I data to date have suggested the potential for significantly lower rates of nausea, vomiting and certainly lower rates of the more chronic GI adverse events associated with GLP-1-based therapies, namely diarrhea and constipation in ZUPREME-1 and subsequent trials, tolerability and acceptability of the entire experience will be the focus of our evaluation. So looking obviously at GI adverse events, but in combination with the injection experience, the experience around dosing and dose escalation.

And back to the question that was posed to Adam on orals versus injectables, if one thinks about the currently available therapies and the target product profile for petrelintide, we anticipate that the weekly injection will consume about 10 to 20 seconds of an individual patient's time, which clearly can be associated with the acceptability of a treatment, assuming that injection experience is without reactions, pain, discomfort, which we have seen in our Phase I trials to date. So I encourage you and others as we will be doing to look at tolerability and acceptability as a collection of these factors, GI adverse events and more.

And to Adam's ultimate point, if that experience is highly acceptable to patients, that will further encourage long-term persistence on therapies and particularly therapies that give patients the weight loss they desire.

We will take our next question. The question comes from the line of Jen Jia from Cantor Fitzgerald.

This is Jennifer Jia on behalf of Prakhar Agrawal from Cantor Fitzgerald. So I was wondering for the upcoming Phase IIb obesity readout for petrelintide, in what way can it differentiate on safety, tolerability versus Lilly's amylin eloralintide, and also for the combo with petrelintide with CT-388. Could you give more context on dosing across the 2 products, titration schedule as well as how you want to mitigate the GI tox previously seen with CT-388?

Thank you for that question. It's as we have tried to convey on this call, the most important aspect for us when we review these data is to confirm that we have a product that lives up to the target product profile, which we have discussed a number of times, which is delivering a 15% to 20% weight loss and a more pleasant weight loss experience.

If we have that, we will have a leading category -- leading molecule within a new category. And I think it's really, really important to also look back at the data that have been generated thus far with petrelintide, which gives us the confidence when we look across the different amylin assets, we have what looks to be the best-in-class amylin analog in development. And that's why we move towards the Phase II data with a high level of confidence, both with regard to weight loss and tolerability data.

But the most important part for us is to get confirmation in this Phase II data with what we have seen in the Phase I and thus, that we are fully on the path to deliver on our target product profile. And thereby, as we have also communicated several times, we think petrelintide and amylin in general has the potential to be a larger category for weight management than the GLP-1s because if you allow patients to stay on therapy and you don't have to go out and capture new patients all the time, you would rapidly see the volumes of such a category outgrow the volumes of a category where people stop taking medicines early on.

So this is the key focus for us when we look at the data, and we move forward based on the prior data experience, which I think we have released to the market. So we all have the opportunity to look at those data that petrelintide has the potential to be the best-in-class amylin of those that are in the clinic today.

The combination product, of course, is also a unique opportunity. And with CT-388, when we did the diligence and the partnership with us, our conclusion was that CT-388 look to be potentially also a best-in-class GLP-1/GIP molecule. And we look very much forward to seeing further data from that program. But the combination -- when we think about the combination with that molecule, our gut feeling, if you will, would be to max out on the potential of petrelintide and then add a teaspoon of the GLP-1 component to enhance the weight loss experience for those patients who need the highest weight loss. And so we look forward to share more on the study designs and of course, ultimately, the data that comes out of the Phase IIb study for the combination that we will start later this year.

We will take our next question. The next question comes from the line of Kerry Holford from Berenberg.

A question from me is just on the planned Phase IIIa study design. I wonder if you can share any more detail on that. It's clear the message here is to expect you to accelerate launch and deal with the CVOT data later. But can you discuss the endpoint, the study time period that you're looking at for the Phase IIIa study? I mean, for example, could we see a scenario where 6 months weight loss is sufficient to get a first approval for petrelintide?

Thank you for your question. I think what we can reassure you is that we, together with us, we are doing everything possible to accelerate, and we have some -- identified some very good levers and have a lot of confidence that we can accelerate and push this program as fast as possible forward. We cannot share the details also the exact details on submission time lines due to the fact that this is a partnership, so we need to agree on when to discuss these things.

But we are all on in both organizations to make sure that things are being accelerated towards submission and ultimately a launch. What is also important here to note and one of the main reasons that we decided to partner this program at the time we did was, of course, investments into manufacturing capacity -- and we have been extremely pleased to see the announcements that have come out with, with regard to investments into high-volume, high-throughput manufacturing capacity, which, of course, is needed if you want to secure a successful launch when these products hit the market.

And I think that's again coming back to the uniqueness of the partnership we have here and the uniqueness of Zealand today is that we are -- as I conveyed at our Capital Markets Day, and we continue to operate as a biotech company, but we -- and that's the -- we will bring in the best from that world. But in the collaboration with us, we will also leverage the strength of a pharma company as we approach the market with petrelintide.

And I don't think you have seen many of these partnerships, but that is why we keep coming back to the strategic value and of course, the profit share we have in this partnership is unique and it's one which we are extremely pleased with to see also how it progresses. We will hopefully soon be able to share more on the exact time lines as we move the program into Phase III, but it's just perhaps one quarterly call too early.

We will take our next question. The question comes from the line of Suzanne van Voorthuizen from VLK.

This is Suzanne from Kempen. Looking beyond the Phase IIb readout that we're all eagerly awaiting and I believe how petrelintide could provide an alternative to incretins and the product profile you're targeting is very clear. But I wonder if you could elaborate for the longer run based on the knowledge today and the data sets that have been reported for the various amylin assets out there, how do you expect petrelintide to be positioned within the amylin class? What would you expect in terms of differentiation versus the other amylin later down the line? And maybe one clarification about the research site in Boston. What will this hub focus on? And how would that complement the capabilities in Copenhagen?

Thank you, Suzanne. It is too early for us to share our thoughts about the ultimate differentiation between the different amylin analogs. We have been extremely pleased with the data that we have seen thus far when it comes to the balance between weight loss and tolerability and safety findings also when we compare across the different modalities, different amylin analogs in the clinic today. So -- and we see a clear opportunity to continue to develop that differentiation that we have already observed in until today.

Another key aspect, which I think is important to note as well is as we enter this market, this will be the #1, 2 and 3 focus for Zealand and to build petrelintide into a leading molecule within the amylin class. Others will have to spend more time thinking about existing franchises and how to protect current molecules that are already on the market. And that's a strength and a force which I don't think people should underestimate.

On the research side, in Boston, as Utpal shared a little bit on our Capital Markets Day, but it's really going to be a site that will complement what we do in Denmark. In Denmark, we are one of the strongest, if not the strongest research group within peptide chemistry and also having worked in metabolic diseases and health for more than 25 years, have very unique expertise in those areas.

In Boston, we will build complementary skills, including focus on high throughput research labs machines that are built -- labs that are built specifically to tap into the automatization that we are seeing in research these days. And on top of that, we are also going to broaden out to modalities beyond peptides. And part of that broadening out will be through partnerships. We just announced one in December with OTR, which has to do with small molecules, but we expect to announce more partnerships, but we will also build some in-house capabilities, so we can become best partners to these opportunities.

So it's broadening beyond peptide modalities, and it's also with a high focus on automatization and high throughput, really leading to our firm conviction that we can deliver industry-leading times from idea to the clinic as we build our infrastructure in the coming few years.

[Operator Instructions] We will take our next question. The question comes from Rajan Sharma from Goldman Sachs.

Could you just discuss the rationale for restarting development of a GIP analog? Firstly, just to clarify, is this the same asset which you previously deprioritized? And then just in terms of strategy here, do you expect to see monotherapy activity? Or is this really a combination asset for the future? And how should we think about that in the context of CT-388, which is a GLP-1/GIP co-agonist?

Thank you, Rajan. I'll hand it over to David.

Yes. Thanks, Rajan. Yes, this is the asset that has been part of our pipeline all along. And as you have likely noted, I mean, the interest in leveraging GIP pharmacology, while it is still in its infancy, both with the development of tirzepatide and other GLP-1/GIP molecules, the recent announcement of Novo looking at combinations with an amylin analog. But our understanding, as we've stated all along, that combination therapies can ultimately be leveraged to target this complex metabolic set of disorders, obesity and beyond. And while GIP monotherapy, as has been reported by others, may not in and of itself have potent weight-reducing effects, the potential to further improve insulin action or insulin sensitivity, the ability to unlock even greater effect of other molecules, including amylin analogs, other incretin hormones and other peptide signals is becoming clearer.

And for us, this is yet another venture into the potential for combination approaches to targeting these complex metabolic diseases. And again, our commitment to improving metabolic health overall goes beyond, as Adam said, simply reducing body weight, simply targeting MASH to improving things like insulin action, targeting aspects of fat cell or adipocyte behavior and using this pharmacology to really target multiple tissues, multiple organs and further enhance the effect of other peptide and non-peptide signals.

So starting with the first in-human to ensure understanding of the PK and safety and tolerability, and then we hope to rapidly advance into assessment of unique combinations with amylin assets and other signals.

We will take our next question. The question comes from the line of [ Susan Shaw ] from Wells Fargo.

This is Susan on for Mohit. Just a quick question on ZUPREME-1 dose titration cohorts. Can you speak a little bit more on the rationale behind the timing and the step-up doses that were chosen for the trial? And as a follow-up, where do you expect to see the most improvement on the side effects?

Thank you for your question. The rationale was for the dose titration or you could even say that it is even a titration because you can expect, of course, to see weight loss even at the lower doses, but it's is the ability to get to the higher doses is a dosing escalation every 4 weeks is a practical way to do it. Our Phase Ib data suggests that we could do more frequent dose escalation and not compromise the tolerability from a GI side effect profile. It was clean, as you remember, except for one dosing arm where they started at a higher dose than what we do here. So it's also about the practical timing for dose escalation.

I don't think we have the same issues as you have with the GLP-1s, where you need to titrate carefully. And remember also a lot of patients, you will have to down titrate when you have decided to titrate up, then you have to back off for some weeks and then back off. That is what becomes -- that's why it becomes so complicated to get patients to the higher doses of the GLP-1, but we have not seen that with the amylin. In all our titration step, we have seen patients being able to tolerate the next dose with any significant new adverse events. So for us, it's more a practical decision rather than something that has to decide with how you have to do it actually from a side effect profile.

We will take our final question. The final question comes from the line of Jen Jia from Cantor Fitzgerald.

On 9830, the channel blocker, what indication would you consider pursuing? And what would be the rationale for that?

Yes. So we have some very good ideas about where we want to take the molecule in next, and also -- but -- and what you should expect is that we will be pursuing several indications also in parallel, because if you look into the biology rationale, we are looking at what could become a pipeline in a product. It's too early for us to share which indications we are going for, but you should expect us to pursue several indications in parallel.

It is a target that industry has been pursuing for a very long time without success because of the difficult nature of addressing this target. And that's also why, as David shared before, we are extremely excited about the fact that we have not only seen PK, but also clear effects of target engagement from a PD perspective in the Phase I study. So we think we have something that could be a future jewel in our pipeline. So -- but the specific indications, we'll have to come back with later.

All right. Okay. And with that, I would like to thank you all for attending and for your questions. We look forward to future announcements and updates and to connecting in the coming weeks and months. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

Good afternoon, and welcome to the Zealand session of the 44th JPMorgan Healthcare Conference. My name is Sophia Graeff Buhl-Nielsen. I'm an analyst here at JPMorgan on the European pharma and biotech team. And today, it's my pleasure to welcome Adam Steensberg, the CEO of Zealand Pharma to the conference. [Operator Instructions]

With that, over to you, Adam.

Thank you, and great to be here, and welcome, everyone. So what better way to kick start what looks to be the most exciting year in Zealand's more than 25 years history in working in metabolic health. A few weeks ago, we launched our Metabolic Frontier 2030 strategy and ambition to really go in and do our part to address what we consider as the biggest health care challenge of our time, and that's the obesity pandemic and all the diseases that follows the obesity pandemic.

What I will discuss today is, of course, our focus coming into the year. But also, I just want to remind all of us that we have actually only taken the first baby steps to address this health care pandemic with what we have seen playing out in the markets these days. We need significant new innovations if we are to get around it.

Zealand Pharma, if you think about where we're going to take the company in the coming years, it's about becoming a generational biotech leading in metabolic health, changing the landscape and chasing the opportunities for the many patients who live with the consequences of the obesity pandemic. I will be making forward-looking statements.

So if we think about where Zealand will be in 5 years from now, then our ambition is to have launched significant to our partners and with our partners, significant new medicines that holds potential to redefine how we think about care for patients living with obesity, both with survodutide in our partnership with Boehringer Ingelheim and with petrelintide in our partnership with Roche.

These are 2 very significant players, pharma players and 2 companies who differentiate themselves towards many other players in this space by the fact that they have had long-term strategies to come in and do their part to make a difference in the metabolic space.

But our ambition as a company goes much beyond just redefining how patients with obesity and metabolic disturbances are being treated near term. It's also about building the world's most valuable metabolic health pipeline.

And I've launched this strategy and this ambition when I launched that in early December, I also shared what I believe is almost what I would call an unfair competitive advantage. What many people have not yet realized when they think about Zealand, is that we have been working with metabolic health and peptides for these diseases for more than 25 years.

And with all those data at hand, combining that with what we are now seeing this revolution in AI and machine learning capabilities gives us a significant opportunity to remain at the forefront of innovation in this space. I have to remind everyone that while AI will come in and introduce efficiencies for everyone, not only in biotech and pharma, the only way where you can create true differentiation towards your competitors is if you have proprietary data that you can train these AI systems on. Otherwise, you have nothing compared to what you -- you don't have a differentiated opportunity compared to what your competitors have.

And Zealand has the data. And we have also the ambition to build more and develop more than 10 clinical candidates over the coming 5 years into the clinic and also establishing industry-leading times from idea to the clinic. I think when you consider this research area, which for a long time have been defined by a long thought process and cumbersome processes.

When you think about getting from lead idea to the clinic, we are now witnessing a revolution, with the speed with which we can move forward with research, and Zealand will be leading that.

We have a very firm financial position with more than DKK 2.5 billion in the bank and near-term milestones of more than USD 1.2 billion. And that also means that we can fund the journey towards profitability with the cash we have and the near-term milestones. So for Zealand Pharma, as we look into the next 5 years, it's about maximizing the value potential of petrelintide, but then building a pipeline next to petrelintide that can carry innovations for our patients into the future.

Zooming in on what looks to be the most defining and catalyst-rich year for Zealand Pharma, then we will see multiple clinical data readouts across our mid- to late-stage portfolio. We have petrelintide Phase II data, which likely is the most important data set for Zealand. It's -- and we'll come back to talk more about that.

We are already now working together with our partner, Roche, with full efforts to get the program into Phase III in the second half of the year. And then we expect to start also a Phase II study with the combination with CT-388.

Survodutide has been flying a little bit under the radar, but it's really, I would call it, the year of survodutide 2026. Boehringer Ingelheim will report the results of more than 6 Phase III studies within the obesity program for survodutide, not only the 2 pivotal studies in obese patients with and without diabetes, but also a large cardiovascular outcome study is expected to read out this year. And then we would anticipate that Boehringer submit the file later in the year.

Then you will see also progress across the early pipeline, including very, very near-term data from our KV1.3 inhibitor for autoimmune diseases. If those data come out the way we hope, it's a completely new value pocket in our pipeline, which we have not discussed a lot until today. But if these data support what we hope this program can deliver is something definitely we'll talk more about.

And then we're going to spend significant efforts also broadening our research footprint, establishing a research hub in Boston, which we expect to be up running by the mid of this year.

So in the coming 5 years, with the pipeline we have at hand today, we expect to have 5 launches, not only within obesity, but also from our 2 rare disease assets targeting congenital hyperinsulinism and short bowel syndrome, which are 2 programs we would expect ultimately to have partners to commercialize. So again, adding to the journey towards our generational biotech aspiration.

Before I discuss Zealand more specifically and our pipeline in more details, I just want us all to take a step back and consider what it is we are trying to solve for here. Sometimes when we discuss numbers and what I've called out as the weight loss Olympics, and it almost feels like a sport to impress each other, we forget about what it is we're actually trying to achieve here.

We are facing probably the biggest health care challenge of our time with the obesity pandemic. And it's not because of obesity, it's because of the consequences of living with obesity for a long time. And if you get obesity as a child, this is even more difficult because it's the duration of time you live with obesity that causes all these comorbidities.

Already today, we have more than 5 million excessive death that you can ascribe to obesity. That is higher than what the number of people who were dying from corona during the peak hours, but it doesn't fight us to the same extent because it has been building up slowly. But we have only looked at the tip of the iceberg here, because it's only now that we're going to see the consequences for those who have lived with obesity since childhood are going to kick in.

And remember, if you get end-stage organ diseases in your 40s, you will have organ failure in your 50s and 60s, and that's what we are looking into if we don't solve the problem. The good news is that we have seen with the launch of the first GLP-1s that you actually can use medical intervention to help people lose weight. More than 12% of the U.S. population have been exposed to a GLP-1.

The problem is with where we are today that only somewhere between 2% and 4% are on treatment people simply stop taking the current therapies, and therefore, they never get to the health benefits. If you don't stay on therapy, you don't get to the health benefits and you don't solve the obesity, the consequence of the obesity pandemic we are looking at.

We also know based on real-world evidence, and that's another reason why I've called to end this weight loss Olympics that for most patients, the average weight loss that you experience in the real world is not the numbers we hear about in clinical studies. And there are several reasons for that.

But if you just look at the 2 once-weekly products that are on the market today, evidence market data would suggest that patients on average experience 8% to 12% weight loss, and they most never get to the highest doses of these molecules.

We believe a lot of that have to do with 2 factors. Number one, which is very much associated to the GLP-1 class is the GI side effect profile, the tolerability. And while people are super motivated to lose weight, once they've achieved the weight loss, people are willing to accept much less. So many patients never get to the high doses and never get to experience the full benefit of these molecules because of side effects.

The other thing is, if you ask patients, most patients are actually not interested in getting into the high-20s in weight loss. 80% of all patients would tell you, at least in most of the market research that we have done that they're looking for weight loss of up to 20%.

This is also backed by recent data from IQVIA, again, demonstrating that if you look at the many patients who stopped taking GLP-1s today, 50% of those are due to GI side effects. The other part is due to cost and access elements.

But I really want you guys to also consider why is it we have seen and why is it we have experienced some disappointment in the uptake of these molecules. And there's been a lot of discussions around pricing. I think that's the less important aspect of the disappointment, that in my mind, the disappointment is driven by the fact that too many people stop taking these medicines too early. So people use the GLP-1-based therapies more as event-based therapies and not as true chronic therapies.

And again, I have to remind you, if you don't stay on therapy, you don't get the health benefits. So have we really solved the problem with what we have today? I don't think so. We have demonstrated that medical intervention can help people lose weight, but for the majority of patients, they never get to experience the long-term benefits of staying on a medical and maintaining their weight loss.

The other thing is, and I shared that before, when you ask people what is the weight loss you would like to see, the majority of patients say they will give you a number up to around 20%, but not above that. It's mostly, you can say, physicians and maybe us who think it sounds great to get a higher weight loss.

But I would again encourage people to really take a step back and think about it, even if these molecules carry serious side effects, it doesn't come for free to lose, let's say, 30% and maintain such a weight loss that actually requires you to change your lifestyle dramatically, and most patients are not ready to make that commitment.

But the good news is if you achieve a 15% to 20% weight loss, you still get a lot of health benefits. Actually, if you achieve a 15% weight loss and you maintain that, you get significant more benefits than achieving a 30% weight loss that you cannot maintain.

The other thing -- and again, people have for some time discussed that is it -- now the market is so mature and there's already the solutions out there that we need to address obesity. Again, I have to remind all of you, we have only taken the first baby steps into solving this health care crisis.

If you look into other chronic diseases, which I would argue are less complicated and less heterogeneous than the obesity situation, there's at least 8 different tools that physicians can turn to, to help the individualized patients to meet their needs for how to manage a chronic disease. In obesity, we have one category called GLP-1, which are fantastic in helping people achieve a weight loss, but have turned out to be more difficult tools when we talk about weight maintenance.

That's why we are super excited about the opportunity of the amylin category in general and more specifically about petrelintide, which we believe, based on the early clinical evidence, holds best-in-class potential. We are super excited about the consistency and the robustness of how petrelintide has read out in our Phase I studies.

If you look into the 16-week study to the right, you will also see that we achieved almost between 8% and 9% weight loss in a predominantly male population and a population of people who had a BMI below 30. So these are almost normal weight patients and almost entirely males, 20% females. This is very, very impressive. It's almost, I would say, comparable to what we have seen from competing programs in patients who were having a BMI closer to 40 and where you had 80% females.

And I have to remind you that in clinical studies, females tend to lose 5% to 8% more weight than males. So these are very impressive numbers when you look -- when you think about that it's a predominantly male population and a lean population. And that's why we approached our Phase II data this quarter with a high degree of confidence for the outcome because in Phase II, of course, we have more obese patients.

So here, we have a BMI of around 30 instead of -- 37, sorry, instead of the 30 we had in the early clinical exposure. And as important, we now have 50% females and not the 20% females we have reported before. So of course, just those study conditions will help with the outcomes of the study. The other one, it's a longer duration study. It's 42 weeks, and we know time is also critical to achieve the ultimate weight losses.

And that's why we continue to articulate that ultimately, what we are aiming for with petrelintide is a product that provides patients with the opportunity to lose 15% to 20%. That is what 80% of the patients are looking for and a much more benign weight loss experience. You could actually even start to talk about a pleasant weight loss experience.

We at least hypothesize when you get to a situation where there's choices you will stop talking about, can you tolerate it? You -- these conversations will change to it, will you accept it what you are on today. And that's where we think petrelintide holds a big promise.

Also, again, the confidence comes from the fact that side effects are mostly seen in the initial part of our studies, and we have already seen the 16-week data that it's more placebo-like than anything we have otherwise looked at.

So we are moving also with firmness and speed together with Roche into our Phase III program, where we're going to start a comprehensive program in the second half of the year and also move towards a large cardiovascular outcome study, really with the aim of establishing petrelintide as a future first-line and foundational therapy for patients who are looking for a weight loss of 15% to 20%. And importantly, a product that can help people maintain that weight loss, so they truly get to the weight benefit -- the health benefits of staying on therapy.

So the partnership we announced in March last year with Roche is -- as one of my colleagues have expressed it, everything we had hoped for. We -- it was a very competitive process when we went out and to find a partner for petrelintide. And ultimately, we chose Roche because we felt with Roche, we found an organization who had the commitment needed to actually establish therapeutic leadership in this space.

And Teresa has been out committing again here at this conference that their aim is to be a top 3 player. That was also what we felt in the partnering process. So of course, it's nice to also hear here. As importantly, it's a company who has a strong history of collaboration. And since this is a 50-50 partnership, this is a partnership that you could have between 2 large pharma companies.

It's very rare that you see a small biotech like Zealand being able to have such a partnership. And we knew that we had to partner up with somebody who would embrace the partnership nature and really play to the strength of both companies. And that is what we have.

We also have committed to actually go out and build up commercial footprint alongside Roche in the U.S. And again, we have a 50-50 profit share. Just think about that, it's 50% profit share to a program where we do not have to invest into manufacturing capabilities because Roche will carry those investments. But still, we are looking to -- we have managed to retain the long-term value opportunity for this program and all the strategic rights that is needed to support the journey that we are embarking on.

Moving on from one strong partner to another one. Boehringer Ingelheim, a private company, which doesn't get a lot of attention on a conference like this, at least not in the investor meetings, they do have quite a lot of attention at partner meetings.

Boehringer is one of the most committed and strong players in the cardiometabolic space. They are the developer of one of the leading SGLT2 molecules in the space. They were the first pharma company to report positive clinical CV outcome data in the diabetes setting. And now they are set to lead in the next wave of innovation in the GLP-1-based medicines with survodutide, which is a Zealand invention together with Boehringer, where we will have high single to low double-digit royalties.

So Boehringer is leading all efforts. We just get royalties from this program. And as Boehringer put it at the conference here at ObesityWeek in November, "See obesity, think liver." We very often underappreciate that the number of obese patients living with liver disease is actually significantly higher than the number of patients living with type 2 diabetes.

And as I said in my introductory remarks, Boehringer is going to -- the complete Phase III program is going to read out from this program this year, starting already here in the first half. And then we would anticipate Boehringer to submit the file later this year. And the data that we have seen thus far, at least in our minds, suggests that the weight loss profile and the tolerability profile is comparable to the GLP-1s.

What really differentiate this molecule is its potential to also get fat out of organs. And that could be not only the liver, but also other organs as one of our -- as one of the investigators in the program said when he saw this slide about, "See obesity, think liver." He then added, and treat the heart. We at least have high expectations for also the cardiovascular outcome study that will also read out this year.

But as I said, the key differentiator for survodutide is the opportunity to address MASH, which is one of the most underserved conditions associated with the obesity pandemic. And the data that Boehringer presented a few years back is groundbreaking data, at least to our minds, it's the best data set we have seen in this category.

And Boehringer is moving forward with a lot of conviction and strength. It's the biggest Phase III program ever conducted in MASH. It's 3,500 patients, not only targeting F2 and F3 patients, but also F4 patients. And that just -- again, I think it's important that we just take a step back and realize what that could provide because one thing is, of course, to slow down disease development in F2 and F3 patients. But if Boehringer can also truly show that they can actually change the course for patients who have late end-stage liver disease F4, that would be a significant clinical game changer for these patients.

The other thing, considering the scope and the size of the program, Boehringer could end up being the first pharma company who do not only have a conditional approval in MASH, but actually a full approval. Remember, FDA has only granted conditional approvals for the products that are available today. And to get a full approval, you need to show clinical benefits. And because Boehringer have more disease patients and the scope and the size of the program, I at least would speculate that they could be the first company to demonstrate that.

So just spending the last minute before we move to my concluding slide, I just again want to reiterate that Zealand's ambition is so much more than just redefining the near-term value of the near-term treatment of obesity and patients living with MASH and associated diseases, focusing in and maximizing the value of petrelintide.

It's also about doubling down on our research efforts. We are going to spend DKK 5 billion on research in the coming 5 years. That is 5x as much as we spent in the prior 5 years. It's a significant commitment to build the world's most valuable metabolic health pipeline. And we're going to do that by a mix of internal innovation, but also partnerships where we're going to partner with the best when it comes to modalities outside the peptide space where we are leaders.

In December, we announced a partnership on small molecules. We'll continue hopefully into the year and expect to announce more partnerships that can help us build the pipeline. So we have clinical -- 10 clinical candidates within the next 5 years.

So that just leads me to conclude that we are looking into a transformational year for Zealand Pharma. We're going to have significant clinical data readouts across our entire pipeline and look forward to share more in the coming months.

Thanks very much for the presentation, Adam. Do we have any questions in the room? Maybe we could just start off on one on amylin. So over the past couple of years, we've seen data that's suggestive of the potential of the amylin class, both from an efficacy and tolerability perspective. In that context, where do you see petre most likely to differentiate itself? Is it still in the potency of the molecule as suggested from a single ascending dose data you showed? Or is it some other aspect we should focus on?

I think it's really a matter of getting the balance right between weight loss and tolerability. And for most patients, and we see that also partly in the real-world utilization of the GLP-1s is you need to deliver -- you need to pass a certain bar from a weight loss perspective. Once you have passed that, it's actually about the weight loss experience.

So for us, it's really about developing a medicine that is not just about weight loss, but more so about how do we get a product to patients that they can actually stay on. And it's actually, in our minds, it's beyond the GI tolerability issues. It's always easy to talk about nausea, vomiting, diarrhea and so on. And those are important topics in the current environment.

I think in the future, it's actually -- we need to change the conversation towards what is the experience that patients are looking for. And at one point, it's not logical for chronic diseases to discuss, can you tolerate or not. It's about will you tolerate if there is an alternative. And with amylin and petrelintide, in particular, what we have seen thus far, we think the weight loss experience is going to be very different. And that's back to this thing that you feel full faster rather than losing your appetite.

So it's the profile of the drug more than the actual numbers. Having said that, we do have a lot of confidence in the numbers as well, but that's not what will make it a winner in the end. That is the profile, the balance between efficacy, safety and experience.

And as you mentioned, it's an important year in terms of data readouts. I think this quarter, we're expecting the Phase II data from ZUPREME. In the context of the importance of trial design and factors we should consider such as the balance of males and females, how should we think about comparing the results of the Phase II trial to those of competitors with slightly different trial designs? What sort of range of efficacy outcome would you consider competitive at this stage?

Yes. One should always be careful to compare between trials and look for head-to-head studies. But it is, of course, also fair to state that we know that BMI has a big impact on how much weight you can lose. If you have a BMI of 30, there's -- I mean, there's a limit to how much weight you want to lose, then it at least becomes extremely unhealthy. If you have more females, we know that females are losing 5% to 8% more weight loss. So of course, all these things matters.

So for us, when we look at these data, the key thing for us is to make sure that we confirm to ourselves that we can ultimately get to a profile that will deliver 15% to 20% weight loss in a Phase III study, which is what will inform the labels. And in a Phase III study, you would naturally have, let's say, 70% females.

So we, of course, can live with slightly lower numbers in this Phase II study, knowing that it's shorter time treatment, only 42 weeks versus longer term and a 50-50 balance. So as long as we get in that range, we would be super excited.

And you've recently -- you've also highlighted here the reasons people discontinue GLP-1s. The majority is due to adverse events, but the second most frequent reason is due to cost concerns for about 1/3 of patients. How willing do you see consumers as to pay for weight loss maintenance as well as purely weight loss. Do you think that this is going to be something more in the prescriber segment so you can derive those comorbidity benefits? Or do you see consumers as also being willing to pay for that?

Absolutely. But it's about -- if you think about consumers and how -- and I guess all of us are consumers in certain degrees, there's a lot of things that we pay for. And if you think about the motivation that people have to lose weight and also maintain those weight losses, the reality is for many, many years, we have had plenty of opportunities to lose weight using different tools, but we have never solved the holy grail of actually helping people maintain that weight loss. So we see a lot of weight cycling.

And people go to fitness centers. They don't use them maybe that much, but they pay for them year in and year out. And so people are willing to pay for weight maintenance as well if they get an experience that they are ready to commit to. But of course, if the experience is so that it's only one which they will accept when they have the weight loss phase, they will not pay for it.

And that's why we think we actually still believe that there will be -- continue to be some disappointments in this market until we see novel agents entering the market where patients actually truly get the experience that they would be looking for. And I think we would all do ourselves a favor if we started to ask ourselves what -- how will things change if there is an alternative as compared to just sitting there trying to fight around patients that are getting the same experience.

And thinking again about the consumer portion, in particular of the obesity market. This year, we're seeing the launch of oral GLP-1s. It's not a surprise, we knew they were coming. But how do you see them as shaping the obesity market? And what do you think that this will mean for the competitive environment when petre potentially launches?

Yes. I think they will likely expand the current market. I think they will expand the opportunities for those patients who enjoy to be on a GLP-1. I think they will have very little to no impact on the success of future categories because it will still be a GLP-1 experience. It will potentially be an even worse GLP-1 experience when it comes to side effects for some of these molecules.

So it doesn't change the underlying deficiencies in my mind of the GLP-1s. It does provide the opportunity for those who don't want to take an injection. It does provide easier supply chain because it's not cold chain supply. So there are certain opportunities to expand the opportunity, but it doesn't change the fundamentals around how do we get around the obesity pandemic. I would expect to see quite significant initial excitement, but that -- and then followed by potentially even more disappointments because remember -- I mean, that is what we saw also with the injectables.

And you're also exploring a combination of amylin with GLP-1. Here, we could see higher efficacy potentially, but it seems that beyond that 20% threshold, you're saying this is potentially for a smaller portion of the market that really needs that higher degree of weight loss. How do you then see the relative opportunity for the combination product relative to monotherapy at amylin?

There's no question in my mind, and I think it's also been clear from my presentation here today. I think the world is in much, much deeper need of alternatives than more, because patients stop taking the current medicines and very few get to actually enjoy the long-term benefits of having maintained a weight loss. So there's a much deeper need of alternatives. And that's why we are so excited about the monotherapy.

But as our ambition goes beyond just providing alternatives and build franchise leadership, that means that combinations will also become very important. For those people who are most morbidly obese, if you're an obese patient living with quite established type 2 diabetes, it's a fantastic opportunity to combine an amylin and GLP-1. It's also a tool which we would expect to be more utilized in the specialist segment. So it's something that will be positioned quite differently compared to a monotherapy for amylin.

So it's -- and for me, personally, I think it's a tool which will require some physician engagement to convince patients to stay on it because as I also shared before, if you're getting into those 25% to 30% weight losses, I personally think you need a very strong voice, a doctor or somebody telling you to stay on because you need to be reminded why you have changed your life so much to an extent that you actually might are dreaming a little bit about how life was before.

Just sticking with that specialist segment as well. You've spoken about the importance of the benefits to different comorbidities. Are there any comorbidities where you think amylin could particularly differentiate themselves beyond a CV trial? What's top of your list for comorbidities to explore?

Number one, I would just reiterate what we discussed until now. If people end up staying on an amylin therapy, you actually have more differentiation than anything else because if you don't stay on a GLP-1, you never get to experience the health benefits. So we might be super excited about the clinical trial readouts that we are seeing. But if less than 30% stay on therapy, there will be very few patients who get to experience those benefits.

So with the amylin on the risk markers for cardiovascular disease, we have already seen those being reduced likely to the same extent as the GLP-1s. But more importantly, if we get patients to stay on, then we will actually suddenly as a society, get health benefits out of it. So that alone is a major differentiator. And that's going to be the #1 focus for us.

And then together with Roche, we are in deep dialogues right now around which additional indications are we going to expand into, and we will expand into additional comorbidities to show benefits beyond the cardiovascular scene.

Thank you. Are there any questions in the room? Maybe we could turn to survodutide, where we also have interesting data coming out this year. I think in your Phase II, survodutide showed efficacy more or less between Wegovy and Zepbound. You've made some alterations in terms of trial design for titration schedule, et cetera. But would you broadly expect that similar efficacy profile in a Phase III? And how should we think about tolerability as well?

Yes. We would expect -- and of course, we are super excited to see the data as they will be reported throughout the year. We would expect it to provide a weight loss that is comparable to what we see on the marketed products today. And then importantly, the glucagon component, I think it has been underappreciated that it's actually -- it's more than just the liver. I mean remember, glucagon may actually increase lipolysis slightly.

So maybe you could also, as a patient, experience a slightly improved energy expenditure. So meaning that it's not only about reducing your calorie intake, but also burning a little bit more energy. That could be a major positive for patients as they -- as we are looking into how can I maintain my weight loss and still being able to enjoy food once in a while. So that's one thing.

And then I think the whole you can say, triangle or the whole connection between liver, heart, kidney and so on, we cannot underestimate the potential from a prescriber perspective. If you have a molecule that truly get fat out of the liver more than the current molecules, that's a major reason for getting on a product like this because you could easily envision that you will have significant more health benefits than just looking into the weight loss.

And the key differentiating aspect, I suppose, for survodutide is going to be its potential in MASH. What's your current thinking in terms of the size of the MASH opportunity? And with that, how common is the screening of obese individuals for the particular condition?

Yes. But I think this is going to be one of the most dynamic markets as we look into it. Remember, there's not -- there's been 0 treatments available a few years back. Now we have the first 2 approved in U.S. medicines to address the MASH patients. And it's not -- it's seen across any other therapeutic area. When we start to see new treatments coming in, you will also see very different physician behaviors and focus on these diseases.

And the fact is that MASH is the most underserved consequence of obesity today. It is scary to think about it because at least in my book, probably the liver is one of the organs that can survive the longest when it's metabolically challenged. That means it's not a problem if you get -- for very few patients, it will be a problem if you become obese when you're 40.

But if you live with obesity since childhood, at one point, if you are disposed to liver disease, you will get to end-stage liver disease. And that's a very serious situation to be in, which leads to transplantation today.

So I would expect this market to change a lot as we start to see molecules that make a significant clinical -- has a significant clinical impact on the outcome. In particular, if Boehringer can demonstrate the effects also in F4 patients, you will see a complete change in this market.

On the diagnostic end, as Boehringer put it, it's -- for many physicians, I think it's enough just to be educated that we have 75% of obese individuals who have excessive fat in the liver, and I think it's close to 40% who actually have some degree of fatty liver disease. If we start to talk about that, so we don't just associate obesity with type 2 diabetes, but actually perhaps the more prevalent situation of fatty liver disease, why would you not take a product that has more potential to address that condition where there's no treatment. And that's -- so I'm not sure we need to change the diagnostic situation. It's more just the notion that a lot -- there's a high likelihood that the patient that sits in front of you actually have a liver condition.

And towards the end of last year, you took the decision to pause the development of dapiglutide. That was going to be an asset not only offering weight loss, but also addressing inflammation. How are you thinking about the path forward for that asset? Is that still something you could seek partnering opportunities for?

Of course, it is. I mean it was -- it is one of the most difficult decisions to close programs where the data is actually great. But we took a mature view and took a step back and looked at the situation from a commercial point of view as well to say, okay, it looks great. The weight loss that we can expect is probably going to be pretty similar to what other modalities can provide. And the clinical benefit on inflammation is something we can only demonstrate very late into the launch on outcome studies.

So how are we going -- when are we going to recap the investments that are going into this program. And it's just again, it made us decide that we can actually spend our money much wiser into the next wave of novel modalities rather than trying to build yet another GLP-1.

I do personally think that GLP-1s will continue to play a role, but I think we have also seen the deficiencies of the GLP-1. So if you truly want to address the obesity pandemic, we need to move on into different modalities. And we don't want to be in the camp of undifferentiated molecules. We actually want to develop molecules that makes a true difference, a clinical relevant difference for the future.

And at your CMD, you also highlighted ambitions of further developments within the amylin class, the development of a once-monthly amylin and oral small molecule. Over what sort of time frame could we expect to see these innovations? And do you think that in the format of an oral considering what we've seen from GLP-1s, could the tolerability benefits of an amylin be maintained?

Yes. So we have for some time been -- as you can probably imagine, we -- when we took the decision to lead with petrelintide in building the new -- the story around petrelintide and amylin as an alternative to the GLP-1s. We also made firm commitments into our research engine to continue to build leadership in this space. And it's early days for amylin biology.

We are now looking at the first wave of innovation in the clinic. And of course, we have invested also in second and third waves. And part of that is to make what we would consider true once-monthly molecules. We are not in the camp that is trying to force a once-weekly profile into a once monthly. We think it's like playing with fire. Others are doing it. They might be successful, but we just have to remind people that we are playing with very potent biology here. So that's not what we are focusing on right now. We are trying to actually solve first for the PK before we then pursue that.

On the oral, I think it's in my personal belief is that all opportunities for amylin are more attractive than for the GLP-1s because of the tolerability profile. So people will actually get the experience that they're looking for. So of course, we are also active in that end. And then we are active in other considerations for how to expand the amylin franchise leadership that we think we have today.

And with that, we're out of time. Thank you so much for joining us, Adam.

Thank you.

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 exactly -- almost exactly 2 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 stand-alone therapy for weight management.

A lot of things have happened in the last 2 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 reinforced many of those perspectives we shared on that day 2 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 interest 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.

[Presentation]

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 health care 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 health care 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, a more effective way of transporting the millions of people in the future.

Great true innovations requires able 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 2 pillars: number one is to maximize the value potential of petrelintide, what we believe is the best-in-class potential amylin analog, and that growth will allow us to establish 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 stabilization scale problem. We now have more than 1 billion people living with obesity worldwide, and is 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 of society. If we don't do something about this, our health care systems will face significant challenge 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 real world experience that 10% to 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 show us that many people struggle to stay on GLP-1. And if you only treat 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 lose their weight. So that is what Zealand is about. That is about truly addressing the health care crisis that follows long-standing 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 fill 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 stand-alone 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 CT-388, then we have opportunities for patients who want to lose the most weight, so the most morbidly obese patients or people with obesity who lives 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 health care providers and for society, this partnership also have 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 a very strong manufacturing and commercial infrastructure that Roche brings to the table.

It will also -- the 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.

[Presentation]

So 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.

And 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 5 times over the coming 5 years as compared to the investments we did in the past 5 years. So it's a significant step up of our research investments.

We will start a Boston -- cutting-edge Boston research hub, which will match what we have in Copenhagen. This Boston site will focus on automatization, AI, machine learning and novel chemistry approaches. So it will be a complementary side 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 a 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 5 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 side. And then as we approach the next period, we will expect to see survodutide being launched by our partner, Boehringer Ingelheim. 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 launch pad 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 5 years is that we will stay true to our DNA. We will continue to be an agile, quick and powerful organization.

We'll 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 is 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 ask 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 best-in-class potential for not only managing obesity, but more specifically in the mass 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 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 on this world with the first opportunity to actually seize and maximize this metabolic moment to do something about what we consider the biggest health care challenges 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. Where I want to focus today is really about bringing you the perspective 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.

So let's first start with the vision you just heard from Adam, our commitment for 5 launches in 5 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 MASH 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. And our crown jewel, you'll hear it a lot, but petrelintide is our crown jewel. It provides us the launching pad to grow Zealand and really change the 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. And 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. But what's alarming to see is what's a peak into our future, and that's about the children in the United States.

Right now, a little bit over 1/3 of the children in the United States suffer from obesity and are 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 want to call out 2 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 a 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 than it is today.

Now this epidemic that we have in front of us and our greatest health care 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. Well, it's also important to note is that 4x 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 long period -- 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. It's about magnitude of weight.

But that doesn't address all the needs of these patients. And when we think about it, that'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. And 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. And those 2 go hand in hand. And 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. And when they add new products and new classes, it expands the treatment segment. And that's exactly where we are today. We're dominated by one class of therapy, that's GLP-1-based therapy, and 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 is starting to shape itself, and shape itself with 2 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, and 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 of the responsibility back to the consumer.

So we talked about comorbidities. We know there's a significant overlap between obesity, overweight and comorbidities. Tends to gravitate to 6 core areas. But we see how much overlap there is between the 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 MASH.

And when you take a look at where the overlap occurs, so here you can see the comorbidities. On the right side, probably 2, the cardiovascular as well as type 2 diabetes and even CKD, they have a significant overlap. And it's -- they're extremely important. But you have to take note of where the 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 1/3 will actually suffer from the more severe side of it, which is MASH.

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 2 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 us 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 9 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 will bring new prescribers, just like the hepatologist in MASH.

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 -- are 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? Has a focus in primary care. But what's more important, they are the drivers of a lot of decision. 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 have 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 the 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 2/3 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 3 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. And then it's the emotional side, it's that confidence. That leads to engagement and the strong willingness to pay. And 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. The 25 is the next threshold. That's a very one-dimensional and near-sighted 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.

And turning to some real-world data. The real-world data doesn't move us from what people desire to the behavior. And here, you can see that the vast majority of patients do not escalate their therapy doses. They never reach the full maximum value of it. Part of that is due for 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 3 months. And knowing this is a chronic disease, you'd expect retention, but you have 80% of the people that discontinue within a given year that never realize that full benefit.

But what you start to see here is the 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.

And you may be asking, why are they stopping? The #1 reason people are stopping is because of adverse events. Nearly half of the population 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 in 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 MASH. But we're not done there. We've gotten more to bring forward, and Utpal 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 in the marketplace, how it's evolving, how it's ripe for disruption and innovation. Well, 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, a very, very pivotal time. We're 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, coco, 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 and 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 for this approach, which is a very focus 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?

It's my pleasure to introduce the Clinical and Scientific segment of this afternoon's discussions in the 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 field of metabolic medicine, diabetes, obesity and other metabolic diseases.

So Carel, welcome back, and please lead us on the discussion of survodutide.

Well, thank you so much, and it's a great opportunity to be here. And so I work as a commission scientist and so I cut my teeth over at the Hammersmith originally doing a lot of the person demand infusions of these peptides. So I think of them in a different way because we sort of lived the dream. But I want to bring up this painting that hangs at the London Gallery at the moment of Joseph Wright of Derby. And what you can maybe see over here, here is the Zealand scientists discovering survodutide. And you guys can see yourself because that's you up there with the pen making notes of today, and you can see your customers looking at you, they're looking to you for advice.

So 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 your misspent use to actually infuse this natural hormone, oxyntomodulin, into humans for the first time. And I remember when we injected these hormone, who should only has a half-life of about 2 minutes, naturally made by the gut, you make it every time you have a meal. And when we do bariatric surgery, we increased it by more than threefold. So this is a natural hormone that your body has.

And when we infuse it into humans, we had this incredible experience where people just say, "I don't feel hungry anymore." They consumed about 1/4 or 1/3 less food even in the short term but of course, there was an infusion. And then what we couldn't do it without an infusion or constant infusion. And when we ran those studies, we also saw an increase in energy expenditures. So it's the only gut hormone is 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 2 for the price of one. And this has been sort of the whole principle of building survodutide, which is a 29 amino acid peptide, is that they behave like oxyntomodulin. And therefore, you get all the benefits of buying in the GLP-1, but you also get the benefits of buying the glucagon receptor.

Now what are those benefits? There's direct benefits and there's indirect benefits. The direct benefit 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 -- 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 obviously but we also talk about the GI effect and we're 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.

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're buying 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, 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 and 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 Valkyrie, 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 as the curves going down. So we are no where near NADA 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 NADA 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 game, right? Because it turns out, patients come to me and you're going to hear, they come to lose clinic in the same way and they come to us for weight loss. And then we start them on these great drugs, and yes, they get 20% weight loss, and then half of them stop the drug within 6 months.

Why is that? 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 we use the 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 improvement in blood pressure. And because that is binding the GLP-1 receptor in the kidney and we also see some weight loss and 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 us reassuring that the thing is doing exactly what it is supposed to do. But what this also helps 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 the 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 are because they can't tolerate the side effects for the rest of their lives. And we always talk about mild, moderate and severe, and we say, this is true. It's absolutely true. That survodutide, there's no extra additional side effects that you wouldn't have seen in the GLP-1 class. Remember, survodutide is a new sort of class of drug because it's a 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 changed 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 noninvasive 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-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.

So 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 has 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, that'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. The best that we could do is slow it down. Now what this shows is anything in biology that goes in that direction can also go in the opposite direction if you change the metabolic milieu. And that is what these drugs are doing. So this is not just an indirect effect because of the way it last, this is also a direct effect because oxyntomodulin, survodutide binds as the glucagon receptor.

So let me sort of put next to each other the 3 major studies in this space. And of course, as always, you have to take this with a health warning because these studies were not the same studies, it wasn't the same patients. But these are big studies. And you know, we actually are quite comfortable. And that's why 2 of these on the left-hand side and in the middle have actually made it now to approval through the FDA.

And you can see over here, what I'm showing you is the number of patients who start with MASH and with liver fibrosis. And then we can show you the improvement 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 combined 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 the 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 benefit 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 these top level of these medications without the side effect. 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 health care 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, and I'd be delighted to talk to -- with David again and listen to his next talk. Thank you.

Description of the status of the survodutide clinical program. Carel will rejoin me with Adam for our initial Q&A. So 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 totally responsible for the development and commercialization efforts. But as Carel mentioned, the discovery of survodutide has its roots in what we at Zealand have done. And as Utpal 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. And 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. So Carel, thank you for that truitive force.

The SYNCHRONIZE program, which is the name given to the development program for survodutide for the treatment of the disease of obesity is 1 of 2 incredibly exciting data catalysts that are energizing the efforts of Zealand and obviously at Boehringer Ingelheim in 2026. The top line results from SYNCHRONIZE-1 will be available in the first half of 2026 and we anticipate the presentation of those data at near-term Scientific Congress following that. Remember that this is a 3-arm trial testing, what I'll call the mid and higher dose than was actually tested in Phase II.

Carel leads as principal investigator, SYNCHRONIZE-1, one of the two key overweight and obesity treatment interventions for the CVOT program. Important to note, the demographics, which Carel 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 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, SYNCHRONIZE, for the evaluation of survodutide in the treatment of overweight obesity is large and comprehensive. They will include a near total of 7,800 participants in the entire trial. As I've already mentioned, SYNCHRONIZE-1 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 pave 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, a 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 Carel 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 the obesity is one that I think is only now becoming widely recognized. 3 or 4 individuals living with overweight or obesity have liver disease of some form, 1/3 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 account 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 Carel 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.

And 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, LIVERAGE cirrhosis is not simply a measurement of the progression of liver disease, but an outcomes trial, with 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 a Phase I study that was completed in a population with cirrhosis. All of these were data presented last year at 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-MASLD, which is an intervention for the treatment of the disease of obesity, but in individuals with coexisting MASLD 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 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 treat the heart component that Carel described. So this program and the preexisting comprehensive Phase II data give us the confidence that this deliberately designed biased to GLP-1, 8:1 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 the schedule. So I'd like to welcome Adam Lange back up with Adam and Carel. Please join us.

Carel and Adam, please join us. So before we move on to the next section on amylin and petrelintide, we would like to do a Q&A focusing specifically on the survodutide program and topics related to that. [Operator Instructions]

Thomas, you can go first. I saw your hand.

Thomas Bowers from ECB. So just on survo. So the commercial landscape and also recent pricing dynamics, so how should we think about optimal positioning for survo? Is there sort of a credible path here to -- or for the program to maybe more evolved into a premium-priced MASH therapy rather than targeting obesity?

You want to go?

Yes. So of course, this is a program that is being developed and commercialized by Boehringer, and we will 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 Carel 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 talked 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 resmetirom in the U.S., which obviously does not compare at least in terms of magnitude of effect, show the desire for treatment in this space, which our BI colleagues clearly recognized. Not to forget too that mazdutide 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 pharma guy perspective, clearly an unmet need.

And maybe Carel can comment on what you're seeing in terms of the need or the desire to fill this position in your clinic?

Yes. And I think the problem is that people have not been diagnosed with liver disease. So when you actually come into a system, be it primary care, and primary care doctors are really the ones driving the system. When they now suddenly make a diagnosis and say to you, "it turns out, now with our noninvasive test, 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.

Yes. Let's go to the next one. Kirsty, go ahead.

Kirsty Ross-Stewart from BNP Paribas. So one for Professor Le Roux on the receptor chemistry of survo. Your slide mentioned the potency, was kind of 8:1 on GLP-1 to glucagon. We've obviously seen GLP-1 only receptor agonists have a benefit on fibrosis, but without the glucon mechanism. So can you elaborate on the benefit of also hitting the glucon receptor, but also whether you believe that kind of 8:1 ratio is optimal and actually whether that will kind of confirm meaningfully differentiated effect on the liver disease versus a pure GLP-1 agonist?

So 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 upside of glucagon, but you don't -- we do not see any of the downsides of glucagon, right? So 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 therapy, is that is fibrosis appears to be weight loss-dependent. That means you've reduced the adipocyte MASH in the liver and therefore, it allows the liver to recover, right?

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, right? But it's not pulling the wagon on its own because it has the benefit of GLP-1. And I think this ratio was just designed -- specifically designed, appears to be an optimal ratio.

Yes, we had a hand over here.

Xian from UBS. Maybe the first 2 questions, please. The first one, maybe just a follow-up on the previous question is that you basically mentioned glucagon, having this glucagon component, you have extra liver benefit on top of the normal GLP-1. So 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 in 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?

So maybe if I take the last one, so the F4 fibrosis for patients who have cirrhosis in our compensated cirrhosis, I'm not a clinical investigator in that study, I'm the clinical investigator for the SYNCHRONIZE-1. So I'd give you an opinion as somebody in the field rather than an investigator in that study.

I think it is ambitious, right? 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, right? 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 with an all-cause mortality is not only driven by reduction in cardiovascular events, it's also driven by a reduction in infectious states. 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. It's -- they die from infection, they die 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 going to come back and say, "For the first time in my life, I can play with my children." Well, 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 the quality of life with these, and I would expect the same to come out with 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, right? But what we do, do is we make them healthier and we make them more functional. And that's what drives quality of that. So I think those are why I think it's a good program and that's what I would expect to see.

Yes. A quick comment on the glucagon component. I started my ill-fated metabolism career studying the 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 and 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 long history that, that low dose glucagon exposure as the solutary effects.

All right. Thank you, David. Thank you, Carel, and thanks for the question, Xian. I think we have time for one last question before we need to move on. So Jacob, go ahead.

Jacob Mekhael from KBC Securities. I have a bit of a technical question, if I may, since we have the scientist 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 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?

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 and when I speak to colleagues at Zealand and others, I say to them, almost like the regulator is the easiest part to get across, right? 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. So -- but I think we are in that ballpark even on an intention to treat analysis.

Thank you, Carel, 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, introduction of the external speakers first.

And my role is 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 science of amylin. Jonathan and I worked 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 Lou Aronne will join us again. Thanks for rejoining us from 2 years ago. Lou is the Weill Professor of Clinical Medicine at Cornell Medical College. He has spent nearly 4 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 Jon.

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 1900. And in 1987, two independent research groups clarified 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 decreases -- it slows the rate of gastric emptying from the stomach to the small intestine, and it reduces postprandial glucagon excursions. These properties led Amylin Pharmaceuticals to develop a stable non-aggregated form of amylin, known as pramlintide, for use in insulin using diabetics. And in type 1 and type 2 influencing diabetics, amylin agonism were shown to meaningfully reduce HbA1c levels and to decrease postprandial hyperglycemia, enabling these patients to lower their total daily insulin dosage.

The FDA ultimately approved similar 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 insulin using population that would typically gain some weight. And that led Amylin to begin exploring pramlintide as a monotherapy for diabetes in obese, nondiabetic individuals.

And in short-term clinical studies, pramlintide treatment were shown to reduce 24-hour caloric intake, reduce meal size and improve binge eating scores. And 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 occurs to restore responsiveness to leptin. And a proof-of-concept study, where subjects took the combination of pramlintide and metreleptin may achieve double-digit weight loss, which at the time was considered quite impressive.

Around the same time, GLP-1s though, we're 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 historic winter of amylin agonism continued until the advent of long-acting amylin analog came to light.

So Cagrilintide– demonstrated significant weight loss in individuals with overweight and obesity, and the pramlintide, which also had a very favorable gastrointestinal tolerability profile. And finally, the fixed dose combination of a long-acting amylin agonist and a long-acting GLP-1 agonist in Cagri-sema 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. So amylin is post-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. And 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, and all modern long-acting amylins have incorporated modifications in this region.

At the other end of the molecule, there is a disulfide bridge between cysteine 2 and 7, which are absolutely necessary for proper folding of the molecule in 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 need 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 amyloid 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 1 of 3 receptor activity modifying proteins to form either the amylin 1, the amylin 2 or the amylin 3 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 week agonist at the calcitonin receptor. But in the presence of amylin 1 and amylin 3, potency is quite improved.

Pramlintide is more of a pure agonist at the amylin 1 and amylin 3 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 agonist 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 adrenomedullin-1 receptor, amylin agonist did not have meaningful activity at these receptors and are more than 1,000 foot 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 migrated attacks and activating the adrenomedullin-1 receptor may carry some oncogenetic risks.

This slide summarizes physiological and pharmacological effects of amylin receptor activation spanning decades of research across multiple laboratories. So 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.

So 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 its activation of this upstream pathway that modulates leptin sensitivity, energy expenditure and favorable effects on body composition.

The effects of amylin to decrease -- to slow gastric emptying and decrease glucagon are also mediated by 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 has deepened our understanding in the multihormonal regulation of energy homeostasis. And briefly, you have short-term hunger signals such as ghrelin -- short-term hunger signals such as ghrelin secreted from the stomach; short-term satiety signals like pancreatic amyloid; and anorexic peptides such as PYY 3-36, 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 value. But under conditions like obesity, it becomes disregulated, and much of this can be attributed to our prevailing levels of leptin and its effects upon the brain.

So leptin is produced by -- secreted by adipocytes in direct proportion to your adipose stores. Let's consider how 3 different levels of leptin are going to impact your hunger and your body.

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 ] and mice or various leptin mutations in humans was associated with a market and an unchecked increase in appetite, which has led to massive obesity in these individuals and metabolic diseases. Metreleptin replacement therapy rapidly reversed effects on body weight and metabolic disease, and was considered to be life-saving in these individuals.

Now individuals that have produced 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, hungry signals, where 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 volume. 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 the 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 multi-hormonal 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 experienced 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 amylin-treated animals maintain or even have a slightly elevated metabolic rate relative to vehicle controls.

And finally, when we measured hypothalamic satiety signals known to be directly downstream of leptin, we find that signals like proopiomelanocortin are twofold higher in the amylin treated group relative to the vehicle group. So collectively, all of these are hallmarks of improved leptin signaling, and they suggest that amylin could be a leptin sensitizer.

To formally test this hypothesis, we conducted a combination study. So in this study, there were 4 groups of rats. One was treated with vehicle, with amylin monotherapy, with leptin monotherapy and one with a combination of amylin 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 hind brain. 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.

So to test whether these effects would translate into the clinic, a Phase II proof-of-concept study was conducted. And the design of this study was as follows: during a 4-week lead-in period, subjects were treated with pramlintide monotherapy, and 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 pramlintide, switched to leptin monotherapy or received the combination of pramlintide and metreleptin.

What you see here is that during the lead-in, they lost about 4% body weight. And in the monotherapy arms, weight loss began to plateau at about 6% to 7%. By contrast, weight loss in the pramlintide plus metreleptin treatment group experienced more rapid weight loss and they ended up at around 13% after 20 weeks of treatment and weight loss did not appear to have yet plateaued and was statistically significantly different from either of the monotherapy arms. So when you look at this figure on the right, compared to -- and the figure on the left, you see that amylin agonism restores leptin responsiveness in diet-induced rats and in humans.

So we've heard about GLP-1 a number of times in today's presentation. And 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. So amylin is a powerful meal termination or satiety signal.

So with amylin administration, what happens is you consume the same number of meals each day, but the size of the meals is much smaller, owing to a rapid onset of flowness, 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 has -- 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 2 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 poststama, leptin pathways, more 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 better -- 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-1s.

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 -- so 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.

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 a 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 okay. 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 a IIb trial of pramlintide in people with obesity, but not diabetes. And you can see there was a 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 3 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 other -- to appetite suppressants that were available at the time and some are still available. And we found that we got additional weight loss. So again, we could have been where we are now, close to where we are now a long time ago.

So 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. And this is a very reasonable weight loss and far better than what we saw with pramlintide. And 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, and 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 1 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 1/3 -- less than 1/3; and constipation, somewhat less.

And if you look at what stops people from taking these medicines, I would say that vomiting is the #1 problem. Like 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 social -- 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 whether 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, 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 cagrlinide 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 cagrlintide, petrelintide and others will move forward.

In the trials of cagrlintide and semaglutide, we see that there is an improvement in cardiovascular risk factors. We still don't have the CVOT that we have with semaglutide alone. But one interesting point is that not only do we see an improvement in systolic and diastolic blood pressure, but also a reduction in pulse.

And 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. And you can see that with semaglutide in this trial, there was an increase of about 3.5 to 4 beats per minute. But with cagrilintide, it was lower than seen with placebo, and that's because it doesn't hit the SA node. That's number one.

And number two, there's greater weight loss, and that tends to reduce pulse. When we look at the change in lipids, not that big a change, but certainly no worse. And when we look in the reduction 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, eloralintide, Phase II trial from Eli Lilly and saying that it reinforced the potential of amylin as a stand-alone therapy for weight management, I think, is modest. When you -- 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. And now look at the incidence of the adverse events, right, nausea, vomiting, diarrhea, constipation, fatigue and alopecia.

Now look at in the dotted line, the eloralintide 3 milligrams, producing 12.5% weight loss, right? So 12% placebo subtracted weight loss -- and you'll see that the side effect profile is identical to placebo, identical to placebo. There's -- 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. But 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, like 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 be -- 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 of the peptides. And then finally, on the right side, again, 79% female fail, BMI of 40 and dose titration over 8 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, if you look at the weight loss here, it is in the same range as the GLP-1 and GLP-1 GIP category, a 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. And here, we have weight loss over 32 weeks with cagrilintide versus semaglutide from an earlier Phase II trial in type 2 diabetes. And you can see greater weight loss. And 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. And in fact, when we look at this comparison, and this is not a head-to-head trial. On the left, we see weight loss with semaglutide in the diabetes trial, the STEP-2 diabetes trial. and the mean body weight at baseline was 100 kilos. So this is the obesity and type 2 diabetes trial. And you can see that with 2.4 milligrams of semaglutide, there was about 10.6% weight loss or 7.5% placebo subtracted weight loss.

And on the right, we see that Cagri plus Sema, we see 15.7% weight loss, which is very, very robust. So that's a 12.5% weight loss, which is right there with tirzepatide. So this is, in my opinion, maybe a little bit more than tirzepatide when you try to read between the lines.

So really -- I don't want to call it transformational, but it is transformational because one of the issues -- I mean, Dr. Le Roux 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, right? And in hypertension, 8 categories; diabetes, 8 categories; hyperlipidemia, 8 categories; us, 1 category, maybe it's 1.5 because you have GLP and GIP, but that's no way to treat people where every single person gets the same treatment.

And 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% to 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 is 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? Like 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, here 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, so in roughly 45 minutes. Thanks a lot.

[Break]

On behalf of our leadership team, as Adam said, it's a pleasure to continue this discussion, particularly focusing on petrelintide, I want to acknowledge we've got a number of our Roche colleagues from our steering committee and the alliance here with us. It's very nice to partner up both on the messages, but also present at Capital Markets Day, the things that we collectively embrace to set the foundation for petrelintide as a foundational therapy.

So in the afternoon session, we'll focus on the petrelintide program a bit, and then we'll turn it over to Utpal Singh to talk about our innovative and evolving research strategy and then Q&A with all of us at the end.

But I want to harken back to what Adam led with, and that's our desire, particularly with the petrelintide program and the petrelintide 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 a 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 analog petrelintide with other centrally acting agents like sibutramine, et cetera.

So 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. And 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 2 diabetes, there is no single foundation. It takes multiple stones to establish that foundation. And we believe petrelintide and amylin-based therapies can be that next foundation.

So 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 John Roth alluded to. Receptor engagement is imperfect but still evolving science. And as I often argue, the balanced calcitonin amylin-1, amylin-3 receptor agonism is intentional.

The body rarely puts receptors into systems that it doesn't need. And the hypothalamus, the hind brain have all 3 receptors that we believe are critically important to leveraging the pharmacologic effects with petrelintide. So that balanced agonism is critical. Obviously, the physical chemical 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 cagrilintide, 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.

Petrelintide at its very low doses, 0.7 milligrams in this single ascending dose study resulted in a 3.2% weight loss 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 6-week trial of 0.6 milligrams and 1.2 milligrams in Part 2, 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 2 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 milligram and 9 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 2 multiple ascending dose, but also the Phase II/III trials for cagrilintide and Eloralintide 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 in 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 readout 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 readout in the first half of 2026. Obviously, there's a lot of activity, as Adam alluded to, in our '26, '27, '28 and beyond time frame. 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% to 70% of weight-lowering therapies are sought by females, not males. Here, this gives us 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 Eloralintide high-dose initial exposure data and as 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 Carl 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-2, we expect the top line data from this study in those with overweight and obesity and coexistent type 2 diabetes in the second half of '26.

And a look forward in partnership with Roche to the comprehensive Phase III program with a clear focus, first and foremost, on the execution of the Phase IIIa 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 IIIb. I was stopped at the break asking about Phase IIIb plans. First and foremost, IIIA and then a 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, CT-388. 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.

So 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.

So I can't begin to say anything more than 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 2 years ago when we said 15% to 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% to 20% weight loss is currently the sweet spot for the vast majority of those seeking weight management. And 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 CT-388.

So 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. So 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.

This is Sushila from Kempen. So 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 amylins?

Yes, 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. John Roth in his discussion showed some of the early data with pramlintide and rat amylin achieving the same thing.

I think for us, given what's been observed with CAGR, we're doing much more careful MR assessments in ZUPREME-1. This would be a value add, a nice to have and certainly 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 would say, even with INHBE activin, 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 clean 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.

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. Roux said earlier, so it seems like the tolerability issue should be very minimal as long as the titration is low enough with the dosing reduction.

So -- and then the second one will be like the amylin, the satiety enhancement as you emphasized in the presentation versus the appetite suppression just like GLP-1s. But again, in the CagriSema REDEFINE-1 study like in the appendix, it seems like petrelintide showed generally similar incidences of decreased appetite versus semaglutide.

So I think I'm just curious, first of all, like how clinically meaningful or relevant do you expect this regulating male size to be for real-world positioning for the amylin-based therapies? And what is -- how should we size the true commercial potential for amylin class over the next decade?

So the only way to know is to do the study, right? And so when you -- I think that right now, when you look at how we're treating patients with GLP-1s, we're kind of over suppressing their appetite and their interest in eating food, and you've all heard of that.

Examples of that where people lose interest in -- we have people who are -- they 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 compound. So I think that it will be very interesting to see if we can change that. Do -- 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 in 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 med returns 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 a little bit aligned 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, 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 get -- you have achieved your weight loss, you are less motivated. You will accept less.

We know that from any other weight launch program in history, once you let go of the patient, they will regain weight, most of them and they're back to square. And that weight cycling is not healthy. And 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 there 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, Yihan, for the question. We have a question here from Lucy.

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 -- and is it higher when in the latter where you aren't being coached through the tolerability? Or is that primarily the consumer base?

And 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 both 2 on the market and one of them is being marketed by Lilly?

So if I should just start by addressing your first question, and you may have some other data or the data available, but I would say I'm not sure we have those data that brings down that experience between a very skilled prescriber versus a patient that achieved 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 Carl, 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 Carl 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. So -- 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. Lou, 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 2 or 3 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 ones to prescribe. Isn't that -- I mean, you guys don't do that card, 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 the people -- I see a number of the people on the marketing team that 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 was 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.

Yes. We'll let you corner, Martin 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 Eloralintide data, the rush to high dose clearly sort of blew up in our face, meaning going on 6 or 9 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 IIIb studies where we can bring it forth and say, here's the value.

I think of one other example, which is the thiazolidinedione, rosiglitazone, and 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 help 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.

Thank you, Lucy. Any additional questions, Rajan over here, if we can get a mic.

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, there was a fatigue signal that seemed to emerge. Do you think that there's a risk that, that's a class effect? And specifically, could that be an effect with petrelintide as well?

Maybe I can just start and hand over -- 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 fill 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 on to 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 have talked about today.

And I think to your comment about head-to-head and the others that is part of that Phase IIIb excitement that we share. But again, we're going to focus on IIIA and get this to patients and providers. I think Lou, he cringed when he said KOLs are no longer important. I let get the last word. So Lou...

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 3 ounces of chicken and 3 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're able -- 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.

And I think it's important that the weight loss limits 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.

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 were relatively high rates of fatigue with petrelintide. We haven't seen that signal or that imbalance relative to placebo. And I'm quite confident that's the same with petrelintide in the REDEFINE-1 trial where Lou presented clinical data from. I think we have time for one last question before we need to move on. Kirsty, go ahead, last one.

I'll be quick. Kirsty Ross-Stewart from BNP Paribas. Just on the time lines, it showed that you're expecting Phase III data for the petrelintide program in '27, '28. So can you confirm that you'll be able to launch in 2029 at the earlier end of your kind of '29, '30 estimation? And can you also just provide a quick comment on -- I think the Supreme 2 time lines have shifted to 2H next year from midyear. Just what has driven that change?

Yes. 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 this specific year right now, but '29 is, of course, a possibility. And on the Supreme 2, David?

Yes. 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 time lines.

All right. Excellent. Thank you, Jens, and thanks a lot, Kirsty, for the last questions. 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 away.

Thank you, Adam. So super excited to be here, guys. The last 20 years, almost 20 years in my career has been synonymous with Lilly. And I have to say there are some key learnings about the discipline in target selection, following your conviction, not following like [ lemmings ] your competition like [indiscernible].

But the other part was about speed being the currency within the biotech ecosystem. So after having spent 2 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 5 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 this 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 we'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 expertise we have in medical with the likes of David Kendall, who has 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 into therapeutics as well as reverse translation, taking data from the clinic and taking 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 5 approvals in the next 5 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 5 approvals in the next 5 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 and an aqueous solution so that patients in the cases of emergency hypoglycemia could be administered medicine directly without having to do an extemporaneous prep -- 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 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 auto-injector. 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 formulatable 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 insight that we have, we're going to redirect that to probably one of the biggest health care challenges in the world. So we're all talked about obesity. That's a 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 South Asian descent, this is something that in my family is an issue, right?

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 2, 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 2 weeks, right?

The reality shows to do that, right? 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 3 prongs. And we're going to go through each of these 3 prongs in more detail to tell you about the concepts 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 Carl 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 on improving peripheral metabolic flexibility and capacity and think 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 -- the first pillar, you guys have seen this graph.

And 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 have done with GLP-based therapies is taken one of the pathways and hit that really hard. So if you take a step back and use an analogy of a sound equalizer, right? What we have done with current therapeutics is we 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 be -- live in a feast and famine cycles. But obviously, with modern environment, with constant surplus, that delicate balance of how insulin and leptin work in the brain have created a disconnect such that you have hyperinsulinemia and you also have very high levels of leptin. So the brain, the hypothalamus in particular, as John talked about, becomes resistance, resistance, I should say, to a lot of the peripheral signals.

Our goal are to develop therapeutics that fundamentally increase the sensitivity in 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-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 immune inflammation and immune response. So our focus is to directly target the brain, and you can imagine the kind of technology 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.

And finally, focused on our central -- focused on our peripheral metabolic capacity and flexibility. Now I'd like to use this analogy of an engine. GLP-based therapies have shrunk the engine, and that's helpful, right? 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 the 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 physiologic levels. With GLP-based therapies and all the clamp 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 does your GLP medicines do? The GLP therapeutics start reducing the overall energy. You start seeing reduction in muscle -- lean muscle mass loss. That's significant. That's reducing the overall metabolic -- peripheral metabolic capacity. Typically, muscles take in about 70% of your overall glucose within your body.

And if you start shrinking the amount of muscle, that's fundamentally not a good thing from an overall metabolic capacity standpoint. And finally, the adipose tissue, right? So far, adipose tissue has always been thought of as a mechanism just to store energy, but the reality is they are far more complex. You're starting to see some evidence with the current therapies that you reduce the adipose tissue. But what you haven't done is increase the adipose insulin -- you haven't fundamentally remodeled the adipose tissue or changed this insulin sensitivity. The only therapies that have ever shown to do that were TZDs ages ago, which had their own set of challenges.

So 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 a 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 metabolic dysfunction that have a BMI less than 25.

So as you think about our 3 pillars, our hope is that by hitting these 3 between the cross-tuning 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 improved 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, right? The first GLP-1s were approved on 2005. And almost every 4 to 5 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, require 2 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 in the DPP-4 resistance was important, half-life extension, certainly oral delivery technologies for oral sema using SNAC-based formulations. And 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. But for a number of reasons listed above, there was actually about almost a 2.5 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 and some of them was really around the fact of not recognizing that this biology has market potential.

Those efforts that we've invested in and the first that we've had on medicine creation have also resulted in some pretty interesting molecules that we have in the clinic and will go in the clinic. KB1.3 is the potential to be a pipeline in a molecule where we're directly targeting over expression in memory cell driving, 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 3 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 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 the expanding the toolbox and a 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, simplified supply chain and just a broader acceptability.

But in addition to that, we're also focused on intentionally designing long-acting amylins. 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 a small molecule medical chemists, 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 human body, 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 that interact with the -- 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, right? Your receptors are constantly wiggling around. Your protein is wiggling around. You have to understand how the 2 come together.

And the dynamics is where the answer is at. So 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 to a new pocket to deliver you the type of activity that you wouldn't generally predict.

So you put all that together. And I think we have a pretty ambitious goals that we have set for ourselves. So with those ambitious goals, I think our physical reality also has to evolve. And this is why you see us making a communication around investing in Boston. But 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, 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. But in addition to that, we're also going to grow in Boston.

But to be very clear, this is not about adding more chairs or more capacity. This is not about just more numbers. This -- 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 2 of what I would argue the most thriving ecosystems in the world and bring the best of the 2 together to do -- 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 access. 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, to deliver at least 10 molecules into the clinic before the end of the decade. With that, what I'd like to do is introduce Henrietta, 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 vision, 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 2 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 a biotech financial discipline. And we have outlined 3 priorities for our capital allocation. So let's just look at what these are. Number one, we will invest to establish a leading multi-asset amyloid-based franchise, both in terms of R&D investments, but also commercial investments, as you heard Eric talk about today.

And these investments will, of course, mainly go into petrelintide monotherapy. But 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 have just talked us through the step change we'll do in research over the coming years. And 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, and 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. And 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 our finances.

We have automated reporting systems, all of this to ensure transparency, but also financial discipline across the company. And 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 glepaglutide 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 3 years while I've been here, and I can assure you it will continue to evolve over the coming 5 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, taking petrelintide through Phase II. When we look ahead, the share of petrelintide cost 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, the Phase IIIa, which is expected to finalize around 2028 and a continued Phase IIIb 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 in the 2030s. Based on the current plans, we expect the development cost for petrelintide franchise to peak by 2030. This is when we have completed the Phase IIIa, but also when we have, of course, ongoing Phase IIIb 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 here mentioned, by 2030, we expect to have more than 10 clinical -- new clinical assets in development. And in terms of research, this will be a step change. We have, over the last 5 years, spent less than DKK 1 billion on research. We will increase this fivefold. So in the coming 5 years, we will spend around DKK 5 billion on research activities.

This will allow us to be #1 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 our 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 can say, execute 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 U.S. and Europe.

So when you look at it, by 2030, we will have a balanced resource allocation between our obesity and inflammation development efforts and our commercial efforts that will support a Petrelintide launch, and we will continue to invest into our research activities. And as Adam just mentioned earlier today, we have very strong and committed partners in Roche and Boehringer Ingelheim to do this.

And 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 give 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. And in the short term, Zealand's 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 license 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 allow us to invest. And we will invest. We will invest to maximize the value of petrelintide 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 petrelintide and survodutide if you have 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. So I think we have one over here to start with. Jacob, you can go ahead.

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 yes, 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 is 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.

Thank you, Jacob. We have -- yes, Thomas over here.

Thomas from SEB. So firstly, just a question on the partnership you just announced this morning as well. So that platform, very early-stage company, no real disclosed partnership so far. So how did you validate that platform going into oral small molecules?

And then second question, just on the whole talk about leptin sensitizing. So I'm just wondering if there's anything -- any evidence for petrelintide that maybe both a stronger leptin sensitizing effects than what you see in -- with the other amylin potentially?

All right. Thanks a lot, Thomas. I think we will start with Utpal some remarks on the OTR Therapeutics collaboration announced this morning, and then we can get back to Lepton afterwards with David initially.

Yes. Look, I think on the OTR Therapeutics, we're really excited about the collaboration. I think if you look at their leadership expertise and their -- the capability 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 for leptin.

Yes. 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 Hakon.

Yes. Hakon Hemme from Danske Bank. And on the next era treatment beyond petrelintide, 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 Uptal, you can fill in and Henriette, you can add. 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 for the breakdown of our health care system. So you ask, can we only expect slight innovations in the next products that comes out. And that, of course, depends on the eyes that you look with.

If we talk about weight loss, the weight loss in Olympics, I think you can only expect slight improvements because we have already seen very, very deep and very fast weight loss. But where you can see significant breakthrough innovation is in how you address metabolic health.

And 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. And we think that wave of a step change for 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 the -- what we believe that petrelintide 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.

Yes, absolutely. And I will point you to my comments around the weight-independent insulin sensitivity. If you really think about the therapies that are out there from a truly weight-independent insulin sensitization, there really aren't many, if any, in 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? And 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.

So 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.

Thank you, David. I believe the second part of your question, Hakon, 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.

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 perceive the commercial opportunity. There was a clear differentiation into the market.

And I think this approach, both look 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. Go ahead. Xian.

Xian from UBS. So 2, 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 25 but actually have metabolism dysfunction. And 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 you -- 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, petrelintide 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're already seeing on social media people doing microdosing every 3 months or whatnot.

So what exactly constitute as maintenance? And how -- what will you actually measure in the study? Would it actually be very long-term study like 2-year outcome and things like that? What would you actually be measuring?

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 is 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.

And any thoughts with 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'll 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 is not stimulating insulin and exhausting beta cells, if you think about treatment 5 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 delivers 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 what Paul alluded to it, expanding and improving health span and Lou's comment about why should I wait until I 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 actually, I 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 find 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 intervention 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, I think we have time for at least another round of questions over here in the back, perhaps.

Callum from Berenberg. My question is around the petrelintide Phase III. You mentioned earlier, obviously, you need sort of 68 to 72 weeks to reach that idea 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 drug, do you think this gives you more flexibility around pricing compared to the GLP-1 assets?

Maybe I can start and hand over to you because I want to reiterate something we also shared 2 years back. When you sit with what we consider a crown jewel like petrelintide, 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.

So -- and this is how we will continue to push this forward with maximum focus and acceleration, but also life have taught most people, I think, that shortcuts may feel nice short term, but long term, they don't.

And 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 3 are part of the benefits of these extended programs, not solely the weight year. Again, clinical trials represent clinical trials, not clinical reality. We hope to gather as much as possible then use Phase IIIb once the IIIa 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.

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 petrelintide, 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 health care 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 NASH.

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 2 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 are going for, the product and the category that can make us move away from the weight loss Olympics, which only interest companies and some investors but not really the patients and not society because we need to get to doable high-quality weight loss.

That is what -- 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 2 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 is almost an unfair competition for others because we have all these data.

And that is what Uptal is committed to leverage now, also bringing in external innovation that can complement where we are the strongest. And 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 petrelintide, building out commercial infrastructure and doubling down on our research efforts.

So that is why we have so much confidence that we will deliver on this vision to redefine obesity for a new era. So with that, I hope you have had an interesting day, and we are here fully committed to maximize this metabolic moment.

And 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 health care space in decades to come. So thank you very much for attending today, and we look forward to future interactions.

[Presentation]

Good day, and thank you for standing by. Welcome to the Zealand Pharma Interim Report Q3 2025 Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, [ Adam Langer ], Investor Relations of Zealand Pharma. Please go ahead.

Thank you, operator, and thank you to everyone for joining us today to discuss Zealand Pharma's results for the first 9 months of 2025. You can find the related company announcement on our website at zealandpharma.com. As described on Slide 2, we caution listeners that during this call, we will be making forward-looking statements that are subject to risks and uncertainties.

Turning to Slide 3 and today's agenda. With me today are the following members of Zealand Pharma's management team; Adam Steensberg, President and Chief Executive Officer; Henriette Wennicke, Chief Financial Officer; and David Kendall, Chief Medical Officer. All speakers will be available for the subsequent Q&A session.

Moving to Slide 4. I will now turn the call over to Adam Steensberg, President and CEO.

Thank you, Adam, and welcome, everyone. The third quarter of 2025 has been a quarter of strong execution and continued momentum in our partnership with Roche. We achieved a key milestone in the petrelintide Phase II ZUPREME-1 trial in people with overweight and obesity, which put us well on track to report 42-week top line data in the first half of 2026. We are also rapidly approaching data from several Phase III trials with survodutide in obesity, starting with top line results from this 76-week SYNCHRONIZE-1 trial in the first half of 2026.

Meanwhile, we are gearing up to outline our path towards becoming a generational biotech company at our Capital Markets Day next month.

Moving to Slide 5. 2 years ago, we laid out our vision to become a key player in the management of obesity through innovation that address one of the greatest health care challenges of our time. Central to this vision was developing an alternative to GLP-1 therapies and to end the weight loss Olympics by focusing on the most important unmet medical need, a therapy that patients can and will accept to stay on. What excites me today is that Zealand and Roche has the potential to lead in the next class of drugs for weight management.

We are very confident in the profile of the petrelintide as a potential best-in-class amylin analog, supported by the clinical data to date and the last robust Phase II program currently underway. We are rapidly approaching Phase II data with petrelintide and Phase III obesity data with survodutide alongside an impressive Phase III MASH program that is well underway. I look forward to this next catalyst-rich chapter and to sharing more from these programs at our upcoming Capital Markets Day, where we will also discuss our intensified early-stage efforts to build a generational biotech company.

Let's turn to Slide 6. 6 months have passed since we kicked off our alliance with Roche. And I'm highly encouraged by the energy and commitment we have seen from both sides of the partnership. The agreement with Roche is more than just a deal. It's a shared commitment to redefine the future of weight management and to establish leadership in what could become the next foundational class of therapies. Last month, Zealand Pharma had the pleasure of welcoming Teresa Graham, CEO of Roche Pharmaceuticals to our offices for an engaging fireside chat about exactly this. I was also pleased to see Roche at their Pharma Day in September, conveyed to you their strong commitment to become a top 3 player in obesity.

This is the reason why through a highly competitive partnership process, we identified Roche as the ideal partner for Zealand Pharma and petrelintide.

Turning to Slide 7. Survodutide is licensed to Boehringer Ingelheim, a leading family-owned biopharmaceutical company with a strong legacy in cardiovascular, renal and metabolic diseases and a global presence across more than 130 markets. We're excited to see Boehringer Ingelheim potentially becoming the next major pharma company to enter the obesity market with a truly differentiated GLP-1-based therapy co-invented with Zealand Pharma. We were also highly encouraged by their strong presence at ObesityWeek in Atlanta last week. This leads me to Slide 8. The scale and complexity of obesity make it a distinct and complex disease area in which we identify different segments.

In the prescriber-driven segment, a key motivation for prescription is focused on comorbidity risk reduction, improving health outcomes and relative weight loss. We believe survodutide has the potential to be uniquely positioned within this segment. The largest segment, however, is patient-driven. A significant focus here is personal weight loss goals and how individuals achieve them with potential to deliver the weight loss that the vast majority of people with overweight and obesity desire, combined with an acceptable tolerability profile and an excellent patient experience, we believe petrelintide is ideally positioned to lead in such a segment. I'm highly encouraged by the potential of both of our leading obesity programs, which holds potential to redefine the near-term future of weight management in key segments.

And with that, let's move to Slide 9 as I turn over the call to our Chief Medical Officer, David Kendall, to discuss our R&D pipeline. David?

Thank you, Adam. Today, I'll focus my remarks on the continued advancement of our 2 leading programs, petrelintide and survodutide. Before doing so, I would like to begin by providing a brief update on our 2 late-stage rare disease programs and dapiglutide, our GLP-1/GLP-2 receptor dual agonist program. For dasiglucagon in congenital hyperinsulinism, our third-party manufacturers facility has not yet received the anticipated classification upgrade. And as shared previously, we have implemented a supply contingency plan, including the qualification of an alternative supplier to ensure we can bring this important therapy to patients in need as quickly as possible.

For glepaglutide, our GLP-2 receptor agonist in development for the treatment of short bowel syndrome and intestinal failure, the Phase III EASE-5 trial remains on track to initiate before the end of the year with the purpose of supporting regulatory submission in the U.S. We remain encouraged and excited by the clinical profile of glepaglutide as a potential best-in-class long-acting treatment for patients living with short bowel syndrome and intestinal failure and look forward to confirming the positive findings of the previously completed EASE-1 trial. We have made the decision to pause the current development of dapiglutide. This decision is a result of a disciplined portfolio review and prioritization, seeking to focus our obesity portfolio investment on programs with the greatest potential for clinical differentiation and those offering the greatest potential for long-term impact for patients living with overweight, obesity and related comorbidities.

Although dapiglutide has demonstrated the potential for a competitive weight loss profile based on the results of clinical trials completed to date, the GLP-1-based therapeutic space has become increasingly crowded, requiring even greater and clinically meaningful differentiation for assets which would be launched in the 2030s and beyond.

While there is compelling scientific rationale for GLP-1/GLP-2 dual agonism to modulate low-grade inflammation more effectively than GLP-1 alone, the clinical requirements needed to demonstrate this differentiation in a dedicated obesity-related comorbidity would be long, complex and expensive. We have significant opportunities in both the amylin and incretin-based therapeutic space with our leading programs, including petrelintide, the fixed-dose combination of petrelintide and Roche's GLP-1/GIP dual agonist, CT-388 and survodutide as well as an early stage pipeline that includes novel mechanisms targeting obesity and inflammation with the ultimate goal of restoring and maintaining metabolic health.

Please turn to Slide 10 and beginning with petrelintide. Our strong confidence in petrelintide is grounded in its overall efficacy, safety and tolerability profile. While amylin-based therapeutics can deliver clinically meaningful weight loss, we are not seeking to deliver the highest possible weight loss with petrelintide, but rather seek to target the weight loss that the vast majority of people with overweight and obesity desire and to do so with an excellent patient experience. We remain fully confident in the potential of petrelintide to deliver 15% to 20% weight loss in Phase III clinical trial and also remain highly confident in petrelintide's consistent clinical efficacy, safety and tolerability, underscoring its unique value proposition and the potential to become the leading amylin-based treatment and a foundational therapy for weight management.

I'm extremely pleased with the strong execution in advancing the petrelintide clinical program at full speed. In late September, we reached a key milestone in the large Phase II ZUPREME-1 trial, which evaluates the efficacy and safety of petrelintide in people with overweight or obesity without type 2 diabetes, with the last randomized participant having now completed the 28-week primary endpoint visit. Additionally, earlier in the month, we completed participant enrollment in the Phase II ZUPREME-2 trial, which evaluates the efficacy and safety of petrelintide in people with overweight or obesity and coexisting type 2 diabetes.

These achievements put us well on track to report 42-week top line results in the first half of 2026, report top line results from the ZUPREME-2 trial in the second half of 2026 and to initiate the Phase III program with petrelintide monotherapy also in the second half of 2026, together with our partner, Roche.

Let's move to Slide 11. We also look forward to exploring the potential of petrelintide as a backbone for future combination therapies, unlocking its full value potential. Petrelintide/CT-388 is the first combination product under our alliance with Roche. This program will target individuals who seek even greater weight loss and/or improved glycemic control while optimizing the dose of each component. We anticipate that use of higher doses of petrelintide and optimized doses of the incretin-based therapy CT-388, a potential best-in-class GLP-1/GIP receptor dual agonist, can provide both robust efficacy while maintaining excellent tolerability. Zealand and Roche remain on track to initiate the Phase II trial with petrelintide/CT-388 combination in the first half of 2026.

Now turning to Slide 12 and survodutide, a potential best-in-class glucagon/GLP-1 receptor dual agonist in late-stage development for the treatment of obesity and MASH. The Phase III SYNCHRONIZE program of survodutide in obesity consists of 6 clinical trials, all of which are expected to complete in 2026. In the Phase II obesity trial, survodutide demonstrated the potential to deliver highly competitive weight loss with doses of up to 4.8 milligrams. Notably, the Phase III trials are evaluating a higher maximum maintenance dose of 6 milligrams.

This leads me to Slide 13. Following the last participant's last visit in the 76-week SYNCHRONIZE-1 trial, which evaluates the efficacy and safety of survodutide in people with overweight or obesity but without type 2 diabetes, we are rapidly approaching top line results from this trial in the first half of 2026. At the Obesity Society Annual Meeting in Atlanta last week, Dr. Carel Le Roux presented the baseline characteristics of participants in this trial, which are also shown on this slide. We are very pleased that Dr. Le Roux has agreed to join us at our upcoming Capital Markets Day next month, where he will share more insights on the potential of survodutide to represent the next frontier in the management of obesity and MASH.

Now turning to Slide 14. We remain exceedingly optimistic and are very excited about the ongoing Phase III program with survodutide in people with metabolic dysfunction associated steatohepatitis or MASH, a serious obesity-related comorbidity with significant unmet medical need. Shown in this slide is an indirect cross-trial assessment of the registrational clinical trials for the 2 approved therapies in the U.S. for MASH today. The thyroid hormone receptor beta agonist, resmetirom and the GLP-1 receptor agonist, semaglutide. In the Phase II trial with survodutide in people with MASH and liver fibrosis, 38.6% of adults with moderate to advanced [ scarring ] achieved a placebo-adjusted biopsy-confirmed improvement in fibrosis without worsening of MASH after 48 weeks of treatment.

We believe this represents the most compelling and strongest clinical data set to date on the critical endpoint of improvement in liver fibrosis. With these groundbreaking Phase II data and a comprehensive ambitious Phase III program now underway, the so-called LIVERAGE program, which includes 2 large trials, 1 in people with moderate to advanced fibrosis, F2 and F3 and 1 in people with cirrhosis, F4. We believe survodutide has the potential to become the therapy of choice in this large and growing market segment, offering a much-needed treatment option for people living with MASH and obesity.

With that, thank you very much for your attention. I would now like to turn the call over to our Chief Financial Officer, Henriette Wennicke, who will review our financial results for the first 9 months of 2025. Henriette?

Thanks, David, and hello, everyone. Let's turn to Slide 15 and the income statement. Revenue for the first 9 months of 2025 was DKK 9.1 billion, driven primarily by the initial upfront payment received under our collaboration and license agreement with Roche. Of the DKK 9.2 billion in upfront payment received in the second quarter, DKK 124 million was deferred as of September 30 as it relates to the progression and completion of the Phase II trial with petrelintide.

Net operating expenses totaled DKK 1.5 billion for the first 9 months of 2025, with 73% of that amount dedicated to research and development. R&D expenses were mainly driven by the ongoing development of petrelintide, including the large Phase II trials and preparation for Phase III. Net financial items amounted to negative DKK 62 million for the period, primarily reflecting exchange rate adjustments related to the U.S. dollar deposits and currency devaluation. This was partly offset by interest income from investments in marketable securities.

Moving to Slide 16 and the financial position. As of September 30, 2025, our cash position totaled DKK 16.2 billion, a significant increase from the DKK 9 billion at the beginning of the year. This increase was, of course, driven by the initial upfront payment of DKK 9.2 billion from Roche, partly offset by operating expenses during the period and the purchase of treasury shares to support Zealand Pharma's long-term incentive programs. I would like to remind everyone that in addition to this very solid financial position, we are entitled to receive a total of USD 250 million in anniversary payments over the next 2 years under the Roche collaboration as well as potential development milestones of up to USD 1.2 billion.

As I stated in our last quarterly earnings call, I am very pleased with our capital preparedness. We are fully able to honor all obligations under the comprehensive Roche collaboration for petrelintide, while at the same time, accelerating investments in our early-stage pipeline to build the next wave of innovation.

Finally, let's turn to Slide 17 and the outlook for the year. Net operating expenses for the year are now expected to be between DKK 2 billion and DKK 2.3 billion, excluding other operating items. The financial guidance has been narrowed from the DKK 2 billion to DKK 2.5 billion, reflecting the decision to pause the development of dapiglutide, previously planned to advance into Phase IIb development in 2025. This decision, as David also mentioned, reflects our active portfolio management and our sharp focus on investing in assets with the highest potential for clinical differentiation, commercial impact and long-term value creation.

And with that, I will move to Slide 18 and turn the call back to Adam for concluding remarks.

Thank you, Henriette. We are now at the cusp of the most catalyst-rich period in Zealand Pharma's history. In just the first half of 2026, we expect to see Phase III enabling data for petrelintide, Phase III data for survodutide and Phase I data for what could become one pillar in the next wave of innovation from Zealand Pharma, our highly potent and specific Kv1.3 ion channel blocker.

Moving to Slide 19. I can only encourage you to join us at our Capital Markets Day on December 11, where we will set the stage for the rapidly approaching data readouts. We will also share more about our ambitious research strategy, which builds on Zealand Pharma's unique expertise in peptide R&D and our strong foundation to lead the next wave of innovation in obesity and related diseases and to continue our journey towards becoming a generational biotech company. I'm excited that we will be joined by Jonathan Roth, a pioneer in amylin-leptin biology as well as Carel Le Roux and Louis Aronne, recognized thought leaders in the field of obesity. They will join us on stage to share their valuable insights.

I will now turn over the call to the operator, and we'll be happy to address your questions.

[Operator Instructions] We will take our first question, and the question comes from the line of Kirsty Ross-Stewart from BNP Paribas.

So 2 on petrelintide, please. So with the eloralintide trial now published, I think interested to hear your thoughts on kind of the differences in the setup of the 2 trials in terms of baseline characteristics, titration, doses being explored and how your -- or how you would encourage us to look at your own dataset in the context of Lilly's data to kind of make a fair comparison there? And then also, David, you highlighted in your opening remarks that you're not targeting the highest possible weight loss with petrelintide, which seem quite in contrast to what Lilly have tried to do with their eloralintide trial.

I think there are some people that have sympathy with that message, but maybe you could argue as well that there's still some way to go to convince the market of the validity or the strength of that message. So I guess my question is, can you provide some feedback from your discussions with regulators or takeaways from market research with physicians and patients that may help to convince this move away from, as you call it, the weight loss Olympics.

Thanks for your question. And then maybe I can start and then hand over to David. We were extremely encouraged to see the eloralintide data last week, which we really see building on what we already saw with petrelintide last year. Remember, Novo demonstrated that petrelintide can deliver 12% weight loss and we consider with a 2.4-milligram dose, which we consider a very low dose. And it really, you can say, underscores the potential that we have been communicating all the time around the amylin class that with amylins, we have the potential to actually develop a new class of medicines that will provide patients with likely a 15% to 20% weight loss and thus a true alternative to the GLP-1s.

And very importantly, we expect this weight loss to be a more pleasant weight loss experience with significant less side effects, but also the nature in which the patients would reduce their food intake, we think would be superior in the amylin class in the sense of feeling full faster versus having loss of appetite. So we are extremely pleased, and you can say it actually increases our excitement around the upcoming Phase II data with petrelintide and our efforts to prepare for the Phase III trial conduct, really underscoring what we have been moving towards for a very long time. And David, maybe you want to touch a little bit upon important trials and design specifics there.

Yes. Thanks, Kirsty. And trial design specifics, I'll reiterate what Adam said. I think 15% to 20% weight loss when we came forth with petrelintide's potential to achieve this. I think at first, there were actually some skeptics that looked at this and said that can't be possibly achieved. We've seen early [ Cagri ] data. But I think the data we saw recently from another compound in this class clearly demonstrate that GLP-1-like weight loss percentages are achievable. And we think, as Adam referred to, that higher milligram dose exposure, higher bioavailability and the excellent tolerability profile we've seen to date with petrelintide up to 9 milligrams once weekly can certainly hit that sweet spot.

You also mentioned what does the market seek. One simply needs to do some math. If somebody weighs 150 kilos, a 30-kilogram weight loss for 65 pounds of weight reduction is substantial. And I think 5 years ago, the world would have thought that's unachievable with what we've seen to date, including with [ liraglutide ]. So both in speaking with clinicians and in speaking with the vast majority of patients who seek weight management therapy, that's 10% to 20% weight loss figure comes up repeatedly. They may not say 10% to 20%, but they will give you a number -- a desired number of pounds or an end target weight that generally reflects that. I think some of the data from GGG high-dose GLP-1-based therapies, which we believe suffer from challenges with tolerability can get you to the 20-plus percent range, but that serves a vast minority of the patient seeking this.

And finally, to your question about the baseline characteristics, just recall that with petrelintide Phase Ib predominantly male participants, predominantly or a leaner mean population with a BMI just under 30 kilograms per meter squared. Both of those factors, we believe, could have significantly muted the response we saw in Phase Ib. We will have a much more balanced gender distribution in Phase II, a much higher baseline BMI as we reported in last quarter's call.

And the likely contribution of predominantly female, very high BMI population, I think, is well worth considering it may amplify the observed results rather than mute as a predominantly male and leaner population. I think it's also important to read the details of both diet and exercise instruction in the trial. We achieved our results in Phase Ib with limited to no other intervention. So I encourage you and others to look at the full construct of all of these trials before jumping to just top line numbers. So I'll stop there.

We will take our next question. Your next question comes from the line of Hakon Hemme Jørgensen from Danske Bank.

Hakon Hemme, Danske Bank. Also a question regarding petrelintide study design. The [ eloralintide ] data from last week demonstrated that patients did not experience weight loss -- a weight loss plateau like we see with the GLP-1 treatments, likely due to the restoration of leptin sensitivity by amylin. So how does this influence your consideration on the trial duration for petrelintide in Phase III? And how do you see the trade-off between potentially achieving greater weight loss with a longer study compared to bringing petrelintide to the market sooner?

Thanks for that question. We're going -- I'll let David answer.

Thank you, Hakon. I think 2 very important observations. The absence of plateau, which I think was readily evident both in our short Phase Ib studies with petrelintide, but certainly offers that potential where longer exposure, some of it required for regulatory review and approval out to beyond 68 to 72 weeks will allow us to assess whether this is a continued effect. And I think importantly, speaking back to the mechanisms that Adam discussed a satiety or fullness where one feels full faster and stops prospective food intake as opposed to a food aversive signal that hit suddenly and may be consistent at least in theory, could contribute to a continued gradual weight loss over longer periods of time.

So in both our own visual extrapolations and I think now looking at the elora high-dose data, noting that the higher doses were perhaps less well tolerated than the 3-milligram dose, you see not only progressive weight loss, but GLP-1-like effects, something we've been talking about for most of the past 2 or 3 years. So I think it will be important to observe what we pull out of our 42-week Phase I trial. And then the design for the longer Phase III trials will directly answer your question, but would expect the potential for progressive weight loss out beyond 1 year of treatment.

We will take our next question. Your next question comes from the line of Lucy Codrington from Jefferies.

Sorry, sticking with the elora data from last week. So in light of that data, do you have any updated thoughts on the importance of the receptor activity that has previously been discussed? And you mentioned that you're confident it will still be best-in-class. I just wanted to know what drives that confidence given the data we've seen so far for elora. Then secondly, just following up on the trial design. Just to confirm, this trial will have no lifestyle interventions, is that correct? And then secondly, related to the trial, did you specify to have a balanced sex ratio in the trial? Or is that just happenstance? And then on dapiglutide and the decision there, I just wonder, you're obviously not short of cash. So kind of what was the thought process in terms of stopping this study? Was there any discussion with Roche about this?

I appreciate you're not partnered, but did you discuss it with Roche? And also, any thoughts on potential combination with petrelintide down the line? And what studies would be need to be done in order to enable that?

Thank you for the questions. I will start with the first one on the pause on dapi. I think it's very evident and it will be even more so at the Capital Markets Day that we have what we believe really a leading opportunity in the GLP-1 space with survodutide, which [indiscernible], which do not only have a huge potential for weight loss, but actually also addressing liver health and in particular, MASH and potentially other organ damages by activating lipolysis. So it actually has a strong profile towards managing comorbidities of obesity.

And now with the Roche partnership, we also, as you know, got shared economics on the combination product with CT-388, their GLP-1/GIP, meaning that's going to be the combination opportunity we are going to focus on. And thus, that became less relevant for combinations with amylin. What we have been exploring over the summer was addressing segments of the obese patients, which were suffering from specific comorbidities. And in doing those in-depth evaluations, it's very clear that it will require, as David also said, very large investments and long commitments before getting to understand the full potential for differentiation. And if you then consider the GLP-1 marketplace in 5, 6 years from now, you will see that it's a very crowded place.

And we came to the conclusion that the level of clinical differentiation we would have to show by coming that late into a GLP-1 market was not worth the efforts, in particular not because we have such a rich early pipeline and fantastic ideas, which you will hear more about that we want to invest in and apply our capital. So we basically believe we can apply our capital better in those early programs. So I would say it's a very, you can say, considered decision and one which allows us to invest even more in our early-stage pipeline as we mature the company towards a generational biotech.

When thinking about the upcoming data for petrelintide, we remain and we are even more confident in the potential to deliver the 15% to 20% weight loss, which we know will address by far the vast majority of the weight loss that patients are desired. And as I said before, the data that came out last week underscores the potential that we also saw with cagrilintide last year. Remember, cagrilintide was only 2.4 milligram, which is a very low dose compared to where we take petrelintide today.

And so the confidence in the best-in-class potential comes from -- when we look at the consistency of the data we have seen across our early-stage clinical trial readout, the balance between efficacy and tolerability has been outstanding in our minds and then the potential to dose high and continue into the longer-term study that we are soon to report gives us that confidence in the Phase II study that we will report ZUPREME-1. We have applied diet and exercise, and we do have a gender balance of around 50-50 as opposed to the 80% females that were reported in the study last week.

But again, that has been done from a very firm development perspective that you want to have exposures in those gender to make the best possible decisions for your Phase III design. You actually introduce a lot of risk by having very few of one gender because you don't get to learn about your molecule in those genders if you skew too much in Phase II.

And Lucy, I'll take the question about the receptor biology and receptor differentiation. I think [ Thomas Lutz ] said it quite well in his introductory talk saying there's still quite a bit to understand elora based on data reported by Lilly has about a 12-fold higher affinity for the amylin receptors than calcitonin. But I think it's important to note that the proposed or the hypothesized improvement in tolerability was clearly not demonstrated. There was significant nausea, I think, up to 64% in one of the treatment groups at relatively moderate doses.

Similarly, if one looks in the appendix, there's not just a transient, but a small decrease in serum calcium, which is also indicative of some calcitonin effect. So our own conclusions are that with balanced agonism as we have seen with petrelintide, we have seen one of the best, if not the best, tolerability and safety profile and that it does not sacrifice tolerability, particularly around GI side effects. I think the other comments that Thomas Lutz made, which is all of this receptor biology work and knockout activity in animal really requires confirmation in clinical testing.

And to our end with a predominantly female, higher BMI population treated with high doses, there was no substantial difference, I think, based on the author's conclusions in tolerability versus historic GLP-1 programs. And we would at least posit that some of the changes, including the drop in serum calcium indicates some and perhaps significant calcitonin receptor activity in clinical treatment. So we will continue to explore how these may differ. But I think as Thomas Lutz concluded, the answers will come from the clinical trials.

We will take our next question. The next question comes from the line of Andy Hsieh from William Blair.

So it's about the patient experience that you comment frequently about. So in the context of co-formulation with CT-388, I'm curious about your take on how important it is to harmonize the number of step-ups between, let's say, petrelintide and CT-388 in the titration step, especially given the tolerability profile, incretins will likely need a more prolonged titration period. So that's question number one. Question number 2 has to do with another adverse event profile that was raised during the conference, which is fatigue. Based on our KOL discussions, I think this is probably one of the overlooked adverse events affecting patients' quality of life. That number appeared to be numerically higher than what we've seen. So I'm just curious about your take on this and also what you've seen with petrelintide clinical trial experience.

Thanks for the question. Maybe I can just start and hand over to you again, David. I think as we have also said all the time, it is about time to move beyond the weight loss Olympics, not only because it's not what patients are looking for, but it's also a clear observation on our end at least. And I would also say maybe you see that in some of these dataset, if you go too aggressive with very potent biology as we have today, especially in the start, you might actually introduce situations you're not looking for. And our observation, and you will also see that in earlier study data from several [ amylin ], you don't want to push this too much in the start.

Could that be driving some of the fatigue that you're seeing? Maybe if you have a, let's say, 4% weight loss over 1 week, that's probably not that, that could be a fluid that you lose and how would that make the patients behave. So recognizing that we work with extremely potent biology, as David also mentioned before, who would have thought that you could achieve a 20% weight loss with a pharmacological intervention just a few years back.

And here we are, but you have to be careful and otherwise, you may see things you don't like. So that is a key observation. When we look at our studies, we have not seen it in our programs thus far, signs of fatigue. So -- but again, let's see, we, as you know, apply actually titration throughout our entire phase of all cohorts in our Phase II study, something that was -- has not always been done with other programs.

So -- and so far, we have not seen it. On the titration steps, before handing over to you, David, I also just want to mention, I mean, what we have seen thus far is that amylin actually deliver weight loss even at the initial doses. And it's, of course, clear that ultimately, when we titrate together with the GLP-1, it will be the GLP-1 that determines how to titrate because those are the ones that really need titration from a GI tolerability approach. David?

Yes, I'll reemphasize that, Andy, and harmonizing those, I think, gives us the opportunity, as I said, to find what is the most applicable dose escalation scheme for petrelintide to get to what we hope is maximal dose with very good tolerability. As Adam said, we've seen less fatigue than in our placebo-treated subjects in the Phase I trial and very limited GI tolerability issues, that would allow you to either simplify the addition of very low dose incretin-based therapy.

So it would further slowdown to get to not a maximal dose as is often done in Phase III trials or Phase III to see the maximum weight loss. But an optimized dose, let's say, dose 3 of the 388 compound and dose 5 of the petrelintide compound is what the alignment looks like. We would base that on the petrelintide dose escalation scheme monthly as what we're testing in Phase II and Phase III.

So the question is then how do you formulate a fixed-dose combo to get to the optimize, not maximal dose of 388. So this is not simple math. I think we have our manufacturing team on edge for the types of combinations that are possible. But this work is well underway, and I think will allow us to do exactly what we set out to do, which is to find a very effective therapy that optimizes tolerability while still leveraging the efficacy of both components.

We will take our next question. Your next question comes from the line of Kerry Holford from Berenberg.

Mine is more bigger picture with regard to the market and your expectations here. So clearly, since the last update, we've had Lilly Trump deal. We now have clarity on pricing in the U.S. [indiscernible] cash pay in the Medicare channel. So I would just be interested to hear how that deal and the details that we have so far may be impacting yours and Roche's forecast and the opportunity for your next-gen obesity pipeline assets? Will it essentially now be more difficult for you to unlock the value and deliver strong returns in this market? Just your thoughts from that big picture perspective.

Thank you for that question. And we will -- actually at our Capital Markets Day in December 11, address our considerations about the current market dynamics in more detail. But maybe just to share a few considerations. I think it's a very dynamic market right now. We have already seen that a very large part of the uptake has been in the direct-to-consumer space where prices have been lower than the list prices. And we've also seen rebating in this space when it comes to the commercial channel. So it's actually a blessing to be where we are right now where we can learn from these dynamics and then design our programs and go-to-market strategy together with Roche according to those dynamics and how we think they will play out in the future.

That allows us to actually define the future instead of just trying to tap into something that work. On the value opportunity, I think the key single most important parameter to unlock the value in this market and actually truly address the obesity pandemic, that is to develop therapies that patients will stay on and thus increase the volume of patients who get to these therapies. It's a huge problem that in today's market, many patients would use the GLP-1-based offerings as a little bit of an [ event-based ] therapy with the majority of patients being off therapy within a year. And a lot of that has to do with side effects we know from IQVIA data.

So we focus to unlock the value of this market and to change -- to get excitement into this space again, I truly believe is by making sure you develop therapies that people can stay on and thus, you will see the volumes go up. And then the pricing part that people like to discuss so much is less of an issue as long as people stay on therapy. It's only an issue if you only stay on therapy for 1 to 3 months, and then you need to go out and find a new patient to capture that value you lose by the patient stop taking it.

So we actually like the clarity that we see more and more clarity. We understand that it's still a very dynamic market. We would expect to see a significant number of changes in the coming years. And together with Roche, we would build our go-to-market models accordingly.

We will take our next question, and the question comes from the line of Prakhar Agrawal from Cantor Fitzgerald.

Congrats on the quarter. So I had a few. Maybe firstly, going back to receptor biology. [indiscernible] is having elora as a more selective amylin, especially on amylin 1 receptor and seems to be balanced on amylin 3 and calcitonin. So maybe if you could talk about whether potently targeting amylin 1 versus amylin 3 receptor has any clinical implications in obesity and beyond. And if you can remind us about petrelintide's activity on amylin 1 versus 3 receptors? And secondly, on the trial for Phase IIb ZUPREME-1, if can you talk about how the discontinuation rates are trending as it has been an issue with some of the recent trials? And when you disclose the data next year, whether you will disclose both efficacy and treatment regimen demand when the data disclosed?

I'll start and hand over to you, David. And we do expect to disclose the top line efficacy data from both estimates, I would expect, including the relevant safety observations when we disclose the data. On the receptor profile, if you look into preclinical data, I remind you that both we and Novo had a firm effort for many, many years and came out with balanced profiles towards these receptors. And as David just alluded to, probably quite a few of the molecules we're looking at right now have some receptor activation on all 3. We have one which is quite similar, we believe, to the one that petrelintide has. Ultimately, we need, as David also said, to see clinical data.

When we look at the early clinical exposure for which we have -- actually have among the different amylin molecules, that is where we see -- get a lot of confidence in our approach if you start to compare, let's say, the single ascending dose studies across the different molecules where we have data now available and published both from us, but also the competing programs. And if you then account for female to male, BMI and other aspects.

But the single ascending dose data, probably some of the more honest datasets here where there's less bias, that gives us a lot of confidence and the robustness of our observations where we have not seen some side effects in one study and then others in another one, the first one disappearing, we have a very robust dataset, which suggests that we have a profile of a drug that has found the right balance between efficacy and safety tolerability. So -- and we will review more of this at our Capital Markets Day, which will answer probably in more detail some of these questions. And David, I don't know if you have more to...

Thanks, Prakhar. And I think as you and we are learning this receptor biology, when it's assessed in vitro, looking at receptor occupancy and activation doesn't necessarily provide the entire clinical picture. And as Adam said, cagri and petrelintide are clearly balanced receptor agonists activate all 3 receptors in our hands with equal potency. [ The Gubra now AbbVie ] asset is similar in our hands, slightly greater predilection for the amylin than the calcitonin receptor. And the Lilly molecule, eloralintide while touted to be amylin more specific, it clearly had GI tolerability issues associated with it, something that calcitonin receptor dialing back has been touted to improve, but hasn't been demonstrated clinically to demonstrate.

I think the other point that Adam makes that's critically important is regardless of this, how does the clinical safety and tolerability and efficacy profile lineup using the elora data as an example. There were in the early phase trials, an increase in the number of headaches, whereas with petrelintide, we've seen less headache than with placebo. The newly reported adverse effect of bradycardia, bradyarrhythmia and syncope reported in the elora trial is unique amongst this class to my knowledge.

I have no idea if that's related to receptor biology or other mechanisms. Again, the clean profile and the balanced agonism of both cagrilintide now through Phase III and our Phase Ib data and beyond for petrelintide give us great confidence that, that is not only an acceptable receptor profile, it is an incredibly effective and well-tolerated profile.

We will take our next question. Your next question comes from the line of Yihan Li from Barclays.

Yihan Li from Barclays. So we have 2. So the first one is the petrelintide Phase III timing. So it seems like you have already completed the end of Phase II meeting with the FDA. So just curious if you could walk us through what remains before initiating the Phase III monotherapy trial, which is now planned in the second half of next year, especially given your competitor, Eli Lilly, actually, they moved very fast for the Phase III will start by year-end. And the second question actually is on eloralintide, the MASH data.

So again, like they showed 60% to 70% of the MASH reduction from [indiscernible] and also the other 30% from the [indiscernible]. However, an interesting thing is that it doesn't seem to have a continued decline in the lean MASH from the week 24 to week 48. So suggesting the lean MASH loss could potentially stabilize after 24 weeks. I'm just like curious, does this suggest maybe amylin-based therapy could inherently preserve lean MASH better over time? Like any thoughts will be appreciated because I'm just thinking like amylin could be used as a post GLP-1. So just curious what your thoughts there.

Thank you for that question. And I can reassure you that we are moving as fast as possible forward to Phase III initiation with petrelintide. Right now, our expectation would be second half of next year and as we have communicated today, we have reached the primary endpoint of the study. And we are, of course, also anticipating a meeting with FDA as fast as possible once these data has been analyzed and progressing as fast as possible. So -- and top line data will be available first half next year.

So it's a shared commitment from Roche and us to accelerate as much as possible to get these treatments to patients ultimately and help achieve their health goals. So this is progressing with a high sense of urgency, but the Phase III start is set for second half next year. I think we need to actually wait for our Phase II data with petrelintide before we will comment more on the balance between muscle and fat preservation.

Remember, we use MRI as an assessment of body composition, which is a much more precise mechanism than the [ DEXA ] scans that have been utilized by other companies. We, as everyone know, have seen extremely strong preclinical evidence for muscle preservation with the amylin class, and we need to now see human evidence before addressing this more, and we think we will get some, at least high-quality data from our Phase II study, which will be able to address this in more detail.

We will take our next question. Your next question comes from the line of Theodora Rowe Beadle from GS.

Thank you very for taking my questions based on dapiglutide, if that's okay. So firstly, why did you take the decision now to pause the development of the dapiglutide rather than further exploring the potential anti-inflammatory benefits? Has there been some data generated internally, for example, that could drive that decision? And then secondly, could there be developments elsewhere in the space that change your thinking on dapiglutide? So specifically thinking about if Novo show a benefit in Alzheimer's in the evoke trial?

Thank you for that question. And as we have indicated today, we have decided to pause the program because we do recognize that it's a very attractive profile, both with the clinical profile we have seen thus far and also its potential to lower inflammation even further than the existing GLP-1s. We actually think it's probably the most differentiated GLP-1 containing mid-stage development candidate.

The decision has been reached now partly, as I explained, due to the fact that we have CT-388 where we can -- as we will combine with amylin, also, of course, very much because we see now -- we see survodutide approaching, but then also just realizing that the investments needed to show the clinical differentiation and then the need for clinical -- the amount of clinical differentiation you would have to demonstrate if you launch a GLP-1-based therapy in the [ '30s ], it's a very, very high bar to pass due to the competitiveness within the GLP-1 class of medicines.

And that's coming back to why we are so excited about the amylin class because it's an alternative. And if you think about how you manage chronic therapies, normally, if you cannot achieve your goal with one class, then you move on to the next. And if you need more, then you start to combine. So -- and if you then -- and we'll talk much more about that at our Capital Markets Day, consider the rich pipeline we have of early-stage assets, we have really taken a view that there's significant higher value creation opportunities by investing in these next opportunities for which we have some -- we consider at least very good ideas for how to drive the next wave of innovation and differentiation in this space.

So for us, it was not, as you can imagine, an easy decision since the molecule actually looks very strong, but we also think we have so much exciting opportunities in our pipeline that the money are actually more wisely spent there.

We will take our next question. Your next question comes from the line of [indiscernible] from UBS.

Just on survodutide. So you'll probably cover this more at your CMD, but in terms of the Phase III readout in the first half of next year, where do you expect tolerability will likely land considering that in the Phase II data we've seen so far, there's a pretty high level of GI toxicity?

Thank you for that question. And we, of course, soon will have the data. And please also remember that the Phase II study design, if you compare the safety or tolerability profile with the Phase II studies of -- of some of the marketed products, you will actually see a quite similar profile of tolerability. So we, of course, what we expect with survodutide is a comparable tolerability profile to the existing molecules and also a comparable weight loss. The true opportunity for differentiation is the activation of lipolysis with glucagon and thus providing better liver health as we saw with the MASH program.

Also remember that Boehringer is actually pursuing higher doses in the Phase II than what they -- in the Phase III than what they did in Phase II. And that gives us a lot of confidence that by using -- applying the right titration being flexible around how you titrate as you have to be with GLP-1 allows them to go much higher. They have already tested that higher dose in the MASH population in Phase II, which is applied in the Phase III program for obesity. So we have a lot of confidence that the profile will come across as a very strong and effective GLP-1-based therapy with a tolerability profile that is comparable to what's on the market today and a clear edge towards their health.

We will take our final question, and your final question comes from the line of Mohit Bansal from Wells Fargo.

So a couple of questions from my side. First of all, so given that with CagriSema, we saw a little bit of tolerability when you combine GLP-1 with amylin. And I fully appreciate the sentiment that combining GLP-1 and amylin could be interesting. But at the same time, do you -- given that amylin does have some GI tolerability issues, and it could compound with the GLP-1. So do you think the better use of amylin could be more of an immunotherapy versus a combo therapy, maybe in post-GLP setting or maybe as a monotherapy in the frontline setting? So that's first question.

And second question is, we saw with eloralintide that, I mean, Phase I was -- tolerability was better versus Phase II, we saw a little bit higher GI issues. So in that context, I mean, what do you expect with petrelintide in terms of tolerability in Phase II trial as you see data in more patients?

Thank you for your question. And we definitely see amylins in particular, petrelintide having the potential to become a foundational and first-line therapy, a first choice therapy. I think what many have not really thought deeply about today is that, and we've -- yes, I think we all recognize that GLP-1 for many patients are difficult to tolerate. Many patients accept these therapies today because there's no alternative. What will the conversation be if there is a more tolerable approach to weight loss?

Then you don't talk about will you tolerate it, then you will start to have a conversation, will you accept the tolerability profile of a GLP-1 if you can actually experience a more pleasant weight loss on a different modality. I think that's what we have to think about now. So that -- and that's what excites us and why we believe we have the potential to drive first choice and foundation therapy.

So we definitely see, as we have said all the time, the biggest opportunity for monotherapy as an alternative and a first choice treatment for obese individuals who want to lose weight and importantly, maintain that weight loss because that is the key to unlock the value of this market is to make patients stay on therapy so they don't regain weight, and it's also the key then to achieve the health benefit. If people don't stay on therapy and they regain weight, they will not achieve the health benefit. There's also significant potential for combination therapy, but that would be for the most [indiscernible] patients living, for instance, with type 2 diabetes.

As David also alluded to before, we have a different approach to the combination where we want to max out, if you will, on the amylin component, which we consider the more tolerable part of the combination and then just add a teaspoon of the GLP-1 component. And thus, we expect to have a more tolerable approach to that combination that maybe has been seen with other approaches to combination. So again, on the expectation for our Phase II study, we have -- as you can hear, we have a high level of excitement and high expectations for the profile that we will see with our upcoming 42-week data with petrelintide. Thank you.

This concludes today's question-and-answer session. I will now hand back for closing remarks.

Thank you all for attending and for your questions. We look forward to future announcements and updates and to connecting in the coming weeks and months. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect.

I think we'll get going if that works for everyone. I'm Charlie Haywood from the BofA EU Pharma team. My pleasure to be hosting David Kendall today, CMO of Zealand. Obviously, I'd say you haven't got any official introduction, but I guess as a quick 2-minute overview of where we're at, where Zealand is at, how has the year been, et cetera, been an exciting year for you. So that would be a great way to start.

Very good. Thanks, Charlie Haywood, and good morning, everyone. I was teasing Charlie. I live in Southern California. So they're pointing out it's 2:45 in the morning on the clock in the back. So I'll do my best to hang in there. So for those of you I've not met, David Kendall, I've been Chief Medical Officer at Zealand Pharma for the past 3.5 years, been with the company for 5 years. Prior career in the metabolism division of Eli Lilly and started my pharma career at little Amylin Pharmaceuticals and the originators of a lot of the technologies we're talking about today.

So in touching on highlights, Charlie, I think front and center is obviously the partnership with Roche, and Thomas just reviewed some of the highlights from their metabolism portfolio and alluded to 2 of those components, obviously, signing that deal in March and kicking off the partnership this summer with rapid progression of the petrelintide asset towards Phase III. As many of you know, we have ongoing Phase II studies with readouts expected in the first half next year and then also with their GLP-1/GIP agonist, the 388 compound, looking for when they can and will share the results of 388 Phase II, so we can initiate the work that is already underway for the fixed-dose combination of petrelintide with 388, and happy to touch on some details of that.

I would say that and the advancement of the Phase II program are certainly highlights both financially and from the standpoint of advancing our R&D portfolio. As many of you know, in 2022, we refocused on R&D, not only advancing -- continuing to advance our rare disease assets in congenital hyperinsulinism and in short bowel syndrome, but look to establish ourselves as a key player in the obesity and metabolism space beyond the Zegalogue franchise, the rescue therapy that was out-licensed to Novo Nordisk.

And I think for those of you who may have been part of our R&D Day, 2 Decembers ago, where we stepped forward and proudly stated that we believe amylin-based therapies and petrelintide in particular could be a foundational therapy and a stand-alone therapy in management of overweight and obesity. A lot of people scratched their head and said, that's wild, robust and ambitious. But we now see -- and I think this is a highlight of the year that's not solely ours, Charlie, but the interest of players like Novo Nordisk, my former employers at Eli Lilly as well as AbbVie licensing the Gubra asset, and now Pfizer with the Metsera acquisition, championing amylin therapies as one of the cornerstones of weight management.

So I think the environment is now telling the story we've been sharing for 3-plus years, and pleased to say that both the advancement of that asset and still what we think are potential best in market or market-leading attributes for that asset and the, I'll call it, the power of the partnership with Roche, both Zealand's inventive and agile R&D environment, but Roche being an established player in the development and commercialization space just further strengthens those efforts. So I'll stop there and let you fire specific questions, Charlie.

Got it. And I think another big picture one, obviously, the obesity market, I think the last year, 1.5 years, we've seen a lot of developments, we've seen shorter stay times on drugs, we've seen the reimbursed market maybe slowing growth, cash market being a lot bigger. I guess within all of that, I appreciate the more R&D side. But where does amylin fit in there? What needs does that address? How do you see that fitting in going forward?

Yes. So before my R&D days, I was an actual prescribing physician. So I have an interest in how these things actually get to patients and get to the market, and I love the tagline from Roche, doing things now what patients need next. I think it is intoxicating to think this market has evolved to its final state, but we are still in the very early stages of this obesity market. If you said 5 years ago, this is going to be a multibillion-dollar market, people would have scratched their head and said, what are you talking about? There's Saxenda and a few other things. But it has transformed, and all credit to both Novo and Lilly for sort of breaking down those walls.

But I think particularly payers, government systems honestly didn't see this coming in the magnitude of the burden of both expense and disease. If you estimate that probably 40% to 50% of the global population will be overweight or obese in the coming decade. That is unlike any other disease state we've seen, and we've seen CBD cancer risk, metabolic diseases like lipid disorders and diabetes, which are dwarfed by the size of this market.

I think there are other unique attributes that are still shaping this market and what it will look like in 2026, let alone 29, '30, when a lot of these assets hit the market is tough to predict. But what we're seeing early on in contrast to a lot of other chronic diseases and chronic metabolic diseases, this is patient driven. And I won't say just cash pay patient driven, but there are very few patients in my experience who came in and said, "Hey, doc. I need a diabetes drug. I need a lipid-lowering agent and an antihypertensive." That has flipped the script. And there, it was providers saying, you need better glycemic control, lower blood pressure, management of lipids. Here, we have patient-driven interest in bettering their health through weight management coming in and saying, "I know there are effective weight loss therapies, what would you suggest for me?"

So it's almost the reverse of what we've seen in other chronic diseases providers are accommodating to this. And particularly in the U.S. market, which is where I live and spend most of my time, you see that patients are seeking therapy and then sort of backdoor applications for coverage rather than front door applications. I'll only take this if I get coverage. I have a personal example of a close friend who has significant obstructive sleep apnea. He went on 1 of the 2 available agents, lost about 15%, 18% of his body weight. The sleep apnea basically disappeared. So now his sleep doc prescribes his medicine. That's sort of the reverse of what we traditionally think of.

So those are some of the dynamics I think we'll be dealing with. Will this be a pure sort of Botox market where there's a cash pay segment that is more driven by patients and their desires versus a medically driven like the migraine side of Botox is where it's reimbursed and for specific indications. I would be only guessing to tell you I know what's going to happen next year or even in 2029. But the market will continue to evolve. And I think having an assortment of assets, not only in our portfolio, but I think with our Roche partners saying, we are a metabolic disease company. We are in the metabolic health business. So we are ready for what comes best we can.

Very clear. And then obviously, the sort of practical standpoint to that is how you look to design your trials, Phase IIIs, whatever, mono, combo. Any -- what are your updated thoughts on any, I guess, novel trial designs if trials will be segmented by BMI, placebo control we still have with this? Where are we at in that whole stage of trial design to -- for how the market may evolve?

Yes. I think two considerations there, Charlie. One is we realize that speed, particularly to U.S. market is primary. So getting too sophisticated, complicated, exclusive with entry criteria, obviously, we'll focus on the obesity and overweight populations, those with overweight and obesity with type 2 diabetes. Given the requirements still in the EU for demonstrating cardiovascular safety, CV safety trial separate from a future potential cardiovascular outcomes trial will be part of the core program.

But beyond that and specific to your question, particularly with petrelintide and amylin agonist, we think there is an opportunity for a very distinct and unique experience. We have said all along that we believe petrelintide can achieve incretin-like, GLP-1-like weight loss. And some have asked, is that mid-teens? Is it 15% to 20%? We've said both. I think you can look at the cagrilintide program as sort of just the first indication that mid-teens is feasible. That is a medication that is somewhat dose limited by the injection site reactions, potentially by antibodies. But even in the redefined studies, they got to the maximum dose of what, 80% of the time. So you realize that maximal dose exposure is achievable.

So we will obviously look at that, look at the dose response from Phase II and identify what we hope is the simplest dose escalation scheme. We do not want to sacrifice what we think is already a very favorable acceptability profile, not just tolerability, but can I persist on this in the Phase III core program, you know these are literally thousands of patients. Yes, still placebo-controlled because that's what U.S. FDA asked for. But that will only be the first part. And then mechanistic studies, Phase IIIb programs in specific populations, and I won't define them, but you can imagine those specific weight dependent comorbidities like obstructive sleep apnea, because of the unique mechanism by which amylin agonists work considering osteoarthritis. If muscle preservation is clearly an attribute of the amylin agonist, will these be particularly useful in older adults, those with sarcopenia, women in perimenopause where keeping muscle mass along with losing body weight will be the best for bone. This is a population where weight gain and adiposity are a significant concern. Much of that is physiology, not anything else.

So those are some of the considerations. So Phase IIIa, as I'll call it, will be straightforward speed to market. Phase IIIb will include all of these things, including the potential to investigate cardiovascular risk reduction.

Got it. Very clear. And then on the combo you alluded to earlier, fixed-dose combos. I guess any updated thoughts on the fixed versus flexible dose combos if you could have multiple fixed-dose combos because we're seeing, I guess, the real-world data suggesting not everyone is on the highest dose of A or B GLP-1. So how do you manage that around the patient versus rather than the specific fixed dose?

Yes. I think a lot of learnings from the CagriSema program where doses were tied together and sort of high, high was the goal. We're chasing the biggest weight loss number, it was clearly part of what they at least put forth. They may have fallen a little short of their own expectations. But I think we have the opportunity to do something slightly different. And the current thinking is how can you maximize what we believe is the better tolerated petrelintide component of a fixed-dose combo and then more or less optimize, not necessarily maximize the GLP-1 component.

What you see in the CagriSema program is the tolerability of cagri, which conservatively has 1/2 the rates of nausea and vomiting, 1/4 of the rates -- I'm sorry, 1/4 of the rates of vomiting, lower rates of diarrhea, constipation. But once you add cagri at full dose, you sort of aggregate all of that advantage. So can we go to a lowest feasible, lowest effective dose of a GLP-1/GIP, the 388 compound, or is it a mid-dose, high, high is really there only if you need the sort of the biggest hammer for that nail. But instead of, as we describe it, playing the weight loss Olympics game to get the biggest number, can we preserve all of the attributes of tolerability and then leverage the known benefits, glycemic control, additional weight loss, likely cardiovascular protection of the GLP-1 component.

So we will be more flexible in Phase II. Obviously, we need to see the Phase II data from each individual program. before we go there. But that's our current thinking, it is not a race to the top because the vast majority of people, based on our own work and others, want to lose 10% to 20% of their body weight. They're not looking for 25%, 28%, 30%. That is reserved for the most significantly affected morbidly obese with major complications. I think it's the NHS where a BMI of 40, and I said kiddingly 56 comorbidities are required to get some of the drugs covered. But that is an exceedingly small minority of the population seeking weight management. So where can we find that spot that meets the majority of need.

Got it. And then I wanted to come on to your petre Phase IIb data, obviously, we'll get the full read next year. I guess the blinded interim is soon, but I'm sure it has been clear that is blinded and you won't see the data. Remind us on the main differences versus your Phase Ib because I think we've seen other competitor data, which we'll get on to in the sector coming through this year. A lot is going to weigh on that Phase IIb data. So what are the main differences? How are you thinking about that read? What are the expectations?

Yes. I mean quite a bit of learning from Phase Ib and probably the simplest one, and this comes to the competitors. We want to leverage the tolerability to as great a degree as possible and lower starting doses with monthly dose escalations because weight management is not a rapid sprint. Yes, patients want to see results, but that dose escalation scheme. And then obviously, seeking to identify, is there a true dose separation at the higher end. When we did the Part 1, Part 2 of the original study, you remember there was sort of the low 0.6 milligram, 1.2 milligram dose cohorts all the way up to 9 milligrams. Some purported similarities between the higher doses, do they actually separate.

The other very important part of that is, obviously, we've got a longer follow-up interval, 28 out to then 42 weeks for the primary endpoints. And in contrast to our Phase Ib, 80% males, lower BMI, we have a much more representative population. We reported that at our last quarterly call, BMIs of around 37 on average, roughly balanced for male and female. Those are 2 key components because higher preponderance of females tend to increase weight loss because of the inherent natural adiposity in larger trials lose, 3% to 4% more body weight than males. On higher BMI, the same sort of 2% to 3% plus difference, meaning greater weight loss. So we wanted to be representative.

Beyond that, obviously, we're doing this 28-week interim to enable regulatory interactions, the 42-week to make full decisions. But obviously, preparations right now for Phase III doses, ultimately, device and the large Phase III program are ongoing pending that. So not major differences other than the balanced gender, higher BMI, much more representative.

And then the second study, including a small cohort with type 2 diabetes, where we think weight-losing effects can be virtually similar in those with or without diabetes, something that does not occur with GLP-1 agonist where you sacrifice some of the weight loss components because of the potent insulin stimulatory effect of GLP-1s.

Got it. And then 2 questions on the design differences. I guess, I don't know if you see them as risk or whatever into your Phase IIb, but obviously, the first one has a higher female proportion of patients, which obviously, from the data we've seen so far on GLP-1s has been mostly female patients, you obviously have a much higher ratio, which you think could bring more weight loss. But is there a risk that the higher female patients also bring worse tolerability? And I guess, do you have any data on that? I don't think we've seen anything from cagri. And then sort of on that is, is there a risk of higher BMI patients bring worse tolerability? So 2 parts.

I think I mean, our position is because tolerability has been so good thus far, we don't see a great risk. And interestingly, and this has been some work done both in animal models and in real humans, no offense to the rest of the men out here, but we tend to be less tolerant than females in response to many adverse effects. There is some evidence that actually signaling of some of the neuronal pathways, GLP-1/GIP, amylin are programmed differently in females, perhaps as a consequence of the high levels of human placental lactogen they'll see during pregnancy. Morning sickness is driven in part by hPL.

So quite the opposite. I would think that a female population, instead of us winding males complaining about adverse events, maybe no more likely and potentially less likely we'll see. We don't see that as a significant concern nor do we think body weight will be a profound concern. Interestingly, and this goes back to pramlintide years ago. The more overweight populations who are amylin replete, meaning they're hyperscreening insulin, hyperscreening their own amylin tend to be the most tolerant to amylin agonists. Those with type 1 diabetes who have wiped out their beta cells have no endogenous amylin are the most sensitive to the GI side effects. So as you go from type 1 diabetes to type 2 diabetes to plain obesity in the absence of diabetes, those that tolerate amylin the best, amylin agonist the best are the overweight and obese population.

Very clear. Any questions from the audience on petre specific before I'll get on some broader amylin? All good. Lots of evolution in the space in the last 12 months, as you've mentioned already, a few deals, et cetera. Remind us where you think petre stacks up versus competition? Yes, big picture, we'll start with that.

Yes. I mean I'll start with saying we have great confidence in the program, not just because it's ours and we own it. But I think looking at the Phase I single ascending dose and particularly the multiple ascending dose, the consistency of response to petrelintide, meaning every patient who's been exposed to reasonable doses, meaning above 0.6 milligrams, has lost some weight. And that's a 100% response rate. I don't expect that in larger long-term studies, but it is a very consistent weight loss pattern in those exposed to higher doses.

We have been quite clear that particularly around the receptor biology, what is balanced agonism across calcitonin and the 2 key amylin receptors, amylin-1 and amylin-3, we believe is ultimately the most advantageous for both weight loss and tolerability, and I'll give some specifics around that.

Many of you know that calcitonin receptors exist in the midbrain and hindbrain, likely there for a reason. They are closely tied to the amylin receptors. They are closely related to the leptin receptor. So all of these homeostatic systems that control ingested behavior, homeostatic behaviors that control body weight are tied to all 3 receptors, and I always sort of say tongue in cheek. The body doesn't put receptors where it doesn't need them. So these calcitonin receptors clearly have some role, at least homeostatic. If you wipe out calcitonin receptors in the midbrain of rats, they become metabolically disadvantaged, greater adiposity, greater weight gain, more dysglycemia, things like that. So we believe calcitonin agonism is not a hindrance, but actually a benefit.

The only pure amylin agonist that I would argue exists is pramlintide, short-acting, very difficult to assess compared to some of the longer-acting compounds. And the adverse event profile for pure amylin agonists or those that are biased towards amylin are at least emerging in some of the early studies as being slightly different. Cagri in that large Phase III program with CagriSema we think derisks petrelintide. Those are very similar molecules from the standpoint of receptor biology. With petrelintide, one of the reasons we believe it is a better-in-class, you get higher milligram dose exposures that are possible. So we can get 5 milligram, 7 milligram, 8 milligram, 9 milligram exposures. They are limited at 2.4 milligram, probably for a variety of reasons, the acidic preparation, antibody formation that they've seen.

Similarly, bioavailability with petrelintide is about 80%, about 30% for cagrilintide. So while that program and its safety profile, we think, derisk petrelintide's safety program, we think higher total dose exposure is likely. So that sort of sets the floor for what we would anticipate we could see in a large Phase III trial. So our mid-teens up to 20%, we believe, is supported both by that and our own modeling.

The other assets in the space, eloralintide got a lot of attention, both at the ADA meeting and the recent Japanese study that they reported. I would say it's still a very limited data set in my mind. The mid-doses, which seem to be well tolerated to me appear quite similar to cagri, petre and others. They do get one high, high dose, I'll call it, that gets a more exuberant response over a shorter period of time, I think, up to 11%. I think both the tolerability there and sort of the overlap in the mid-doses tells me I don't have enough data yet to say, is it better, worse, no different.

I would expect similar results with something like eloralintide. The difference we're seeing, just like with pramlintide, they've reported more headache, they reported some of these neuropsychiatric adverse events, which I don't know that they're related. Headache appears to be actually from the old pramlintide days. If you have a person at risk for migraine and you provoke with pramlintide, probably from profound activation of the amylin receptors, not CGRP, you can induce migraine. So although we think eloralintide has some calcitonin receptor activity, you see acute lowering of calcium, it, in their mind, is amylin predominant. Does that contribute to headache as an adverse effect? I think we've seen so little data from that.

Metsera talks about its monthly dosing, and now Pfizer and they are lined up to put forth monthly dosing of that and their GLP-1/GIP agonist. We have not yet seen data that convince us that the half-life of this or any other asset can readily be given once monthly. One of the risks with longer dose intervals is we know with GLP-1 agonist, amylin agonist, that trough to peak variation between doses is what contributes to the potential for particularly GI adverse events, meaning the more variation, and we did this with lixisenatide and pramlintide in the day because they were so short acting. But if you have a relatively moderate half-life and you see even with a monthly injection that rise and fall, I think that certainly doesn't abrogate the risks for tolerability and may actually amplify them a bit. The half-life that we've seen in our hands, we have a 10-day half-life with petrelintide, that could be given monthly, but we think we would sacrifice those same things.

I'm not yet convinced that the Metsera compound is readily or fully amenable to monthly dosing. We'll see in the data. And I think the MariTide data taught us a bit of a lesson on monthly dosing, what happens with variation. And I think in the Metsera, Pfizer studies going forward, they're going to do weekly and then go to monthly or transition to monthly. That's what they've reported, which may abrogate that, I don't know. But again, we are still confident that the pan-receptor activation, the higher dose exposure, the consistent Phase Ib data and hopefully Phase II data that we have with petrelintide sets us up as a better -- certainly better or best-in-class.

Got it. And then I guess, I mean looking at least timelines, it feels like cagri is going to be there first as the mono, probably Lilly and then probably you, I guess, a bit of a mix. So how do you assess the potential -- I'm happy to underwrite amylin versus GLP-1s and potential differentiation on tolerability. But how do you assess potential differentiation within the amylin class even of a slightly worse amylin, but is it amylin and amylin? Or do you think -- how much differentiation do you think it will evolve how the GLP-1s do? Any thoughts on that?

I mean I think I've already alluded to where I think cagri and petrelintide may differ, getting higher dose exposure, potentially greater weight loss with that dose exposure without sacrificing tolerability. So the tolerability profile of cagri, I think, is quite good compared to GLP-1s in particular. And as I already alluded to, I think that derisks some of the potential safety signals with very similar receptor biology.

As I've also alluded to, eloralintide just has a different character of the adverse event profile. It's very limited data, so I can't judge better, worse, no different. But I think a couple of things about our asset. One is it both for us and for Roche is being put forth as a foundational therapy, stand-alone monotherapy. And yes, the others will go with monotherapy. They also have very important GLP-1 franchises to protect. So how will they put that forth and still protect what are very important, both clinical and financial platforms for them. I think we have the opportunity with Roche to say, let's put this front and center. 388 is an excellent compound in my mind, but will it be part of the sort of additive portfolio. The fixed-dose combo, I think, as I've said, we can maximize petrelintide, optimize 388, and maybe make this the better option for the big number chasers that are out there.

So Phase II data and Phase III data for all, I think, will ultimately allow us, are they more similar than different? Are we in a space that is like dulaglutide and semaglutide, where they were quite similar in clinical efficacy? Or will we see a step change? The differences between tirzepatide and some of the first and second-generation GLP-1s I think showed us that improvements can still be made, first-in-class. If you remember, semaglutide was what, seventh-in-class. Dulaglutide was fifth-in-class. So first-in-class doesn't always mean best-in-class. But I think those to me are sort of the 3 leading candidates at this point, Charlie.

Yes. I would agree. And then I guess, how -- it sounds like -- just remind us in terms of any signals you've seen on the CNS side, Lilly on the CNS side. What have you seen in your profile? Are you confident you've not seen anything along similar lines?

Yes. We really have seen no neuropsychiatric side effects. We had one episode of jitteriness, another of a change in libido, which we report as neuropsychiatric. And in fact, the rates in our Phase Ib study of headache were lower than placebo. So quite the opposite of what some have reported where the rates are higher. The cagri program, I think, also supports that neuropsychiatric side effects despite some mumblings to that effect really did not show a significant change.

Higher dose amylin agonism, if you do rodent studies, looking at signs or symptoms of depression are actually antidepressant or should be antidepressant. Pramlintide was actually being investigated as such in animal studies. So I think there is, in fact, more than likely to be no effect or a beneficial effect, but that's based on nonclinical data, not on clinical outcomes, but nothing in our portfolio or the profile thus far with petrelintide that suggests any of either neuropsychiatric or headache-related events.

Got it. We'll have a look for the early data coming soon, I believe. And then on -- and obviously, we saw with the Gubra compound, adrenomedullin backbone, and then elora suggested to be more amylin specific, that turns out. I think your sort of previous commentary is actually in vitro, it looks to also have some effect on calcitonin. So it sounds like mechanistically, there's one side and then actually in the clinic, they seem to be all looking a bit more similar than expected. Is that a fair assumption? Or what are you -- how are you feeling about that?

Yes. I think receptor biology studies, for those who know them maybe even better than I, and I have to be careful, my wife works for AbbVie, Allergan, so I have to be kind to Gubra and their asset. But the receptor biology studies where you overexpress receptors in an artificial way in a cell line really is just mechanistic. Does it bind the receptor, does it generate cyclic AMP at a specific rate, and what's the affinity and potency of that receptor activation.

That's very distinct from what happens in clinical studies, and I alluded to the fact that calcitonin receptor agonism with virtually all of the DACRAs or pan receptor activators, what you see is a transient but acute and short-lived drop in serum calcium that is the consequence of peripheral calcitonin receptor activation that is not long-lived. In our hands and in other people's hands, Novo alluded to this in a presentation at the diabetes meetings this year, you see an acute drop in serum calcium with eloralintide, which suggests that while it may be amylin predominant, it is not purely amylin specific.

The only one, to my knowledge, that doesn't see this to any great extent, although there's some minimal cross-reactivity, is pramlintide, the old SYMLIN molecule. The others, I think clinical data will tell you much more ultimately than the receptor biology studies.

Very clear. And I will -- unless any other questions on competition.

It's Ben Yeoh from RBC Global Asset Management. I was wondering on the regulatory pathways as the sort of current drugs are pass through. Do you think the regulators will potentially raise the bar for classes and things coming through versus where we've seen? Or do you think as it is currently, we can expect that because sometimes they kind of do raise the bar on some of these things. And obviously, chats with the regulators have been a shifting landscape. So I was interested in your interactions so far. You kind of feel as trials are designed as of now, it's likely, obviously, they're clean and things like that, that will pass through.

Yes. I think, I mean the "most recent guidance," which is a bit older now than recent, but there were changes, but in the bar itself, not profound differences as we read it and as we interact with the regulators. I think the old 5% threshold, which was sort of, can we get an oral of some type across the line is sort of in the rearview mirror. We know clinically now that double-digit weight loss ultimately is probably where people will target therapies and virtually, all the therapies in active late-stage development are going to get there one way or another.

The real interest to me is categorically, even though we've had a few efforts to push for the highest number, the metabolic advantages of weight loss, some of the effects on comorbidities actually don't require 25% weight loss. Diabetes prevention is probably optimized at 10% or more. Most of the effects on blood pressure and lipids and lipid trafficking occur in that 10% to 15% range.

So I think as it relates to comorbidity, there may emerge some requirements if you're going to make that claim that you have to achieve a certain threshold that's much higher than the traditional threshold. I think there are a few components of the guidance. For example, all this talk of muscle mass, without actually showing functional differences, 6-minute walk grip strength, something else in a sarcopenic population. It's fine to talk about it in theory, and overfed rodents do really well with amylin agonist as an example, but showing functional changes in muscle mass or functioning, which is alluded to in the guidance. It's not enough to just do DEXA or MRI or something like that. So I think some of those secondary claims, if you will, or label language that we may see will be the ones where there's still a bit of an unknown.

Yes, thanks, Ben. And I guess sort of on that similar more big picture topic, orals, not something you have currently in your portfolio. I mean, yes, I guess, interested in bigger picture perspective of them. Is it something -- again, we see a lot of hype around it. Just interested in your view whether that we assume at some point.

Yes. I mean we keep our eyes and ears open for potential oral options. I think oral delivery of peptides remains a significant challenge even with the RYBELSUS asset and the soon-to-come obesity preparation, just cost of goods, the amount of drug substance that's required with peptide-based therapies.

I think orfo and related compounds, the Roche compound from Carmot have changed the conversation that these oral GLP-1 agonists in particular, maybe the oral amylin agonists like that from structure and others can play a role.

I think my own bias and I think our company position is while in other spaces, the diabetes space, for example, orals took 80%, 20% were left to the injectables, we see sort of the opposite here, monthly injectables, semaglutide now the tirzepatide franchise, the emerging longer-acting incretin agents and amylin agents really have become sort of the status quo, the standard.

If orals were to compete profoundly, I think they have to meet the same bar in efficacy and the same bar in tolerability. What I see in the orfo data, even in the complexity of taking an oral semaglutide is they do not achieve the same bar in terms of weight loss, at least in some populations and tolerability is no better, and in some cases, maybe slightly worse when it comes to GI adverse effects from the oral GLP-1s.

That makes sense to me sort of teleologically because you're taking an oral daily with a short half-life. And as I talked about earlier, trough to peak variation in exposure. And if you miss a dose, now you're taking another dose a day delayed from that decay. So while you can achieve steady state, I think if orals have met or exceeded the bar of injectables, the weekly injectables, but for those of you who know people or have yourself taken these weekly injectables with auto-injectors or multi-dose pens, it is becoming a sort of ridiculously simple approach. And I think the efficacy is there. We understand the tolerability, dose titration, managing adverse effects.

So if you were to ask me, and I think our sort of corporate position, this is still going to be an 80 parenteral, 20 oral market. There will be very important things about the orals, no cold chain. So you can get it there. Cost of goods is very likely to be lower. Certain markets that may wish to take orals versus injectables, some East Asian populations much prefer orals to injectables. I think in the West, with both sema and tirzepatide, we've seen a significant lowering of the resistance bar to injectables. But if a good oral makes its way known to us and we can develop it, by all means, we will. But like I said, it has to meet those tolerability and efficacy bars for us.

Very clear. And then just in the last minute, obviously, we've seen another GLP-1s reading out with some data in Alzheimer's fairly soon. You've got a GLP-1, GLP-2 both on the inflammatory side of that. So what do you want to see from the competitor read for you to get excited for your own asset to maybe move into that space or tangential spaces?

Yes. I mean I think I credit Novo for the work on evoke and evoke+. I think there is plenty of suggestive evidence. I mean we've known this for years that weight reduction, probably some improvement in glycemic control is likely associated with the lower risk of progression.

I think there are a couple of risks here. These early cognitive changes are tough to discriminate. So how will the treatment effect sort of emerge? Is it big enough to convince us to go forward? The second is the dose exposure is relatively low, which makes sense. This is not a population that needs to lose lots of weight or significantly improve glycemia. I do think if there is even a numeric shift in -- towards benefit, that will raise the interest in the community. And whether GLP-1/GIP, its effects on oligodendrocytes, GLP-1, GLP-2, which also targets the potential inflammatory component of neurodegenerative diseases, I think you will see a significant amount of enthusiasm if this is even directionally positive, whether it is statistically significant, clinically significant. If you can measure it, but it makes no difference functionally, how important is that versus something that truly transforms the rate of progression of disease.

So I won't try to predict the results. I think the risks are low dose in a relatively early stage of neurodegenerative change. The benefits are -- I think any evidence of benefit will go a long way to keeping people excited about that area.

Perfect. Well, we're up on time. Much appreciate the time. Always very insightful. Thank you all for joining.

Thank you very much, Charlie.