Novo Nordisk A/S (NOVOB) Earnings Call Transcript & Summary

Welcome again. Welcome, ladies and gentlemen, to Novo Nordisk Capital Markets Day 2022. My name is Lars Fruergaard Jørgensen, and I'm the CEO. And I'm delighted to see all of you in the room here today, and also a warm welcome to those of you participating virtually. Two and half years has passed since our last Capital Markets Day in 2029 (sic) [ 2019 ] and I would say a period with quite unprecedented events. If I start by Novo Nordisk, we are very pleased with how we have executed on our strategic aspirations, the progress we have made. But we've also gone through a period with, first, a pandemic and now war in Europe. So I think we should just take a moment to acknowledge that a lot of people have been suffering and some have been paying the highest price of all. It's during times like these that we put our priorities right, the safety of our employees but also, each and every day, making sure that we are there for the patients and making sure that they get the supplies they need. Those are our key priorities. And I would actually like to start this meeting by focusing in on our patient. I would like to invite you, Lisa, to come to stage here with me. Thanks for being here, Lisa, traveling all the way from the U.S. to be with us today.

Thank you for inviting me.

And you have been living with obesity a significant part of your life.

Yes.

So could you please tell our story.

Well, first, I would like to say thank you to all of you for what you do, it has changed my life. I have been living with obesity since I was very young. And it was -- difficult is an understatement. And I had tried everything I possibly could to lose weight, gain back, lose weight, gain back, the yo-yo everybody has heard about. And I heard about the trial and I got on the trial, and it changed my life. For the first time, I didn't feel -- and this is not -- I didn't feel crazy that I couldn't -- it was -- there was something, once I was on this trial, that in my mind, it changed. There was a switch. That's all I can say, a switch that turned on. And it's the best thing I ever did. And so thank you, all of you, who had all to do with that trial because it truly changed my life.

And how did it change your life?

I'm here. First of all, I never would have had the self-esteem or the belief in something that would allow me to speak about such a personal -- obesity, everybody sees it, but nobody talks about it. And to have the belief in something that I can actually stand on a stage and talk about something that is so incredibly intimate and private to me, although everybody sees it, it's that -- it was obvious. It changed -- that's how it changed my life. It changed my life in the sense that I'm a better person. I'm a better mom. I'm a better friend. I believe in myself. And I believe that I can do what I've set out to do. And I think a large part of that is to be an ambassador and to share my story with people.

Could you tell a bit about the importance of your physician or perhaps also a bit how the rest of the world looked at you?

Yes. Exactly. It took many years, so I found a doctor who believed that it just wasn't a lack of willpower, that it was an actual physical chronic disease that I have. And talking with her, she introduced me to the trial and very much supported and said, there's -- this is a chemical. There's something in your brain that isn't quite right and this trial will help you with that. And part of me was skeptical because I didn't want to put too much effort -- I didn't want to put too much belief in it because it was kind of the last straw. And when I got on the trial and I felt that change, I knew that she was right. And she supported me 100%. Unfortunately, there aren't a lot of medical professionals who do that. They tell you, you need to exercise more, you need to eat less. And 9 times out of 10, they themselves are obese. That doesn't seem to make sense, but okay.

So can you tell a bit about when you started using, what did it do to you?

Yes. It was -- as I said earlier, it was like a switch was flipped. I lost -- the cravings were gone. I knew when to stop eating. Something in my brain said, okay, you've had enough, you're full. You can stop. I didn't think about food all the time. I had more energy. I just -- it was -- as I said, it was like something had changed. And then when I went off the trial and I was off the trial for probably 2 weeks and I had a very, very emotional experience because I felt those cravings and I felt that desire come back. And I was like, this isn't right like I can't go through this again. And so I went back to my doctor, I'm like, you got it. We've got to do something. And so very thankful that Wegovy was FDA-approved in the United States because now I'm back on it and I'm feeling wonderful and that I'm here.

It was not just losing the weight? It was actually...

No. It wasn't just losing -- it really wasn't just losing the weight. It was more of the feeling of control and that it wasn't such -- that I wasn't thinking about food all the time. And I would hate to say normal, but I felt normal and that it wasn't such a big deal anymore. And using the drug has been beyond easy. So again, I thank all of you for everything that you do, whatever role you play.

And you can still find products in the U.S.?

Yes. It's been a little tough, but they're becoming more and more. I have a small local pharmacy that carries it. Some of the bigger ones don't. But I believe that they're starting to get more. I get lovely updates from you saying that it's coming. And so I like to -- I kind of think like it's because of me that everybody is wanting it, but it's slowly becoming more available. And so I hope more doctors and more health professionals learn about it. And I hope more patients discuss it with their health care professionals the possibility of getting on it.

I can promise you, we'll keep working at it.

That's right. I appreciate -- again, it's just -- it's wonderful. So thank you.

Lisa, thank you so much for being here and sharing your experience. You're quite an inspiration for all of us.

Thank you again for inviting me. This is truly an honor, and again, thank you all.

Good. Thank you very much. So I'd like to start today's meeting by just recapping our corporate strategy. It starts by our purpose: driving change to defeat diabetes and other serious chronic diseases. And the notion of driving change is something that's really important for us. It's about both forging on prevention, making sure that patients have access to our medicines, but of course, our biggest contribution is the innovation we make, the products we produce and bring to patients like Lisa. We do it with a focus on our values, the Novo Nordisk Way, so how we do things. And I hope you'll feel from my colleagues and everybody you know in Novo Nordisk that how we do things, our value is the Novo Nordisk Way, is really important to us. We also do it with a focus on being a sustainable company from an environmental point of view, from a social point of view, and of course, from a financial point of view. So this is a cornerstone of our corporate strategy and we have these 4 priorities around it. Strengthen our leadership in diabetes by bringing innovation, driving better outcomes for patients. Similar for obesity, by advancing treatment options like we just heard about the obesity market because there's still a lot of understanding to be established for this to be a market that's opening up. The third priority is in Rare Diseases, and this is a new name for biopharmaceuticals. Basically everything we're doing in Novo Nordisk is biopharma. So we said, okay, let's be a bit sharper on the terminology. So going forward, we'll call it Rare Diseases. And you'll see during today that we have a really exciting late-stage pipeline and we have a perspective on how we can go into adjacent areas and sustain growth in this area. And then we have the other serious chronic diseases, areas where we, based on technologies, adjacencies, think that is obvious opportunity for us to explore, to diversify into areas like cardiovascular disease, NASH and others. At our Capital Markets Day in '19, we introduced our strategic aspirations for 2025. So this is a slide from 2.5 years ago, and I'm really pleased with how we have managed to drive our strategic execution based on these aspirations. So both when it comes to purpose and sustainability, when it comes to innovation and therapeutic focus, when it comes to commercial execution and making sure we turn all of that into attractive financial growth and return to our shareholders, we are really pleased with how we're executing the business. I'll not go into all the details because you will, throughout the day, hear from all of my colleagues how we are progressing on each one of these. But I would like to share one slide about how we have managed to accelerate our sales growth since we were together in '19. And this is, of course, driven by our innovation and our commercial execution and we're very encouraged by the growth momentum we now are in. So throughout today, we'll try to explain how we believe we can sustain that growth; how we can, by maximizing our semaglutide opportunity, really drive growth in diabetes, in obesity in the short- to medium-term period, while investing in our pipeline, our technologies to make sure that we can also sustain growth after semaglutide. So this is our laser-sharp focus in Novo Nordisk and we'll share with you our plans behind how we execute on that. We have put together, I think, an interesting agenda. It's organized around the 4 quadrants of our strategic operations, starting out with purpose and sustainability, taking a temperature of where we are on ESG; moving into innovation, therapeutic focus and commercial execution in diabetes, obesity and then in the afternoon Rare Diseases and other serious chronic diseases. And then we home in on the financials, how we're executing in our 2 commercial operations, what's our perspective on product supply and what are the financials. And you can see that throughout the day, we have made ample opportunity to have dialogue with you so there are a number of Q&As, there are a couple of breakout sessions and we end up with a panel Q&A. So that's our plan for today. We will be talking a lot about the future, so I think you're all keenly aware of our forward-looking slide here. So please bear in mind that we will be making predictions of the future, which could end up turning into a different reality than what we preached. With that, I would like to hand over to Marcus Schindler, our Chief Science Officer, because it's all about the science we have in the company. So over to you, Marcus.

Thank you so much, Lars. And good morning, good afternoon. It's fantastic to be there. And I don't know about you, but for me, the ability to speak to a room full of people seemed like a distant memory for a very long time. So it's fantastic to actually have you here in person but also we're actually getting better at running hybrid meetings where we combine a virtual presence with us being here on stage and live in the room. My name is Marcus Schindler. I've joined Novo Nordisk 4 years ago. Actually, initially, I came in to help lead external innovation and bring more collaboration, more partnerships to Novo Nordisk. And I think if I look back over the last couple of years, and it'd be interesting to hear your reflections on this, I think external innovation, collaborations are no longer something very awkward or strange for Novo Nordisk. They have become way of our working. They're integrated in what we do. And as a matter of fact, we're going as far as saying that 50% of our pipeline by 2025 will be run in collaborative projects. And why is that a good idea? Because the world out there is pretty smart and they have good ideas. They might be even better if they work with us. And I think that is the value proposition for this piece. I then went on to lead global drug discovery. And last time you saw me here in 2019 together with Mads, we were talking actually about new disease area, which, when you see the pipeline later in the session on Obesity, Diabetes care and Rare Diseases, are maybe not as new as they used to be. And I think that is also a good signal for all of us. At that time, for those of you with a good memory, we also talked for the first time about a strategic collaboration, which seemed really big for us with a company called Dicerna, bringing SiRNA into our portfolio. And obviously, we have advanced on this position significantly. And I'll double-click on that a little bit later. What I'll try in the half hour we have together is to give you 3 pieces. One is detail our approach to drug discovery. There are things that remain and we continue, but there are also new elements that we are stem cell based on our existing baseline. Second, we'll talk in depth, also in the breakout session which we have this afternoon, about our technology platforms because this is really the toolbox for us to utilize when we think about which modality, which chemistry is best used for a particular target or particular treatment. And last but not least, I'll share some commitments we'll make with you and some expectations you can have on us. And of course, everything I say is future-looking and might not happen in the way we anticipate. But why are we here, right, and I think Lars already alluded to the purpose, we're here for Lisa, but we're also here for millions and millions of other people. Patients suffering from diabetes, obesity, cardiovascular disease, renal disease, NASH, Alzheimer's and rare diseases. And despite our best efforts, and I think you would agree in particular in diabetes care, we, as a company, but actually we, as an industry, have made significant progress over the last decade in particular. And for those of you, like me old enough to remember, in the early 2000s, it looked rather bleak for diabetes care. And since then, I mean, we have many, many more offerings. But look at those numbers, we're only serving a fraction of people who are actually in need of care. And I think that is something we want to change. So it's addressing unmet needs at scale, and I think this is really important. It's what kind of molecules, what kind of approaches do we need to take to have much, much broader offerings than we have today? But at the same time, for patients on good care, on standard of care, there still remains significant unmet medical need in all our disease areas. And I'm actually going to talk about both of these today. You might also remember last time I was here, we actually spoke about the powerful scientific basis that we have called GLP-1 receptor agonist, in particular, semaglutide because actually we've learned through this mechanism, and I think many of us were surprised, the multiplicity of biological effects we have seen with semaglutide. We started out thinking that would be a powerful glucose-lowering agent, and yet it has proven to be equally, if not more powerful, as an anti-obesity agent. We see very promising data on cardiovascular. We also understand actually how those effects come about. So it's not just taking a molecule and then putting it in new disease areas for good use, right, and I think that's the right thing to do. For me, to start with science is actually to understand why it works, what are the fundamental biological mechanisms that we are interfering with, that we're activating or blocking, that help us actually to see those effects. And that was our starting point, I would say, a number of years ago. And it's been very successful. I think we understand much, much more about this molecule than we ever did before. But I think it's also fair to say it has been an iterative process and one that has spanned probably the better part of 2 decades. So what if we put this biological inquiry, this deep understanding of molecular mechanisms at the very start, and we make our discovery biology-driven so we try to understand what are actually the key drivers of disease. What are some of the root causal genes? And then actually learn more about those rather than starting out thinking a target, a particular target, could be the best diabetes treatment. Stay what we call disease-agnostic and say, is this fundamental biology we're working with? And we'll come to some of those examples later. So we leave it a little bit open for longer to say whether we have a diabetes, obesity, cardiovascular target until we actually see for the first time data in the species that matters most to us, and that is humans. Now drug discovery, as long as I can remember, has relied heavily on observational studies. A lot of academic work that has been done largely based around animal studies. And then we observe those animal studies. We try to understand the systems, largely in rodents. And then actually, we try to make this leap of faith into humans. Does it actually predict what happens in humans? Are the biological systems similar, overlapping or are they actually distinct? And I would say the results are mixed, yes. Some mechanisms actually translate beautifully even in a quantitative way, but many also don't. And hence, this reliance on animal models has led us down a particular path. Just imagine for a moment all the targets that we have actually dismissed or devalidated in animal models that have never ever been tested in humans and we simply don't know whether they could be useful. So placing the species of relevance, humans and human data, at the very starting point and at the center of everything we do, I think, is a novel undertaking. It builds on what we have, which we are not going to displace entirety -- in its entirety, but it will actually add, I think, value. It will ultimately lead to an improvement also in our probability of success from target hypotheses certainly to first human clinical testing. Now you might ask me, so why is this new and why are you only starting with this? Now the point is to be able to do this, you need to generate data, human data, and we're now in the fortunate position. Maybe also after the earlier disappointments on genome-wide association studies in the early 2000s where many people were initially excited, but we didn't really see it coming through and turning into novel hypothesis for drug discovery, we're now in a position, largely through computing power, but also through a collection of what everybody calls Big Data to interrogate those systems much, much better and much more detailed. I am actually a great fan or very, very interested in what we call polygenic risk scores. So it's not a single gene that will drive whether you become -- have a propensity to become obese or be diabetes, but it's the multiplicity of small players, the interplay in a biological system that predicts whether you're more or less likely to progress. And understanding that, I think, is key, and we're making first attempts towards this. When I say data, it largely means, at this point in time data out of clinical, data out of cohorts. But imagine, we start stem cell based hypotheses for treatment out of wearable data. And I think this is the future we need to face. That ultimately leads us also to precision medicine because if you understand patient populations and root causes of disease much, much better, you can actually zoom in and say which part of the population has this particular biology in a very prominent way? Where will it make most sense to intervene with drug target x or y? That actually leads us to the fact that from a situation where we've given our drugs to everybody and we're looking at defects, and if we're lucky, we had pronounced defects, but sometimes we also saw a large heterogeneity in our response. Really, really strong responders but also people who didn't. Let's try to disentangle this at the very beginning and make it hypothesis-driven and that will actually leave us then to groups of patients. And they might get different drugs, different targets or different versions of it. Now when we talk about this precision medicine, we obviously also then need tools, molecules to address it. It's not just enough to observe it and say this is it. How can we then actually deal with it? And of course, you all know us as a company that is leading in peptide and protein therapeutics and that will not change. And later on today, but also in particular in the breakout session, I think we'll give you some very exciting examples on how we're actually taking our peptide and protein capabilities to the next level. This is our anchor point and this is where we stand. But we've also expanded our toolbox significantly. We now have SiRNA therapeutics to block intracellular targets. We're engaging on cell therapies. And we're making actually first steps in gene editing and gene therapy, largely for the benefit of rare diseases. But everything you see here has the potential. Whilst it might not be realized today, it has the potential to be applicable to a wide range of our disease areas that we're working today. And the fun fact is not only as injectables, but we can turn many of those treatment modalities, when it makes sense, also into oral therapeutics. I might have shown this to you before, but we've been excellent to work with targets that sit on the surface of the cell or are present in the circulation because then with our peptidic approach with antibodies, you can get to those targets. And we've, I think, been very good to make precise molecules that do exactly that. Now through some analysis, actually transcriptomic genetic analysis, we realize that this number of target is actually a fraction of the entire target space. And the vast majority, 21,000, sits within the cell. So we can't easily address that with our technologies of peptides and proteins. So how do we deal with this? And this is actually what led us initially to the collaboration with Dicerna and now to the acquisition that we've realized by the end of the year. Because what SiRNA can do is actually get inside the cell, and once it's there, it does a pretty cool job because with extremely high precision it knocks down a particular gene. And this gene is knocked out for a very long time, 3, 6 months after a single injection. But it's also reversible. So we're not actually altering something fundamentally here in the genome. So it gives you an opportunity to be safe, certainly well tolerated, but also extremely long-lasting. Now for those of you who've watched the field, you know that SiRNA antisense oligos have been around for the best part of 25 years and they've been interesting modalities, but they haven't really, in the past, made a big impact. I think for me, a game changer was when the so-called GalNAc technology was discovered. So basically, this is a molecule that hits a specific receptor on hepatocytes, on liver cells. And the SiRNA molecules can piggyback on what we call GalNAc. And GalNAc takes SiRNA highly selective to hepatocytes, it binds and it gets internalized into the cell and does its job. That's a cool starting point. And this is the fundamental value proposition we had when we entered the liver-specific collaboration with Dicerna. So why did we go to the acquisition? Because we feel, why should we stop at hepatocytes? What if we could do exactly the same for each and every cardiometabolic-relevant cell type in the human body? Muscle cells, adipose tissue and so forth. And we're doing exactly this. And for that, our capability on peptide and protein technology comes into play because many of the surface markers on those cells, the molecules we want to target and the targeting moieties will be peptides and proteins. So we feel it's actually a real ideal combination to bring our capability together with what we call the payload, the siRNA molecules, where, of course, companies like Dicerna are excellent. And we go as far as saying that we would like to unlock on an annual basis one new cell type with high selectivity. Now why should that be of interest to you? We have actually seen that from systemic application of SiRNA to the GalNAc molecules, which are liver-specific, the dosages, the cost of goods significantly drop roughly by factor 30 on the dosage. So we're actually making highly specific molecules for the cell type in question, right, which also don't burden the system as much. So I hope you can sense I'm very excited about this technology and I better be because we've made a commitment on this. But it was also an interesting journey. We had a productive partnership, so we had nearly 2 years actually to get together as partners. And I really want to call this out because it's important. It was not us assessing Dicerna only, it was vice versa. Can a small biotech, actually can they work with us? Do we have the right attitude to partnership? Are our competencies in this partnership, in collaboration actually clear? And are they tangible to the biotech partner? And the good news is the answer was yes. We've had not only a very productive partnership, but also an incredibly good culture of working together. And this is obviously something we will continue. Why were we productive? Because we set out in '19 and we actually started formally the first project early 2020. This year, those molecules were under clinical development and having First-time-in-Humans. So less than 2 years from idea, from entering the pipeline to clinical development, I think, sets really a precedence. And we'll come later back on our commitments, what we want to see in terms of time lines between what we call pipeline entry into First-time-in-Humans. It will significantly cut down those times. The molecules that were delivered to us were of high selectivity and high potency, low doses, right? And I think for every -- if I can't think of any one, every target we made those molecules together. So that's what I would call a scalable and reliable platform. And I would hope that you actually see this. It might -- some might have called it a bold move, I think it's actually a very logical move and a very rational move to complement our technology platform with this. Your next question to me might be, so I mean, you've never actually integrated a biotech company in the last 20 years or something like this. Are you not worried that you're basically destroying the value? And of course, we need to be very careful and we probably don't have a lot of experience in integrating biotechs. What we do have though, and I don't think we've talked about this a lot, is a concept that we call Transformational Research Unit and our cell therapy unit is actually a prime example for this. When we started to turn science ideas and research into an organizational setting to say we want to deliver on a novel technology with cell therapy in 2018, how can we find an organizational setup for us to succeed? How can this not be swallowed up or slowed down? Some companies choose spinouts, we actually chose a spin-in. So we created a unit with high autonomy, with a ring-fenced budget, with very clear purpose and leadership whilst being embedded in our purpose and our quality systems. But how they work, how they do their science is entirely left to the leadership team of this unit, which basically is the closest to a biotech that you can see. And we measure them entirely on output. And the output for the Dicerna TRU will be roughly 3 First-time-in-Humans per year. There might be good years, there might be years where we have less, but on average, this is what we expect from this platform. And I think we have good evidence to believe that this will be the case. And of course, it will penetrate, in effect, all our disease areas. But let me give you, and change the tact a little bit, I think a super exciting example of protein or peptide therapeutics innovation. And one question I think I often get also internally, are we done with insulin? I mean really is there anything left to do, right? And you see on the left-hand graph, and I apologize for it being overly simplistic because the reality is actually rather complex behind it, and we spent 30 minutes just talking about a single slide here. But you all know, insulin does its job to lower blood glucose regardless of where the blood glucose is, right? So it's a very powerful molecule, but somewhat unintelligent, right, if you provide it exogenously. And that obviously carries the risk of hypoglycemia, right? It requires frequent blood glucose monitoring. So what if we were stem cell based in a sensor, a switch, which would actually activate insulin when blood glucose is high and it's needed, but immediately switch it off when you reach normal glycemia and have a safety buffer built in that you're actually not dropping below normal glycemia. That is the value proposition of what we call the glucose-sensitive insulin. And we've actually, after years and maybe even decades of research, now put the first molecules in humans. And what we see is exactly what I've just described to you. It's early days. But we've seen the dynamic of the molecule doing exactly that: being active in higher glucose levels, being inactive at lower glucose levels. Now this is a molecule which we still need to understand. We need to understand the quantitative dynamics of this. And you will, by the way, see more and more of this. We are not stem cell based a motorway where everything will race through. This is a learning journey, a journey to understand which features of this molecule are useful, which features do we need to improve upon. But the really cool news is that the principle that we're seeing here holds true in humans. We're now taking it to the next step to actually not only test -- and sorry, I forgot to say that we've done that under glycemic clamp conditions, whether this principle actually holds true in something which is more of a real-life example in a meal test situation, yes? And that will happen by the end of the year. And I think by that, we'll have very exciting data to see where we take those molecules next. And I hope you agree with me this wouldn't be able by actually combining everything we know about insulin, but also being open about opportunities, novel chemistry space, novel binding mechanisms, to actually provide this high-fidelity glucose sensor. It's actually not only a sensor, it is an active switch. Another example here in obesity, right? And I've been around now for a while. I've worked actually with Novo Nordisk in the early 2000s in obesity in a joint collaboration when I was at a different pharma. And in the early 2000, many of our peers walked away because they felt obesity was so difficult. The regulators set this incredible hurdle of 5% weight loss, yes? We're looking back and I think we're smiling a little bit about this now, yes? But still, is it good enough? Is it powerful enough? Is it useful enough for everybody out there? You've heard about amylin. You're excited about the weight loss that we've seen and you know, of course, all the good features that come with the GLP-1 molecule. So imagine for a moment we combine those 2 properties. And we're not combining it just in a vial so they become co-dosed, we're combining it in a single molecule that actually activates the amylin receptor and activates the GLP-1 receptor. And to give you a bit more icing on the cake, we're not making that in injectable, but we're making it actually an oral molecule. And that is the reality. So this molecule will be tested in humans for the first time this year, and we're obviously excited to see the data on this molecule in obesity where we feel it has a huge potential. Cell therapy. And in the title, it's cell therapy and its collaboration because I think it's really important. And remember what I told you about this Transformational Research Unit, they're not inward-facing, they're outward-facing. They have more than 30 collaborations by now, working with different partners to really get the best out of them from devices to technology to biology. We've partnered, and I want to highlight 2 particular examples and we're going to double click on those in the breakout session a little bit, Heartseed and BioLamina and Lund. But let's start with the left-hand side actually because what you see here is both the opportunity space where we are concretely working in today in the disease areas. But the world is open because these are pluripotent stem cells. So in theory and actually in practice, we can make calls that replace many of the organ systems or cell types in the human body should they be broken. On the left-hand side of this circle, however, you also see that this is not just a science play. It's great to be able to make those cells in a lab and it's super cool, but that doesn't mean it's a product. We believe our strength comes actually from thinking end-to-end right from the beginning. We've invested early on and quite significantly in a manufacturing capability in Fremont, U.S. And we're actually thinking about commercialization even today about commercial models before we have the First-time-in-Humans. But we believe this is what it takes to actually think about the entire value chain, apply rigorous quality criteria, best practices in manufacturing to make those cells a reality as a product. And I think this is the winning formula. Human data will be informative. We're learning and it's exciting. But at the end of the day, turning this into a true scalable, sustainable product, I think, is the most important thing. On Heartseed, we're working on stem cells that replace cardiomyocytes in people suffering from heart failure, end-stage heart failure, right? This is where the place is. And we're actually working hard with them to have the first time in human this year in the first half. We're actually a little bit set back through COVID in Japan, this is where the trial will start because the first trial will be on open-heart surgery and we inject those cells directly into the heart. I can already see you're thinking that's certainly not a scalable model, and you're absolutely right. But we'll learn from it. And the next iteration will be to actually put this in a stent. So much less invasive and yet precise procedure to do this. And that is the journey for those cardiomyocytes. The second one is also very exciting in Parkinson's disease, high unmet medical need, in collaboration with Lund University and BioLamina. So those cells will actually directly be injected into the brain. This is where they need to be and this is where we can give a relatively small amount of cells that produce dopamine, so-called dopaminergic neurons, to the right brain center. And this study will also start in the first half of this year. So I hope you're seeing 2022 becomes a year of starting. Cooler is even to see results. So we'll share that with you, of course, when we're ready. If we put everything together, this is all very nice. It's new tools, new ways of thinking. At the end of the day, what my job is, is to deliver good molecules, new principles and work closely with Martin then in an informative interface to take those molecules all the way through clinical development to launch. What you will see from us in early development, and this is maybe the new thing we haven't touched upon, is our workhorse will become early clinical testing. The Phase I unit, we're actually stem cell based a physical Phase I setting not far from here. And this is the place where we will test hypothesis. We will spend significantly less time in the preclinical space. Many of the experiments we're still doing today in vivo hopefully will be replaced through modeling. We actually, on the outside world, see the first companies that take an entirely -- a molecule that is entirely based on machine learning into clinical development, right? And I'm not saying that it's true for all disease areas, it might not be a reality for everything that we do, but this is starting, right, and it's also starting for us. So taking -- making molecules as fast as possible, stem cell based new hypotheses, putting them in human, you see much higher throughput in First-time-in-Human testing. And I think that is really good news because this is where we test the hypothesis. You might also see and you will see that not every hypothesis holds true in humans. And that, by the way, is a good thing because we're testing it early. The winners, however, will go on to the proper Phase II trials, to the larger scale Phase III trials. And if you remember what I shared with you about precision medicine, hopefully, we're actually going to load the dice and have a higher probability of success than if we target a particular patient population, they will also uniquely benefit from the molecules that we've made. I hope what you've seen resonates with you is that we are stem cell based on our strengths. I don't usually like to say heritage or past because that's looking back where it's all about looking forward, but we're standing on a foundation, yes, and we're not leaving that, but we're actually expanding this foundation. But it's also our job to expand this. Human data, human data-driven decision-making, human data at the very core, this is, I think, the thing I want you to remember. And it's not just hot air. We will have concrete example this year out of all our new therapy -- out of new, sorry, our technology platforms to substantiate actually the claim that they will be an important benefit for our future. And of course, with that comes an increase in research productivity; a significant reduction in time lines, cutting it by 2/3 of what we are now having; and a significant cut in costs. And maybe that isn't actually the thing I wanted to end on, talking about cost as a scientist. But I hope you see we make deliberate and thoughtful choices in our way how we approach drug discovery, and I'm happy to have questions later on. Thank you very much. [Presentation]

Welcome to this session about the ESG, environmental, social and corporate governance. It's my pleasure to talk a little bit more to that together with my colleagues. And in just a second, we will be diving into some of the activities that we do in this area. Before we do that, just a kind reminder of our foundation on ESG, it actually goes many years back. And what you see here is a recap of our ownership structure with the Novo Nordisk Foundation, but also giving us the opportunity to provide long-term value, of course, for the foundation, but of course, also for our institutional and private investors. So that, together, gives an opportunity to focus both on the short term but also on the long term of driving a sustainable business. And what you see on the right-hand side here is the way that we focus on being a sustainable business really has 3 elements, something we worked with since 2004, something that's anchored in our Articles of Association. It says in there that Novo Nordisk has to drive a business that takes social responsibility, environmental responsibility, and of course, also financial responsibility. And when we add that all up, that's what we call driving a sustainable business. So that's what -- is what we will be looking into today. And it all relies, of course, on the foundation of the Novo Nordisk Way, the way that we do business. It's not enough just to reach results, but the way we get there is very important to us and very dear. So we will be looking at today, first, our environmental focus, our environmental strategies with Circular for Zero. After that, we will look at our social responsibility strategy articulated in our Defeat Diabetes strategy. And then we'll be looking at how we drive our business as a sustainable employer. And finally, how we reported all of this because that's a field that is developing a lot in recent years in terms of ESG reporting. So with that, let's just get into it and we will start with a focus on our environmental strategy. And for that, I'd like to invite Henrik Wulff, our Head of Product Supply, IT and Quality up here. Please, Henrik.

Thank you very much, Camilla, and good morning. So I look at our environmental strategy, we -- it's clear that it's one of our pillars in the company nowadays. And it's also important for you to understand, since I'm heading up both manufacturing, the quality and IT, I have a lot of impact on how we are moving this together with what we are doing together with our partners. What we have done in the company is that we have put it into 3 buckets so that we understand how -- what we are driving and which kind of aspiration we are setting. So first of all, in this ever-growing world with ever-growing activities, we thought it was important to state what the end goal is. And the end goal is basically to have 0 impact on the environment. And we want to do that both how we operate internally but certainly also around us. So we have put in sort of 3 dimensions here, what we called a circular supply. It's basically us and our surroundings around the company working with environmental activities. That means that we are working actively together with 60,000 suppliers to Novo Nordisk to discuss to progress this agenda. It's a tall order. We have some experience, they have a lot of experience and we try to share these experiences and put pressure on ourselves to improve on this. Secondly, we, of course, also know what we can do, how technology and advancement has created opportunities for ourselves internally in the company and we are working a lot with our internal processes to improve those. Thirdly, then I'm painfully aware of the requirements from quality and from our patients of delivering high-quality products day in and day out worldwide. You might know that we are heavily depending on cold chain, for example, and there is no way that I can compromise cold chain deliveries worldwide. All these things goes together in our products to make sure that we deliver high-quality products, but that also comes with high-quality plastics, high-quality glass, high-quality metal, high-quality needles, high-quality protection of our products and that we need to work with because right now there is no 0 environmental impact solutions for all these compounds that we are using in a global operation. So that is a heavy burden that we need to work with and we are, of course, very aware of that. If you look at our emissions, then we basically also have a 3-tier approach. We are, first of all, also trying to have 0 ambitions on our emissions. And the reason why we have put '45 on this is that we want basically to have our entire value chain and supply chain to be a part of this. So that also include our suppliers. If you look at the different pillars, then you can say that Scope 1 is what we do internally in the company. And just one simple example I think we all understand nowadays is adjust all our company cars worldwide. They must go into CO2-neutral solutions and that means that we are into a heavy push for electrical cars. The Scope 2, the indirect emissions for our part is, of course, what we have already announced around our direct buying of sustainable energy: wind power, solar power and we also are working with biogas solutions. And then, finally, you can call it the rest or you can call it the wider and the more complicated part is basically to have the whole ecosystem working with this. And that goes our collaboration with our suppliers. It's our business flights. It's -- now we just announced that now we also try to help the flight industry to get on more sustainable fuels. So we have also committed ourselves to help in that way. And all in all, we have now seen a reduction since we were together last time in '19 of 43% of our CO2 emissions. And we will continue this journey in all 3 dimensions when we move forward. And one important part of that, also a part of our deliveries nowadays, is our pens, high-quality pens that we are using for all our products. And there is a significant activity surrounded by that to get to more sustainable solutions.

Yes. Exactly. Thank you, Henrik. So also on the plastic footprint, we are starting to work on how we address that. We are not as far, as Henrik just explained, that we are on carbon emissions. But on plastic, it is clear that if we need to develop better and better solutions that Marcus was just talking to, how do we ensure that we don't leave a much bigger plastic footprint? And if we just continue the way that we do now, our plastic footprint for the future will, of course, increase significantly just like the volume that we get out there. So we need to look at 3 different opportunities to address that. And I think it's fair to say that we haven't found sort of the silver bullet on how to do this yet, but we are starting to engage in partnerships with others on how we do this the best way. Three different logical option is, one, of course, to source better plastic. It could be bio-based plastic, it could be even biodegradable plastic. This doesn't exist today in amounts that would be sufficient to the volumes that we need to produce, but maybe over time it could or it would. That's why also we are putting some of these pleads out there so that other companies are willing to engage with us on how we do that. Another way to do it is, of course, to change our devices to more durable devices where we actually have a lower plastic footprint, also a lower carbon footprint. That has, for many years, not been the desired approach from regulators or from payers and for patients either, not. But of course, as we develop some of those, they might be more attractive for the future and then we have an opportunity to change to that. At the same time, we also, in our innovation and in our device research, need to look at how we can, of course, base everything on newer types of devices that are more friendly for the environment when it comes to plastic. And then we are also, at the same time, looking at if all of this does not work out in the first coming years, we need to pilot about how do we find a way to get the plastic back, how do we find a way to take the devices back? So we've now initiated pilots in Denmark last year on taking our pens back, so that could be our FlexTouch, our FlexPens, that, that could be handed in the pharmacies. We experienced a 20%, you can say, take-back rate or device return rate, which was quite satisfying for us to see that this is something that people living with obesity and diabetes would like to do. So we are embarking on new pilots now in different types of countries, but primarily will be now the U.K., Brazil and also France. And at the same time, we are also now expanding the pilot in Denmark to be for the full country. So for those of you who live in Denmark, you will benefit from that now. So that's the way that we address the plastic footprint and more to come on this in the coming years. If we then move on to our social responsibility strategy, then that is defined in what we call Defeat Diabetes. It really has 3 elements, and Marcus was very nicely talking to the first element. Our core contribution from Novo Nordisk to society is really the innovation that we bring forward. That is what can really change things. But we also understand that not everyone gets access to innovation immediately. And still in this world and across all countries, also richer countries, there are still groups of vulnerable patients who do not get access to insulin primarily or other very, very important and life-saving products. So based on that, that's a core element in our social responsibility strategy. And then when we developed the strategy discussing with NGOs and others, it's also clear that one thing is to solve the problem that has happened. A much better thing is, of course, to make sure that the problem doesn't happen. So what we also need to do is to invest our efforts both in research, but also, of course, with our partnerships with big cities to look at how can we bend the curve, how can we prevent more people getting diabetes and obesity. So let me just give you a few examples on prevention first and then we can move into access and affordability. So on prevention, we have now established partnerships with UNICEF on preventing childhood obesity. We have started in Latin America in countries where the prevalence of childhood obesity is above 30%. So it really means that if nothing is done, this will escalate. And as you know, obesity being a chronic disease, this is something that will impact many of these children for the rest of their lives, the societies in terms of cost but also, of course, the health status in the country. UNICEF themselves expect that based on the learnings from this, we can impact situations for more than 1 million people in other countries, in 30 other countries, just based on these learnings. At the same time, we're also working with our Cities Changing Diabetes project. Here we have now more than 200 million inhabitants in the 41 cities that we are collaborating with. This gives us an extremely good opportunity to work with them on how do we make cities more livable, how do we make sure that there's access to healthy food and that there is access to exercise opportunities also. So this, in combination, means that we have -- there are strong partnerships to execute on some of the opportunities to bring down the prevalence of diabetes and obesity. But prevention, of course, is one thing, but a lot of people are already looking for how do they get access to the treatment that they need. And in 2021, as part of our access and affordability program, we helped 5 million people with that. One solution doesn't fit all. So this program consists of many different ways to do it in different countries. What you see here is that we have an access to insulin commitment in 76 countries where we now have reduced the price of 1 vial, they last for about a month, so a monthly insulin support to $3 per vial. And that basically means that we reduced it from $4 and that now helps 1.7 million patients across the world in these countries. You saw in the video just before we started this session, we also have a Changing Diabetes in Children program that gives access to free insulin for now more than 32,000 children. This is on our way to reach 100,000 children that we estimate do not have access to life-saving insulin in low- and middle-income countries. We now have 18 countries joining this program and more and more lining up. So I think already this year, we will be able to add very soon a number of new countries on this program. And just want to reiterate that for these children, there are no alternatives. They don't have access to any other insulin. But then in every country, there are groups of vulnerable patients that do not have access to medication. And those we are addressing by doing an assessment in every country who are those vulnerable patients. And of course, they exist in all countries, even in the U.S., which I'll come back to also in a minute. And then finally, in the U.S., our suite of affordability offerings that goes on a number of different efforts. We have a $99 insulin approach. We also have approaches for people who drop out of insurance and need a rescue treatment. And all of that can be found at novocare.com. This is an important way to make sure that no one should be in a situation where they cannot immediately get access to insulin if they need it. So we now have around 1 million people involved in this program. But actually, if we take in other solution, co-pay cards and other things, it is even more patients that we are addressing with this. So affordability is one thing for those that are not insured, but also in the U.S. for those that are actually part of either commercial or private insurance or government insurance, we also have addressed how we work with our list and net prices. And here you see for insulin how the -- over the last 5 years, how the list prices have developed from index 100 to 115, but how the net price at the same time for insulin has developed to index 16. And if we do the same for the full portfolio, you will see that net prices are now index 40 compared to what they were -- whereas list prices is of, as you know, a completely different picture in the U.S. with index 122. So this is just to say that there is -- in the U.S., net prices have declined in the last 5 years on a net basis. And of course, list prices doesn't reflect that true picture. But unfortunately, price is not everything. In a number of areas, we are looking at barriers beyond price and just very briefly working with the World Diabetes Foundation on how to digitalize capacity because we find that even when we lower prices in low- and middle-income countries, more people do not necessarily get access to treatment because the infrastructure is lacking. So if we can replace that infrastructure with a digital infrastructure, can be on the phone, then of course there's a much better opportunity to provide care to many more people. At the same time, innovation also plays a role here because we are now developing a thermal solution for human insulin that would be stable out of -- under 30 degrees for more than 30 days which we have submitted to European authorities for approval. It's not approved yet, but this is just a way to prove how innovation can also bring access to more people. And then finally, iCare is a good example of how we work with diabetes in Middle Africa, where we give access to many people, but not just access, we also help with capacity stem cell based, education, reach and so on. And this, of course, means that we can help build an infrastructure so that more people can get access to treatment. So in summary, a lot of different initiatives because that's what needed to make sure that more people have access. And with that, it concludes our environmental and social part, but then we will talk a little bit more about how we would like to be a sustainable employer. And for that, I'd like to welcome Monique Carter.

Thank you, Camilla. Good morning, everyone. I'm Monique Carter, and I'm responsible for people and organization. And without our people, none of these ambitious plans would be possible. We are a purpose-driven organization. And despite the growth in our company, we're now at 48,500 employees, we continue to have a high employee engagement and high employee retention rates. And one of the reasons for that is because we have an employee listening strategy. So we conduct a global employee survey, where we measure ourselves on questions which are important to our employees. It's simple. It's data-driven and it's benchmarked against 113 other organizations. Some of those organizations are some of the big boys like Microsoft, Apple, Google as well as some of the pharma peers like AbbVie, BMS, LEO Pharma, and of course, ourselves. But what we're really interested in is making sure that we benchmark ourselves against the most engaged companies. And what I'm going to share with you now is how we fare here. So we have an overall engagement score of 84. What I would like to highlight, though, is that we have a really high score on purpose. We scored 94 here and this is in the top 1% of the most engaged companies. And I think this is really a testament to our employees' commitment to our patients and some of the stuff that we've talked about already here today. We have some areas that need improvement, and inclusion is the area that I'd like to call out here. I'll talk more about that later. But I think all in all, we are really listening to our employees, and that's why we get an 81% response rate. Now I want to talk about the kind of employer we want to be. And what I need to call out here is that this is the reason that we're updating our strategic aspiration. We want to be recognized as a sustainable employer. So we talked previously about core capabilities and about our culture. We've got some other elements that we want to focus on. And as I mentioned previously, inclusion is one of them. So the kind of employer we want to be is an employer that actually represents our patients and the markets that we serve. We want our employees to be able to thrive in this environment, to be able to innovate and to be able to perform at the fullest extent of their capabilities. And that's the reason that we call out these 3 focus areas. So when we talk about being an employer for the future, we want to recognize that with a changing world, we have to be modern and progressive. And things like flexible working and working from anywhere become more and more important, particularly in the last couple of years with COVID. We also want to be a talent incubator. So if you think about the company and the growth that we have, the new therapy areas, the new technologies, we need to systematically and deliberately develop our people in order to be able to fulfill that growth. And then, lastly, we want to be inclusive and diverse and I will talk about -- more about this on the next slide, but I think it's fair to say that we're not yet satisfied with how we're doing on this dimension and that's the reason that we recently made an aspirational target about gender. So on that aspirational target about gender, we are looking to achieve gender balance of 45% women and 45% men in senior leadership positions by 2025. And you will notice that our definition of this target, there is a 10% flexibility. And that's to account for non-binary and also for employees that do not wish to be categorized. Now I have to call out that, for us, diversity is more than gender. There are so many different aspects of diversity. However, we have to start with this one because we also recognize that in the countries that we operate in, it is not possible to set targets for some of the other dimensions of diversity. But it starts with being an inclusive culture where our employees have a sense of belonging and can deliver their best work every single day. And to do this, we also have backed this up with a number of other initiatives, including HR policies and practices, things like offering parental leave for nonbirthing parents, doing work on equal pay analysis, looking at recruitment policies and ensuring that we have diverse slates, looking at linkages from STI and LTI, I could go on, there's a huge long list of things that we've done. But not least, the most important area in the line of business is local action plans. So we have a kind of market-fit approach where we empower our leaders to actually come up with local actions, which they can focus on in their particular geographies based on the specific things that need to be improved. And with this, I'm confident that we will be able to tackle some of the issues around inclusion. And over to Karsten.

Thank you, Monique. Just closing out on the ESG session. We deal with ESG data as we deal with financial data: we drive performance, we track performance on an ongoing basis and we are incentivized on performance on an annual basis on STI, LTI, management incentives. It's not IFRS-like financial data, it's SASB, TCFD, and other types of standards we are adhering to when we report our ESG data, but we are linking to the outside world to report in a way that we all understand in a global setting. And as a result, we are being recognized. You know many of the third-party raters, so whether it's MSCI, Sustainalytics, CDP, Access to Medicine, so we're being performance managed, we're being assessed by third parties and they assess us really positively. So that's a simple story around our reporting and transparency on ESG. This is something, it's a maturing field. We continue to drive it. So in conclusion. On ESG, clearly, you can hear we have clear plans. We are executing on the plans. We're performing. It's integrated in our business, whether it's manufacturing, commercial, R&D, it's fully integrated. Lot of progress, Defeat Diabetes, Circle for Zero. And we have a lot of activities going on within access and affordability. 5 million people with diabetes globally benefiting from some sort of access and affordability program provided by Novo Nordisk, I think that's an impressive number. And then as Monique said, we have a new aspiration linked to being a sustainable employer. This is a core advantage for Novo Nordisk going forward, a core competitive advantage: to be a sustainable employer, having the best people on board, being the greatest place to work. So with this, we're now moving into our Q&A session. So I'd like to invite my colleagues from the first 2 sessions on stage.

And to cover the logistics during Q&A, then I would like each person asking a question to restrain to one question per person. And please state your name and affiliation. And doing so, we should be able to get through the room. And I think Michael Novod was the fastest down here.

Michael Novod from Nordea. Maybe a question to Marcus regarding now you have [indiscernible], so you're also getting all the fancy names. But just all the progress seen regarding bioavailability of the SNAC technology, how is that going? And including in there, also how do you optimize so you can avoid the significant fasting state after taking a tablet containing either semaglutide or [indiscernible] or whatever.

Yes. Great question. And you all know, we've obviously been working with the SNAC technology for a number of years. We've acquired the Emisphere Technology, not that long, 1.5 years ago. And this is what we call Version 1 or simple SNAC. And this is what we're using in our current drugs. We've now actually in research and some things in early clinical development moved towards Generation 4 and I might go as far as saying Generation 4.5. So we're seeing significant process -- progress in moving the chemistry and the technology forward. Now the iterative cycles, of course, because we need to make and test, but it's an ongoing journey with actually a significant commitment internally.

Thank you, Marcus. Thank you, Michael. Then we move to Richard Vosser.

Richard Vosser, JPMorgan. Actually, also a question on the [indiscernible] product as well. And just thinking about the preclinical data you've seen relative to free GLP-1 and free amylin. What does that look like? And how do you get the right balance in the molecule between the activity on GLP-1 and amylin?

Yes. I think that is a great question in any dual molecule, what the right balance is, I think we'll find that out in clinical testing at the end of the day. Obviously, we've hypothesized here that potency on either of those agonistic principle makes perfect sense. We see very promising preclinical data. Otherwise, we wouldn't have progressed into a clinic. And the combination product or the new molecule is superior to the individual components, of course. And we'll show those data when we're ready to do that.

Thank you, Marcus. Then we move to Florent.

Florent Cespedes from Societe Generale. Question for Marcus again. It's a question on the Transformational Research Units. Can you share with us what is the specificity of these units? You mentioned that you are already some which are available. How could -- what do you do differently from your peers? And what could be the most relevant metrics beyond the one which is mentioned on your slides?

A fantastic question. We started those TRUs when we found signs or technologies that didn't quite fit our we called core at that point in time, which also then meant maybe we don't have the efficient systems, governance setups or matrix working to actually deal with those technologies, and cell therapy is a prime example. But we're also calling out our research unit in Indianapolis, which actually works on peptide innovation. If you remember, it comes out of the group that Richard DiMarchi has built. And they really think proverbially out of the box on what you can do with peptide therapeutics. And we leave them this space to innovate without interruption, yes. And I think it's the culture that is created in those units that maybe is the most prominent feature and I think I would argue also an important output of those units. So that house is not only to produce to the pipeline, but also to learn, test and bring back to the larger organization organizational ways of working, how you give autonomy to more self-forming teams, how you can actually derisk novelty in a very smart way. So that's what we're actually learning from those units, which is a very important output for us. And we'll try to use those concept whenever we see something, which we think deserves a special attention in a good way. There's no one size fits all. I think you also said it on one of your slides, it's bespoke and it's a deliberate choice every time we do this.

Thank you, Marcus. Super exciting. So now we move into cyberspace and to London, I believe, so over to you, Wimal Kapadia.

Can you hear me?

Yes.

Yes. Perfect. So Wimal Kapadia from Bernstein. Apologies for not being there in person, we can blame COVID. So maybe just another one for Marcus. Maybe we come back to in the breakout session, but just the glucose-sensitive insulin, how are you thinking about the reception to this molecule? I know it's quite some time away, but Tresiba-reduced hypos was met with some hesitation at least from payers. And the absolute rates of hypoglycemia, at least for Tresiba, are relatively low. So I guess my question really is, is a glucose-sensitive incident that different? Is it a big enough step-up in innovation in a commoditized market?

So I can speak about the science. And maybe, Camilla, you can take the piece around the market. For me, it is giving insulin basically the best possible environment to unfold its action, but doing it in the most possible best, safest way we can think of. And I would argue, in talking to a lot of patients, that actually hypoglycemia remain a concern for many people suffering from diabetes out there. And it is our task. If not we, who else should drive the science forward to bring those novel molecules forward? And over to you, Camilla, on the positioning.

Yes. Exactly, Marcus. So when we talk to patients and their families, the biggest worry is that the blood sugar keep being either too low, which is very uncomfortable and even dangerous, or too high. So how to get this balance right, of course, is a daily, you can say, struggle for people. And now with our connected pens, we have been able to provide the data on how many units has been injected by when and then combining that with the data from the continuous glucose measurements. That's a kind of a way to approach this. But of course, much more complicated than if the insulin was just so intelligent that it would only work when it had to. So there is no doubt that this will be a major relief for patients, in our view. Still difficult to work it out, I hear, but we are progressing on it.

Thank you, Marcus and Camilla. Then I think we have time for one last question. Keyur, Goldman Sachs.

It is a slightly broad caution, which is, Marcus, what you are suggesting today is a very fundamental rewrite of how Novo has developed products kind of moving forward. So if you're indeed successful, my question is, what does that mean kind of for everybody else on the podium? So Karsten, what does that mean from your perspective, evaluating kind of R&D spend, R&D success? Henrik, what does it mean from your perspective on production time lines? What does that mean for production technologies you're going to need over the next 5, 10 years? Camilla, what does that mean relative to the ESG stuff because you'll take away a lot of kind of plastic, perhaps not, [ if it is all about ] injection. But just if that fundamental rewrite of how you're doing research changes successfully, what does it mean for everybody else?

Thanks. Keyur, I think it was a very broad question. And I think, Lars, perhaps taking a top down based on our operating model, moving into new disease areas and new modalities?

So I don't see it as a complete rewrite. I see it as something we do on top of a very strong platform, and I think Marcus also mentioned that. So we basically think that by adding additional technologies that, to a large degree, are synergistic compared to our protein peptide platform, figuring out also considering when we can go the [ order ] route, we are stem cell based more choices to apply up against the biologies we know really well. So I think the go-to market, of course, if it's a stem cell-based model it's quite different. But I think it is also quite attractive because you can get to a very few centers to reach patients. So from a commercial model, it's much simpler. But I think largely speaking, we are leveraging the biologies we know and the market approach we know. And we know that we have a really long tail on the products we have. So we will have to keep producing all the volumes we know. We will have to still have many devices. But we are adding some more technology choice to it that will, of course, expand a bit the complexity of what Henrik has to manage. But as we look at Novo Nordisk as a growing company, that's what we believe we can handle. So it's not a fundamental rewrite. It's actually giving additional options on top of what we have. And I think throughout the day, you will hear how we talk to some of these new opportunities, both from a commercial point of view, a clinical point of view. So maybe we can recap on it when we have the closing panel discussion at the end of the day because I think we will address many of these elements throughout the day.

Definitely.

Thanks, Lars. This concludes the first 2 sessions and the Q&A. So now it's time for a break. You will be able to corner us somewhere around the coffee machine, management. So for the questions not asked, please reach out. And then we'll be back at 10:35. [Break]

All right. Welcome back to the diabetes session, which we will now get into. And we just heard about social responsibility. And now we'll take a deep dive into some of our strategic aspirations in diabetes and how we are going to fulfill those. So with me on this session, there will be several colleagues, but we will introduce those as we go along. You will recall, 2 strategic aspirations that we have in diabetes. One, of course, is to reach 1/3 of the global diabetes market value in terms of our share and then further raise the innovation bar for diabetes treatment. So both of these things, we've talked already about, the innovation and the science, but we will get further into some of this now. But let's just take a starting point in the problem that we are trying to solve. Because today, 1 in 10 people have diabetes, are living with diabetes. WHO expect that in 2045, it will be 1 in 8 people that are living with diabetes. And this, of course, gives rise to a company like ours to say we have to do more about solving this problem. So today, we also know that not everyone is diagnosed and not everyone is treated. We help treat 35 million people. But of course, many -- and that is approximately 40% to 50% of people are not in good control of all the people that are being even treated with -- for diabetes. Our approach to this is, of course, to continuously build our pipeline. And here on the upper part, you see our in-marketed products. You see that we have solutions in place no matter where you are in the treatment cascade. If you are uncontrolled on OADs, Rybelsus will be a better treatment for you. And we have also high dose oral semaglutide in development for this particular group of patients. When it's time to get to the first injectable, Ozempic is our solution to that. And Ozempic actually has proven in clinical trials to get 80% of people in good control, down below 7% in terms of HbA1c, but also to reduce the weight profile and have a very, very strong cardiovascular risk profile. For the next step, we have Ozempic 2.0 in development and about to be approved and launched. And this, of course, means that there is an opportunity to stay on Ozempic for a very long time to keep the product that you know and stay on the device for several years in a row. And this, of course, is an opportunity for patients to just keep having a blood sugar that is in the healthy range, having a lower weight profile and the increased cardiovascular strong profile that Ozempic can provide on GLP-1 treatment. Then at some point in time, some people will need to get to the first basal insulin. Here, we have Tresiba, and you'll hear a little bit more also about icodec later, our once weekly insulin, and the opportunity that we can provide with that. And then, of course, we have combinations of insulin for those that need more basal insulin in terms of Xultophy and also meal time insulin in terms of Fiasp and Ryzodeg in the future. And earlier on, I also talked about that we complement some of our insulins with injectable devices that actually now can send information about what insulin has been injected, by when, how many units and combining that with glucose sensors. Then, of course, the data provides much more information to patients and providers. And we know that patients can get 2 hours more in good control on their insulin if they combine the data from the injection device with the glucose monitoring device. And we are now partnering with more than 99% of the CGM companies for this in a nonmonetary partnerships that actually just work so that the data will be shared with the patients and the doctors. So this should be the best possible opportunity for patients to get in good control. When we look at the market and how it has developed, total diabetes market, you see here that between 2018 and '21, there has been approximately a 5% CAGR on the value growth. And of course, going forward, there are a couple of dynamics important to be aware of. The growth so far has been led by GLP-1s and by SGLT2s. We expect parts of that dynamics to continue. But be aware, of course, that growth is now on a much bigger base. So that, of course, might have an impact on the actual growth rates. On the DPP-4 segment, they -- here, of course, growth has been significantly smaller, but also we need to take into account that in the next couple of years, DPP-4s will lose exclusivity. So that is an impact that will also be seen on the total diabetes market. And then on insulin, we expect a continued relatively modest volume growth, but there also a continued price pressure giving more entrants into the field, more biosimilars in the field. So these are the 3 most important dynamics to take into account when looking at what to expect for the future on the total diabetes market. Having said that, the potential for GLP-1s is still big. We now today know that approximately 3% of patients are on GLP-1 of the total treated patients. And this, of course, is around 6 million people treated. But of course, this has expanded significantly over the last years and has been driven by new launches. You see here, Ozempic and Rybelsus being launched and how that drives the growth of the market. But 3% being treated is still a relatively low number compared to the total potential. So here, of course, there is also a potential for continue to do that, and that is a big part of our focus. And to make sure that we just get into that, we will talk about our 2 operating units in a minute and how we do that. But before that, I just like to show how Novo Nordisk has progressed over the last few years in terms of our growth in diabetes, but also in our market share achievements. And you see here that we are now above 30% on market share at 30.3%, and we are progressing towards our strategic aspiration of achieving more than 1/3 of the global diabetes market share. So that is our aspiration and now into a little bit more on how do we then drive that in our 2 operating units. And Mike Doustdar, we'll start with you and the International Operations.

Thank you, Camilla. If you deep dive into the diabetes sales in International Operations, then the graph shows a picture that the double-digit growth has been maintained for the last number of years. We have had a record year last year. And then when you try to see where that comes from, it is really stabilizing and slightly growing our insulin franchises while really getting majority of the growth from our injectable GLP-1. And you have seen nothing yet on the whole oral GLP-1, and I'll speak to that as I go forward. It is really on the back of the next-generation insulins where we are able to deliver the insulin results. Tresiba now has gotten leadership in 20 markets. That's something we could have never done with Levemir. You had, after 10 years of Levemir, only 2 market leadership in the basal segment, now we have 20 and ever growing. Our aim, of course, is to take the 37.7 to 50 percentile, which then gives us the absolute leadership we have in the other segments of the insulin. And we have Ryzodeg for the markets that have decided to predominantly give a premixed insulin to their patients. And that, of course, to a large extent, is China for us. On the injectable GLP-1, it is about Ozempic. And of course, Rybelsus is bringing us to the whole new world of the orals, and I'll try to touch upon all of those. Let me first start with our largest market and the one that, of course, as a single country, we pay the most attention to in International Operations, and that's really China. China is about 1/4 of our patients. It's about 1/4 of our diabetes sales in International Operations, and you can see that. Now it's a market that holds huge opportunities due to the unmet need, more than 100 million patients with diabetes live in that market, but it's also a market that gives us a lot of challenges with regards to the risks. And we have seen some of that this year with the introduction of the volume-based procurement; the change of the health care system, which is taking 3 percentage off of our growth rates in Novo Nordisk. In short, for those of you guys who are not familiar with a VBP, it is really a tender-based system where the government came and decided to reduce the prices of all insulins by around half. Then depending on which category, based on your price, you ended up in, you could keep some portion of your volumes. We ended up keeping 50% of our volume, but we did have to go down some 40%, 50% on our prices of certain products. The good news is those products were the older products. And we have a few of the newer products, specifically speaking, Ryzodeg and Xultophy, and then, of course, Ozempic, who are not -- which are not part of the so-called VBP platform. So the strategy for us to move as fast as possible the older generation products and the patients on those into some of the newer platforms of Ryzodeg, Xultophy and so on and so forth. All in all, it's a very large market. It says DKK 25 billion. That's actually according to IQVIA, which only covers half of the market. It's DKK 50 billion market, growing around 7%. If we can do the market growth plus gain market share like we have done for a number of years, I'll be incredibly happy and proud. That's really the name of the game. And to be able to expand within the GLP-1 segment on the back of Ozempic now being reimbursed and eventually bringing, of course, Rybelsus is really the strategy in a nutshell for China. Now speaking of GLP-1, that ends up to be, of course, my biggest growth driver in terms of diabetes and the future of diabetes in the mid to near term. As you can see, it is growing relatively fast. It has gone from 5 percentage of the value of the diabetes market in International Operations just a few years back to now 14%. That is a good growth rate. But if you put it in the perspective of Doug, who will speak right after me, that 14% of mine is 32% for Doug right now. So I, of course, see a bit of a future and a bit of a hope that we can move fast into a larger section of the diabetes market in value and volume being GLP-1 on the back of phenomenal products that we have. You could see that when you dissect International Operations, actually, GLP-1 usage in volume is just incredibly small. From every 100 people that have today used a diabetes product, 98 of them are not using a GLP-1, only 2 are. That just shows the future for us in International Operations. And of course, those numbers are pretty much low, no matter which part of International Operations, which country you look at. So I'm incredibly hopeful of GLP-1 for IO for a long time to come, looking at the results we delivered last year on the back of Ozempic. We have never seen something like this, a product that was just launched a couple of years back. Then in IO, we are able to basically sell close to DKK 9 billion of that 2, 3 years after the first launch. We have never ever seen that in our history. So this is really, really exciting. And if you think this is exciting, then you should look at the oral market in International Operations. IO is a market of DKK 200 billion diabetes-wise. 55% of this DKK 200 billion is oral medications today. Actually, if you look at it from a volume perspective, it's 75%. And we have played nothing, 0 on that 55% space. Now we're coming with Rybelsus, and we're very, very hopeful. Of that 55%, 75% is what we call the modern OED segment. So these are the DPP-4s and the SGLT2s. And that's really where we're working very hard to get leadership in due course. When you dissect it into countries, then the single largest country in IO that really stands out on its own is Japan. Japan is 24% of that segment that I'm speaking to. And together with basically 12 other markets, so 13 markets all combined, they give you 70% of the business. And those are really the 13 markets we are going to put a lot of investments and attention to. Then the other, of course, number of markets give us the remaining 30%. Now I brought a picture from Japan that shows what we possibly could do when we execute right. The hockey curve that you see there is after Japan basically went out of their restrictions and people were able to go to the pharmacy and pick up a box of Rybelsus. This is really, really good results and super exciting. And I hope, of course, we can copy this in a number of different places. Now that's just half the story. The other half, I think, is on the other side of the Atlantic, which Doug will talk to.

Thank you, Mike. If I didn't know better, that sounded like a complement before [indiscernible] U.S. business. Thank you. That doesn't happen too often. Partner in crime. So five years ago, we started on this transformational journey of the U.S. business -- North America, but specifically the U.S. business. And what we know we needed to do is we needed to switch some legacy products, older products, into more novel newer products. Now it sounds easy, but it takes a lot of strategy, investment choices and execution. In fact, 2.5 years ago, I stood right here on this stage and I described this transformation. And if you remember, I did it in the form of a racing car that was in a pit stop, and we were changing our tires. I said something to the effect that we are changing from insulin tires and we're going to put on our GLP-1 tires. So if you look at how we're progressing in that, I'd say the transformation is happening. We can conclude that it has been successful. And it's been successful primarily in the form of our diabetes products, as you can see here, this double-digit growth. The aspiration when we set out on this journey was to transform 70% of the business. At the end of last year, we reported we were 60%. So we're well on our way to achieving that 70% by the end of this year. So that's exciting. One of the things I also communicated at Capital Markets 2.5 years ago was that we want to put more patients on our products. We're a patient-centric company, you'll hear that throughout the day, it's important. And as you can see over this period, we've also added 30% more patients on our products, which is something we're very happy about. And then lastly, what I talked about 2.5 years ago, it's nice to stand back up here and be able to reflect on how we've done. We want to talk about commercial execution and being able to launch products. We had aspirations to get to blockbuster status, if you remember. And Ozempic was the fastest product to blockbuster status ever. It's 3-plus times that now. I'm going to talk to you a little bit more detail about that product because we're extremely excited. And Rybelsus, I'm also going to talk to you about. We're pleased but not satisfied. As Mike alluded to, there's a great opportunity here, and we're excited about that. So let me get into a little bit about Ozempic. So Ozempic is growing the entire category. And as reported in Q4 of last year, the category is growing at 30%, and we're disproportionately taking share. We feel really good about that. Year-over-year reported, we did 45% year-over-year growth with Ozempic. That represented 96% of the growth in the U.S. So it was the workhorse. What's really important, and Camilla alluded to it earlier, there's still room to grow. In the U.S., we're still only at 8% of the prescriptions. Now we have guideline support and we're making progress, but there's still room to grow, a little over 30% of the value. And I think what also gives us some strength or encouragement is the fact that we still have access in this market at over 95%, which is fantastic. It gives us the ability to market and commercialize this. We have approximately 130,000 writers on Ozempic today, and we're adding anywhere between 1,000 and 1,500 per week. So this was a workhorse, will continue to be a workhorse. It's the product that is outperforming in a growing market at 30%. So we're very, very excited about that. What it's also doing is it's changing the paradigm. So it's not only putting more patients. And by the way, we eclipsed 1 million patients on this product. Super excited about that. But what's also doing, it's changing the paradigm. As we know, this is a -- it's a disease that gets progressively worse over time, and it needs intensification. So patients start on metformin, we know that, and that's what this blue bar represents. And then what happens, they make a choice when it comes to intensification. And what we know is about 15% of those, that choice comes in a nongeneric form. Now prior to Ozempic, 17% of that nongeneric form came in the form of GLP-1. But what we now know is as a result of Ozempic, it's now up to 25%. And if you peel that back a bit, we see that over 60% of that choice goes to a Novo Nordisk product, and the biggest one is Ozempic. So it's performing well in a growing market. It's beating the competition. We're the market share leader, and it's changing the paradigm. So we're really pleased with what this is doing and what this can do. Now Rybelsus, as I mentioned, we're pleased but not satisfied. Maybe if I step back for one second and remind the room that, as you all know, but this is a very crowded competitive space, the oral antidiabetic space. There's lots of products. You can look at probably 14 products, 5,000 plus representatives, there's a significant amount of spend. There's been label updates, and we did launch into a pandemic. But having said all that, we grew last year 142% year-over-year. And this product was the second largest contributor to growth at 33%. So we're pleased with that performance. We are taking market share in a growing market. What's also important to note, it's a sizable market, roughly USD 16 billion or DKK 100 billion. So it's a sizable market. That's about 1/4 of the value of the overall market. And what we know is we're positioning this product directly after metformin. And you can see from the center of this, our positioning is paying off. We're seeing 90% of the prescriptions come outside of the GLP-1 category, which is good. And the largest component of that is in metformin, which is exactly how we're positioning it. We're also encouraged by the fact that we're seeing now 55,000 writers of Rybelsus, and we're adding anywhere from 800 to 1,000 a week there. And again, here, we have significant market access. So we have the landscape to be successful. We are confident in the product, and we are absolutely confident in the long-term aspects of this product. So with that, I'm going to bring up somebody that's also confident in the development of not only insulin but other areas of diabetes. I'm going to bring up Martin.

Thanks very much, Doug. So you heard throughout this morning us talking about us being in areas of unmet needs. And we oftentimes get the question, is diabetes still an area of unmet need? We have a lot of drugs out there in the insulin, in the incretin, but also beyond insulin and incretins. We just have to say the answer is yes. We still have not reached the full number of patients, Camilla alluded to that, but we also still see patients not achieving optimal glycemic control. Patients still suffering from increased risk of comorbidities and increased risk of mortality. This calls for more innovation. This also calls for raising the innovation bar. If we are to break those curves, we need to raise the innovation bar. What we've defined for ourselves, what we have defined for Marcus and good luck with that, is obviously looking towards what goes beyond glycemic control. We know without GLP-1s, we can actually touch more than glycemic control. We can touch body weight. We can touch comorbidities. I'll come back a little bit to that. You've already seen the data on cardiovascular safety. And we need to build on that and we need to take that to the next level. Obviously, we also need to optimize what we do with incretin. So we are looking towards next-generation incretin-based molecules, potential combination that are differentiated from what we already have out there. We'll do the same thing in insulin, still need for insulin innovation. [indiscernible] the glucose-sensitive insulin. We believe that we can take it to the next level. And then, obviously, also, we need to combine our drugs with support for our patients. Part of the insulin inertia that we see is to an extent driven by lack of compliance, lack of convenience to what the patients see in their everyday life. Camilla alluded to if we can provide proper insights through connectivity, connectivity of the device, connectivity of the glucose monitoring, we can improve the everyday life of our patients, but we can also improve their treatment and their outcomes. And this is specifically what we're aiming at. So across the board, looking towards integrated solutions. This is obviously why it's a little bit gratifying for me to stand up here and looking at a very, very robust clinical pipeline. Marcus talked to what we are doing in the preclinical space. So there's more to come. But what you're seeing is across injectable incretins, across all incretins. We are providing innovation -- transformational innovation that will take us to the next level. But we are also looking towards maximizing the value of semaglutide, increasing our knowledge base so that we can really, really maximize what we know about semaglutide and how to use semaglutide. We're doing the same approach in the insulin space. Obviously, we want to maximize what we have, but we also want to take innovation to the next transformational level. We'll come back to that. And then obviously, also for -- I need to call out for our prevention efforts, for our cure efforts, having DNA immunotherapy, having cell-based therapy in our pipeline is incredibly gratifying. What you don't see in this slide, but what I need to call out a little bit is, obviously, all incretin. Some of you asked about that. We'll also take that into the area of diabetes. It's not in the slide because it's not yet in first-in-human dose. Marcus alluded to, we'll get there this year. So next time we meet, hopefully, we will progress to also oral incretin in the space of both diabetes and obesity. I'll do a little bit of a deep dive, obviously, calling out that -- and you've seen this data before. But later this month, we expect a positive feedback from the U.S. FDA in terms of high-dose semaglutide. Now why high-dose semaglutide? Why do we need more? Camilla already alluded to, 80% of patients on either 0.5 or 1.0 milligram of semaglutide are in good glycemic control, and they are in good glycemic control in a safe, [ adorable ] way. They don't need anymore. Few patients need a little bit more. And what we wanted to with high-dose semaglutide, 2.0 milligram, is to provide just that. So adding to the glycemic control, and this is what you see in the slide, but also adding to the body weight lowering of what semaglutide can do. You saw statistically significant and clinically relevant improvement on both parameters. And the interesting thing is this is without compromising on tolerability and on safety. So we can achieve even better glycemic control, even more weight loss without having to compromise on tolerability and safety. So we're a little bit excited about, obviously, having already the European approval, but expecting the U.S. approval already later this month. This is completing what we can do in order to serve our patients with semaglutide. It's a great drug, and it basically serves the purpose for more than 80% of our patients. I obviously also need to mention insulin icodec. This is potentially the transformational insulin offering. What we've seen in Phase II is that it's not only a convenience drug. That's important. Again, back to the inertia of insulin treatment, patients sometimes forget to take the insulin. They take a too low dose. It's not nice to take these daily injections. Icodec has the potential of doing only once-a-week basal insulin injections instead of 7x a week. That in and of itself is a nice feature, but that's not enough. What we saw in Phase II is that icodec also holds the potential of showing superiority on efficacy hemoglobin A1c. In the insulin space, that would be a first. So already there, you see transformational and innovation. Thank you for that, Marcus. But also, at the same time, going back to my medical textbooks, it basically said if you dial up insulin, you do it at the expense of risk of hypoglycemia. But with icodec, what we've seen in Phase II is that we can improve efficacy without again compromising safety. So actually on par or lower risk of hypoglycemia with the potential of superiority on efficacy. If we get that triad of efficacy, safety and convenience, then we're looking at a transformational insulin drug. At the same time, we also had to drink our own Kool-Aid or whatever it is called in U.S. slang because we had to be serious about the digital offerings that we want to put around our insulins, making it easier for patients to live everyday life, but also to achieve better glycemic control in a safe way. So in the development space, we are introducing digital tools through connectivity to allow patients to get better glycemia control, and we aim to take that also into the marketplace. The interesting thing is that this actually also allows us to do real-world evidence data generation in the development phase. Again, first, in insulin development, we've never been able to do real-world evidence data generation in development. We can do that with insulin icodec. And then obviously, also going back to our sustainability agenda, it goes without saying if you can do with 1 injection instead of 7 injections, that's good for the environment. So we believe -- and again, I have to show this in Phase III, that icodec holds a tremendous potential for being a transformational insulin. So we designed ourselves a very nice, very ambitious development program. It's focused across all aspects of type 1 and type 2 diabetes. And the really, really interesting thing is we're doing it for regulators. Obviously, we need to get the drug approved. So we live up to the regulatory requirements to treat the target. We are obviously doing it to inform patients and treating physicians. But as the first, because we can do real world evidence and we do this in ONWARDS 5, I'm looking very much forward to see those results. We are also generating data for payers to be available at time of launch. This is a first again, and this is going to be really, really interesting. ONWARDS 5 has been discussed and designed together with U.S. payers. And also, obviously, the U.S. FDA, but also decision makers in Europe and in Asia. Really exciting program. I have received a lot of questions on when this will read out. It's not today. I apologize for that. We'll see the first data from ONWARDS 2 coming in a couple of months, and then the remaining stories will roll out over the course of this year. stem cell based on maximizing value of semaglutide. It's amazing to see a drug. And it's going back to the point that Marcus made, if we're disease-agnostic, maybe our drugs can be disease-agnostic as well and work in more than one disease. We know semaglutide is good in diabetes. It's actually the best drug out there. We know it's the best drug in obesity. We know it's cardiovascularly safe, but we also need to conduct the SOUL study in order to get cardiovascular claims into our label, preferably the 26% risk reduction for MACE that we saw in the SUSTAIN 6 trial. And similarly, in chronic kidney disease, in peripheral artery disease, in retinopathy and eye disease, we want to demonstrate the benefits of the semaglutide molecule for diabetes patients. These 4 studies will read out during the course of '24 for the SOUL, the FLOW and the STRIDE trial. And the FOCUS trial will read out in 2027. Finally, I just want to call out again, taking innovation to the next level. You've heard us talk about the combination of amylin and semaglutide in the obesity space. That's a really, really strong offering. I'll come back to that also in the next session. But amylin is not necessarily only for obesity, as actually a fast-acting amylin already approved for the treatment of obesity in the U.S. The idea is that amylin, first of all, has a slow or lowering of gastric emptying, thereby preventing blood sugar levels rising too fast after food intake. It lowers the glucose production in the liver. It increases satiety, and it lowers the glucagon production in connection with meal intake. That basically means that in theory, it has glycemic properties in and of itself. When then combining it with the best GLP-1 analog that is out there, this could be a very strong and powerful diabetes drug as well as a very strong and powerful obesity drug. This is specifically why we are taking this combination into Phase II. It will read out later this year. And if it reads out positively, you'll see us initiate Phase III for CagriSema in both obesity and diabetes later this year. So in summary, still a tremendous unmet needs in diabetes, not only because of adverse outcomes, but also because of an ever increase in pandemic. And we need more innovation to break that curve. GLP-1 treatment, through that innovation, are driving the growth of the diabetes care market, yet there's a tremendous potential to lift. Only 3% of the total diabetes prescriptions are towards a GLP-1 on a global level. We're looking obviously much forward also to breaking that curve with innovation in the insulin space. Insulin icodec has that potential. And at the end of the day, through strong innovation, thank you, Marcus, but also strong commercial execution from our 2 friends in U.S. and IO, we'll achieve the more than 130 -- 33%, easier to say, of the diabetes value market. So with that, I'll invite all of us to come up to the stage and ask Lars to moderate us in Q&A.

Yes. Start here.

Richard Vosser, JPMorgan. Just thinking about Rybelsus, is there a hockey stick moment for Rybelsus in the U.S.? We've seen that in Japan, but is there one in the U.S.? Is that the SOUL trial that could do that? Or should we think about this as just general grind of market share gains?

Thank you. Doug?

Yes. I would put it in that category of general grind. I'll use your terminology. I don't think we're going to see a hockey stick moment. But what we're going to see is a progression of success in taking market share. And we believe that with our positioning and with the efficacy of the product, we can do just that, but I wouldn't characterize it as a hockey stick.

Good. Simon?

Simon Baker from Redburn. Another one for you, Doug. If we can go back to Slide 16 of your presentation, but not your presentation today, your -- one of the previous years.

I'm not sure if that's fair. But let me...

You were word perfect on what you did quote from there, by the way. You said that you saw the future of GLP-1 as a 50-50 split between Rybelsus and Ozempic. It feels like, if anything, the pie is a bit bigger, the split is less than 50-50. How do you see it now in the future? If you were to update that slide of where we are now to where we're going to be in the future, where do you see the split of Ozempic and Rybelsus in the U.S.?

Yes. Maybe it dovetails on the prior question as well. I think that -- we see the trajectory now as we see in Rybelsus. We're pleased but not satisfied. We think we can do better. We're going to continue to take market share. It's well positioned. We continue to pressure test that, and we have the right promotional mix against it. So we're going to continue to see this trend. I think what we're seeing in Ozempic is a step change. We're now clearly the market share leader, greater than 50% of NBRx, if you look at the injectable space, and gaining. So I think that, that split will not to get into exact, but we'll see a bigger piece in Ozempic in the future.

Let's go to the virtual participation. We have Emmanuel.

Hopefully, you can hear me okay. A question for Doug. Competitive risks in GLP-1, you talked about how well Ozempic has done. But of course, we have a potentially formidable competitors coming with this appetite. What's the risk that destabilizes the mutually beneficial duopoly in GLP-1 you've seen in recent years? How confident are you that pricing and access stability are going to remain intact going forward? And what do you hear from payers about the risk of, for example, exclusive contracting, any potential escalation [indiscernible] If I could, a quick one for Martin. The Phase II CagriSema data is pending later this year. Is there any reason you would not expect it to look very similar to the Phase I combination data you published last year that saw almost double the weight loss of 2.4 mg sema for the combination of 20 weeks with a relatively low rate of discontinuations?

So we'll make one exemption since this was a virtual participant on 2 questions. So first, Doug, on competitive dynamics as we see more launches into the incretin category.

Yes. Thanks, Emmanuel, for the question. I mean we're prepared for competitive launches. And I would say that what we've seen historically is that products that have entered into this space have continued to expand the GLP-1. As you saw, it's only 8% of prescriptions. So -- and as Martin alluded to, we expect to hear back from the FDA at the end of Q2 with our own products. So we have a portfolio approach, and I think we're well positioned for any competitor. And let's wait to see what their label looks like.

Martin?

Yes. Thanks very much. So the data you saw readout last year were exclusively in obesity patients having no diabetes. So not a possibility to look at the impact on glycemic control. So what we're doing in the currently ongoing Phase II study is to look at glycemic control more so than -- sorry, obesity and weight loss.

Thank you, Martin. Yes, Pete?

Pete Verdult, Citi. Just 1 question for Lars. You probably don't want to go down this road, but you did say right at the start of the CMD that if you execute on your strategic aspirations, you can sustain growth. Now you did 14% top line growth last year, and I think consensus is high single digit for the next 5 years. So can I at least invite you to quantify whether sustaining growth is like that 14% or at least double digits. So you probably don't like the question, but I think it's the question to ask.

Yes. Thanks for that challenging question. And obviously, you know that you're not going to get a number. But I think we have clearly articulated some ambitious commercial aspirations getting to at least 1/3 of the diabetes care market share. We are going to review obesity after this session, but we are also very encouraged by our opportunity in obesity. And it's really short term, the growth that's fueled from the sema molecule. So the product we have, that's doing really well. The Wegovy launch, that's at an inflection point since it's being launched, means that we think we can sustain a very attractive growth for the coming period. We also know that there are one-offs from time to time like this year where we have VBP impact from China, so not every year will be to the same magnitude. But we're confident in the growth we can drive based on these dynamics, and we'll get back to more of the underlying drivers of it, and Karsten will also talk to the financials later on.

Eric Le Berrigaud, Stifel. Maybe we're not there yet, but first idea about how you think about pricing icodec going forward? If we think about 1 insulin versus 7, and if we think about annual price, what latitude do you think you may have to re-price? Taking in consideration that you deliver on promises, any kind of guidance you can give us in terms of come back to previous levels or versus current levels of insulins?

So pricing without noting clean profile is always tricky. But Camilla, can you give some perspectives on how we look at that?

Yes. So of course, we're excited about what we've set up to do in the Phase III trial, and now we're looking forward to see the readout as Lars says and Martin alluded to. There is no doubt that a once-weekly insulin that can replace 6 injections a week with a profile that is competitive on glycemic control and also on safety is, of course, a very compelling bring to the market. And I think that in itself is a great opportunity for us also from a market share point of view. I know you asked about prices, but for competitive reasons, it's difficult for me to comment on. But from a market share point of view, just from the profile of what we're hoping to see from the Phase III trial, that is, of course, encouraging given the fact that the insulin market is only growing a couple of percentage points and that we only have 37% market share in the total basal segment. So there is a great opportunity to bring a better and a once weekly insulin to the market.

Great hopes there. We'll take 1 virtual question. So Wimal, please.

Wimal Kapadia from Bernstein. So maybe one for Martin. There's a lot of competitor data this year, but in particular, the [indiscernible] that's dual agonist and the Lilly triagonist, and these are targets that Novo looked at before but decided not to pursue, in either diabetes or obesity. You said the same with GIP, but you're now pushing forward with that program. So just curious for the GLP-1 glucagon combo and the triagonist, why you have conviction that these are not priority approaches for Novo? And any intention of moving in that direction?

Wimal, it's a super relevant question. And obviously, something that we have discussed in great detail in our end, we are always trying to balance efficacy and safety. And what we saw with specifically CagriSema followed hopefully soon by an incretin is being able to do a combination therapy where you optimize efficacy without having to compromise on safety. What we saw in our own hands in the triagonist is that we did see a good efficacy profile but also some longer-term safety issues in more than 1 organ, specifically in the liver, on glycemic control, in the heart -- on heart rate and other aspects of heart that warranted us to say we have stuff in our pipeline that is much more attractive from a -- specifically on efficacy, but certainly also safety profile. This doesn't mean that we don't want to pursue, for example, a semaglutide/GLP combination as a potential fallback should we see a less attractive profile of the amylin and semaglutide combination. But so far, we are aiming for better efficacy but also better safety.

Thank you, Martin. Thank you very much. Keyur?

Keyur Parekh, Goldman Sachs. Just I guess, Martin, for you. How confident are you that if the icodec program does show what you expect or what you wanted to show that the regulators are on the same page as you? Because historically, there has been a slight difference of them being happy to give intra-class superiority claims. And -- so we all know what happened to the placebo hypoglycemia label. So your confidence on getting the superiority on efficacy and potentially anything else you can see on the label if it does show that?

So important to call out that from a regulatory perspective, superiority is difficult because the regulators ask us to do treat-to-target. So first of all, we had to convince the regulators that we have done proper treat-to-target. And if we then in that setting, this is specifically what we potentially can do in ONWARDS 1, can show superiority anyway, basically because of a better pharmacokinetic profile, then we have a good chance of getting those data into the label. ONWARDS 5 is not going to be a treat-to-target. It's going to be real world evidence. The FDA had reviewed the protocol, and they will allow us to show the safety data, but not necessarily the efficacy data in that. So the bar from a regulator perspective is high. We had to show first treat-to-target and then superiority. But then we have a good chance.

Thank you. Question here?

Evan Wang from Guggenheim. Just a question for Doug. Can you talk about Rybelsus? How access compares, compared to, I think you mentioned 95% for Ozempic. Now where is that in 2022 versus 2021?

Yes. That was 2021, and we're not done, and I wouldn't want to forward look. But access, we assume, will be in the same range. And they're both equally above 90%. So both very, very positive relative to the market or any other product. We feel good about that.

Good. We take a final question over here?

Peter Welford at Jefferies. Perhaps a bit left field. But glucagon, you don't have a sort of glucagon rescue pen or device and you're probably all equally pursuing an artificial pancreas or similar using the sort of glucagon. Is this because you think it's just a stop gap measure and, ultimately, cell therapy, et cetera, is going to get in there? Or I guess, why not consider glucagon and its [ role ] potential for that sort of a type 1?

So we do actually have glucagon on the market in the rescue setting. From a development perspective, again, we've been looking at the safety profile on long-term glucagon treatment. And we've not really seen an attractive risk-to-benefit assessment in that. That being said, we are actually working with both device manufacturers, but also glucagon manufacturers on the artificial pancreas. Our role in that game is, however, the insulin.

Good. Thank you for great questions. We break for a short 10 minutes. So we look forward to have you back here and discuss obesity. Thank you. [Break]

[Presentation]

So welcome back to this session about obesity, which where we will now dive into our strategic aspirations on obesity and talk to you a little bit more about how we are developing this market as a first entrant almost into this. As you will recall from our last Capital Markets Day, we were working with 2 strategic aspirations. One, strengthening obesity leadership and double our sales based on a 2019 base. And secondly, develop a leading portfolio of superior treatments that we would bring to the market. And today, we will give you some updates on this. But before we get into that, we will just like to start with remembering what this is all about. And you heard this morning from Lisa on what is like living with obesity -- but I just want to let you know that obesity is not a problem that is isolated to a few countries. What you see on the left-hand side here is that 650 million people are living with obesity. It's widely distributed across the world also in developing countries. It has big impacts, as you can see in the middle on people living with obesity. They have -- would have more than 200 possible health complications associated with obesity. Needless to say, this also has implications for the health care authorities, for the pressure on the health care system, in addition to the pressure on the individual person and those living with obesity. It also has an impact -- a negative impact of 3% on the global GDP and of more than 8% on health care budgets. So the impact on the global GDP is comparable to the impact from smoking, just to give you an idea about what we are talking about. However, the narrative around obesity is changing. And in recent years, also driven by COVID-19. We have seen that the talk around obesity, the stigma that relates to people with obesity has been changed. There is a more empathetic tone in the media. And there is also different interest from health care professionals to treat obesity. Policymakers are now in different countries accepting that obesity is a disease, obesity has to be treated. And if we want to avoid the main complications of obesity, we have to do something about it. So also payer and patient groups are meeting, we are driving groups of payers that are meeting to discuss what to do about this, but also patient groups are very, very active in this field. So that is all good. But we are starting at a point where too few are being treated. So if I just take you through this scale that you see here at the top, you see 650 million people living with obesity. But only 10% of them are seeking help, mainly because they -- we're quite convinced that there is no help to get. Many have been visiting the physicians. They've been told to go back home, eat less, exercise more. Everyone has tried that. It doesn't last and it is not a solution to a problem if you're living with obesity. That means that only 2% of those are being treated with antiobesity medication. And if we take a look at the right-hand side around our approach to this, then only 1 million are being treated with Saxenda, our first product in obesity and only 25% of them stay on the treatment for more than a year. So compare that up against a serious chronic disease that leads to severe complications, then this, of course, has the potential to be improved on. So in Novo Nordisk, you will see 2 boxes here, the -- on the left-hand side and on the right-hand side of what we are trying to do. First of all, trying to make sure that obesity is a health care priority and that is understood. And on the other hand side, providing the medical treatment that can help with this because, of course, it doesn't help if we cannot bring anything to the market that can solve this problem. So under what we call the market development, there are 3 things that we are trying to do. You see those in the boxes at the lower left side, trying to activate people with obesity to know that there is help to get that there is information to get. And the way we do that, and just turn a couple of these boxes. So you can see a couple of specifics on how we do it. We have rolled out a global website in more than 30 countries that talks about the truth about weight, where you can, for example, see people like Lee Kaplan that you saw before, professors that understand obesity that gives more information about why do people keep regaining weight. What is it in the body physiology that makes that happen. Also on the health care professionals, we're trying to engage them on rethink obesity and direct care and Doug and Mike will talk a little bit more about that later on how we specifically do this. So I won't speak too much to it now, but it's about engaging health care professional and also patients and maybe in a setting that is less traditional but more online driven because, of course, obesity is easier to diagnose online. It's easier to send the prescription online nowadays and easier to have the conversation also online. So there's a lot of opportunity in that, that can also minimize the burden on the health care system. And then finally, the value proposition to payers where, of course, Martin will come back to SELECT our big outcomes trial with 17,500 patients that can give us an idea about what it really means to be living with obesity. And then on the portfolio part, we have Saxenda approved. We have Wegovy approved in the U.S. The launch of that has been phenomenal in terms of people wanting to get access to Wegovy. And of course, this has been overwhelming. And as you know, this -- and we'll just come back to it in 2 seconds about what it looks like in terms of supply for us now. But I just also wanted to say that Martin will also be talking to what we have in the pipeline because Wegovy might be our second, you can say, product -- in our cascade of products to come to the market. But later on, we will also see all semaglutide 50-milligram and then [indiscernible] that you just heard a little bit about before also. But before we get into all the details, I think a question is on all of your minds about what does it look like in terms of supply for Wegovy, specifically in the U.S. So Henrik, you just give very short update on that, and then we'll move over to Doug.

Yes. So normally, I do not disturb my commercial colleagues in the middle of their presentations. But I guess, I mean between all the strategies of obesity and then Doug coming up and telling about the uptick in U.S. This slide -- that was Slide 9, by the way, in the previous investor call that we have on works, at least the message is the same. So it's very important for me to stay it upfront. That our expectation is that we are back on the growth that you are providing in the second half of '22 this year. And the reason why I'm saying that is because basically, what we have announced a couple of times in a row now, is that the plan that the CMO that we are relying on in this phase, in natural phase of this manufacturing, they are holding on to their plans. So they will restart manufacturing here in Q2. And why do I know that? That's because within the coming weeks, they are starting their so-called media field for you that don't know manufacturing within pharma is basically advanced test manufacturing -- testing the manufacturing set up, making sure that everything is in order for commercial manufacturing. So they will do that in the next couple of weeks. And we also normally do that and Dale will continue the commercial manufacturing for us. Right now, we are still holding our hands under our current patients in U.S., as you heard from Lisa, she has available product in the pharmacies. And we will continue doing that with the stocks we have, our small internal manufacturing. And then this large-scale CMO, they will step in and take the growth up to further levels. I will not jump into the broader manufacturing strategy. I'll come back to that later, but I'll just say upfront in this session, that when we are done, getting back on track with the single CMO more manufacturing capacity will come online in '23. And then, Doug, what can you do with that?

I think a lot, Henrik. So let me talk about it. Thank you. But Henrik, thank you for all that you and [indiscernible] are doing. It's really appreciated. So simply put, we can consider this one of the best launches, if not the best launch in the history of Novo Nordisk. And it takes a village, but we're really proud of that. Some just measures I can give you of success. It took Saxenda product we launched in '15, about 5 years to get to 10,000 TRx. It took Wegovy 5 weeks. The highest level of TRx that we got to with Saxenda, and that took about 6.5 years, it was about 14,500 per week. With Wegovy, we're already averaging over 20,000. So it has been called a game changer, and we really believe it is. And there's 3 pillars that Camilla talked about. I'm going to give you a U.S. context, which is getting more patients like Lisa to see treatment, we need more prescribers and then there's this element of market access. So let me just start with some of the things I jotted that Lisa said. She struggled her entire life. Everybody sees it, but nobody talks about it. Wegovy has changed her life. And then lastly, she said it took her many, many years to find a doctor. So we know that in the U.S., 4 in 10 patients don't have the strength and there's a lot of reasons for that to go out or maybe it's not strength, it's a lot of reasons, but to go out and actually talk to a health care professional. So we know we need to activate more patients. If you think about this big number that I'm showing, 140 million patients with the BMI 27 or greater. Now we're breaking that down into different cohorts, but simply looking at it, 90% of them have a weight-related comorbidity. So this is a health crisis. And this is a big population that we're looking at. If you think about that 75% currently are patients that are new to the category, that is encouraging, and it also speaks to this unmet need. So that's also encouraging. And then when we look at the demographics of the patient, that patient today is very similar to what we're seeing with the patient that we saw with Saxenda, primarily female, comorbidities, a significant portion of them. And certainly, their BMI is in excess of 35%. So how do we do this? Well, we do this through unbranded campaigns, and Camilla talked about some of these. This truth about weight is that we want to encourage patients to give them that strength, to understand and let them know that it's not all about just eating less and exercising more. There is a biologic component to this. So we're encouraging them. And we also have programs like when we've just started with Queen Latifah, It's Bigger Than Me. And this really tries to address the stigma and the bias, which is also very, very real. Now the second component is just prescriptions -- prescribers, excuse me, we'd like -- prescribers. So Lisa talked about it. It took her years and years and years to find a prescriber. Now why is that? With a disease state that has over 100 million of population, you think there'll be many more prescribers. Part of it is they don't get enough training. Part of it is they don't want to tackle something that is so challenging and cumbersome and lengthy. So we're doing what we can to increase the number of prescribers. Now we're encouraged. We're seeing about 11,000 prescribers currently. These are reoccurring prescribers, and then we're adding about 1,100 per week. So it's already clips Saxenda, and that's encouraging. And how do we do this? Well, we do it with a direct sales force, first of all. We have 250 today, and I would suggest that will probably increase over time. But it's important. So we have a direct sales force that does it. The targeting that we're looking at right now is 35,000 physicians, which is small relative to the size of primary care. And then we also have a complement of educators and medical liaisons. It's really important that we need health care prescribers that are treating this like the serious chronic disease that it is. We have to get that done. For us to really unlock this potential, we have to have that. And then lastly, when you think about this market access component. This is not simple. And it's a bit of a funnel like we talk about in many areas of our business. And so one of the things that I'm very encouraged with, and I'm pleased with the team is that we achieved the level of market access of Saxenda in 6 months. Now to put that in comparison, if you look at Rybelsus, it took about 9 months to achieve the same level of market access as Ozempic. And took Ozempic about a year to achieve the same level of market access Saxenda -- or as Victoza. So relative to our other launches, we've done a nice job. And again, this speaks to the fact that payers and PBMs, they do want to tackle this. They are willing to put it on. But unfortunately, there's another element to it. Employers have to opt in. So we're hard at work there. But when we look at the left-hand side of the slide, this really talks to the story. So again, depending on the BMI and how you're looking at it, let's just say it's 100 million patients. Today, the commercial coverage is about 60 million. We're seeing about 50% of employers today that opt in to this, which gets us to again, around -- excuse me, the formulary access for Wegovy is about 40 million, about 50% of that opt in, which gets us to, again, $20 million in the market that would have access to the product, about 1 in 5. And what we have on the brand today is about 125,000 patients. So in a lot of ways, that's good, and we're encouraged by that. But in a lot of ways, we're only scratching the surface. When you think about the size of this market. So what I'm really encouraged with is our partnership with PBMs and that can't be understated. We have partnerships with PBMs today where we haven't had them in the past in this category to go out and help with this. What they call plan sponsors or employers, this is that element that we need more to opt in, and we're hard at work with all the major PBMs and ESI in particular. So we're really, really encouraged by that. In the end, we still have work to do on a state and federal level, and we're hard at work there. In the end, we want to unlock the potential of this disease, and it's going to take all those efforts to do it, but we're certainly encouraged, extremely encouraged with what we've done and what has been a challenging start with not only COVID, some of the supply situations. But extremely encouraged with the amount of patients we have on board, the receptivity of the market, a viral component that's happening and what we know we can do. This is a significant unmet need, and we have a game-changing product. And I know my friend here and the other part of the world also thinks the same. So Mike?

With bigger number.

Bigger numbers.

At least bigger numbers when it comes to the total number of people suffering from obesity. While we wait for Wegovy, then we have to do well with Saxenda in international operations. We have plans towards the end of the year to launch Wegovy. But for now, it's Saxenda, and we are doing really, really well with that. You see the growth of some 20% plus growth the last few years. Actually, last year, we grew 53% with Saxenda, which I'm incredibly proud. It is really coming from 2 of the 3 geographies, namely EMEA and the rest of the world. A number of countries have launched Saxenda already and are doing phenomenally well. We don't see much of that in region China. You see a bit of red color on the Chinese section, that is really Taiwan that has launched the product. We don't have obesity medications in China as of today and waiting for Wegovy for that. I said the numbers are large, 550 million people from the 650 that Camilla showed are actually living in international operations, not surprisingly. So yes, while only 4 million people have tried a medication in this area. Yes, while only 700,000 people have been on Saxenda last year. The pool is very, very large. And that, of course, gives me a huge opportunity and hope that if we do the right thing, if we get the right products, then we are able to, for many years, also drive growth out of this section. As Doug a little bit alluded to, the problem is where do you go when you want to manage your obesity. It's really difficult. If you have cancer, you go to oncologists. If you have diabetes, you go to an endocrinologist. If you're heart aches, you go to a cardiologist. Where and what do you do if you're suffering from obesity? It's this lack of not knowing who prescribes. So we have to find those prescribers. We have to educate them, but we also have the possibility to try and think a little bit out of the box and see, are there different ways? Can we go directly maybe to the patient? Can we play around a bit more than we have done in diabetes with telemedicines, with online pharmacies? And some of the things you see on the right-hand side of the slide is exactly pilots and activities that are happening in different parts of the world. The healthcare health care professional locators that choose about weight, creating communities with various different websites, bringing people together are some of those initiatives. So Rose in Germany, Lloyds Pharmacy collaborations in U.K., Eucalyptus in Australia, a number of different initiatives in Latin America are things that we're piloting trying to put the support of our innovation in the hands of those who are actually seeking it and maybe don't find that middle person as they usually do, i.e., the health care professional. We also are, of course, eagerly waiting for Wegovy because we need to really bring these types of solutions to our 2 largest IO markets that right now do not see Saxenda: China, Japan. Wegovy will be launched in both of those markets. So all of a sudden, of course, a very large population that today do not have opens up again through increasing the growth rates that we possibly have been able to do -- we have been able to do more recently. Now the big question, I think, is, who is it that actually does prescribe the medication today. It is really the same group of people who prescribe the diabetes medication for us. And in every market, it's different. I have brought just 2 examples here. If you think about Australia, it's the GPs. If you think about Spain, it's the endocrinologists. It's much, much more related to mindset of the physician rather than the specialty of the physician. And that's how we are really actually operating now. At the same time, we realize that people are looking for a dedicated obesity location clinic to go to. So we're putting a lot of investments in our efforts in stem cell based those obesity clinics across international operations, and you can see the growth on those numbers there. It is really about educating the health care professionals, connecting those health care professionals to the patients and also realizing that some of the people in the value chain that we previously did not pay enough attention to, i.e., let's say, the pharmacist in this therapy area, play a much bigger role than they did in the diabetes field. So we have, again, a lot of collaborations with the pharmacists around various different countries. And again, you see some examples here from Saudi Arabia, Australia and what have you. But we will not crack this big way unless we get the payers to recognize that obesity is a disease, and they need to slowly start reimbursing these medications. Right now, 20% of our sales in IO is coming from small restricted reimbursement. And I say restricted because you can see from the 3 examples here, before they restrict the whole area, the payers are going baby step forward because they're really afraid, 650 million people out there will break anyone's budget. So we are making a lot of dialogues and deals. Can we try this for some subpopulation. And then you can see that in Colombia, they say, okay, we can do if the person has a BMI of 30 and above, but has to have 1 comorbidity. In Israel, they say, again, 30 BMI, but they have to have visited 2 dietitian before we can basically consider them or in U.K., BMI of 35 is really set forth. But I think it's a really good start. I think it's a really good start and quite encouraging. 15 countries that right now are benefiting from these so-called restricted reimbursement, 8 of those have happened in the last 2 years. So it's accelerating. And I do think COVID is helping the dialogue much, much, much more. The French government realizes that some 80% of those who went under respirators because of COVID had a BMI of 30 and above. They can save so much more elsewhere if they solve their obesity problem. And that's, of course, what we're looking into. And they need a very potent drug and Wegovy brings that. So that gives me even more hope. And then I'm incredibly excited, of course, when the result of SELECT hopefully prove what we have been thinking for a long, long time. And who better to talk about SELECT than my selected friend and colleague, Martin.

Thanks very much, Mike. So Mike just said it, when we do obesity innovation, we need to increase our knowledge base. We have a clear understanding what obesity does to the individual patients. It impacts their quality of life. It impacts their productivity, but it also introduces comorbidities that are detrimental to them but also to society. And to Mike's point, this increasing understanding of not only individual impact but also societal impact is paving the way towards better obesity treatment. But we also have to provide more innovation. Going back to addressing the unmet need that we discussed also during our diabetes session. We scratched the surface with Saxenda and very nice 5% to 10% weight loss. This is where we start to see an improvement in quality of life, in impact on everyday life and productivity in comorbidities. But the really big step came with Wegovy. You heard it from Lisa, this is a transformational impact on everyday life. I'll get back to SELECT and the potential impact on outcomes and comorbidities. And obviously, our aspiration is to take it to the next level. normalization. While we so far have only seen through bariatric surgery is sort of the gold standard. It's not just the weight loss. It is also the quality of life. It's the impact on comorbidities, but we can achieve that through even more fundamental rate loans. So we are already now, even though we are super heavy with Wegovy, looking towards what comes next. This is obviously also why it's nice to have a good and robust clinical pipeline and looking towards Marcus and his team having a good and robust preclinical pipeline. Aiming at addressing the weight loss, aiming at addressing the comorbidities driving towards normalization. Down the road, we'll talk about prevention. We'll talk about cure. But for now, we have to talk towards normalization I was speaking to a slide that was not there. I apologize there. We have a good strong pipeline. I'll talk about the SELECT. You heard us talk about oral semaglutide and [indiscernible], I'll go into a little bit more detail on that. And then obviously, also here calling out oral [indiscernible] that could be a real game changer in this space. Why do we think this is a game changer? I received a question in the last Q&A on the balance between efficacy and safety. When a monotherapy increasing is not enough, we look toward combination of different modes of action. The really, really interesting thing about combining amylin and GLP-1 analog is that they have distinct different modes of actions, one working primarily in the brainstem, one working more centrally in the brain. You've seen this data before, the survey actually a little bit of repetition. In a Phase I/II study, we managed to achieve a 17% weight loss in 20 weeks. 16 of those 20 weeks were titration. So patients actually only had 4 weeks on the maintenance dose. Nevertheless, 17% weight loss. This is to be compared with the 17% weight loss received for semaglutide in monotherapy in 68 weeks. I promised not to talk too much into what our modeling shows, but I think we are really confident that we can approximate 25% weight loss with this combination drug, again, being in the realm of bariatric surgery and normalization. Going back to the question of how to combine different molecules. The really, really interesting thing is we did not only achieve unsurpassed efficacy. We did it without compromising on safety. As you see in the right-hand slide, no difference in overall side effects. But maybe more importantly, no difference in tolerability. So when we've seen combination with GIPs and glucagons, a dramatic increase in GI side effects and patient dropouts of clinical trials. With this specific combination, we see a safety and tolerability profile that is comparable to that of semaglutide in monotherapy. So we basically get the best of 2 worlds, unsurpassed efficacy and a safety and tolerability profile that is as good as the monotherapy. That holds a tremendous promise. And just to call out for the keen eye. We've now added cohort #6. Some of you have asked about that. You will see that we don't achieve more weight loss with Cohort #6 that we did with cohort #5. Still a good and attractive safety profile but no reason to go beyond what we've already set out to do, namely test, the 2.4 plus 2.4 milligram dose. We'll do that in Phase III. Obviously, everything comes down to Phase III. Everything I just talked about we have to show in Phase III. We are super excited about the prospect of [indiscernible]. In obesity, hopefully, also in diabetes. This is why we have designed a very, very focused Phase III program. 2 trials for regulatory approval. one in obese patients also comparing to the monotherapy of the -- or the mono components of the drug and one in a combination of type 2 and obese patients. And this is sufficient for the regulatory approval. Obviously, we'll follow up with more data in Phases IIIb and IV, including leukin a cardiovascular safety. But with the weight loss so that we can potentially accrue with [indiscernible], we believe it warrants a fast approach to market. You heard talk about -- talking about 90% of patients suffering from obesity has comorbidities in some shape or form. It's a big impairment on everyday life. It's a big impairment on society. When introducing a substantial weight loss like we do with Wegovy. Obviously, we would like to see those comorbidities being impacted in a positive way. We conducted the SELECT trial for that specific reason. We also know that it requires a substantial amount of body weight loss to touch all of the comorbidities. You see that depicted in this slide. But what you also see depicted is that in addition to looking at cardiovascular safety, which is obviously the primary assessment of the SELECT trial. We are also looking at other comorbidities; including the potential prevention of type 2 diabetes. Can talk about the game-changing potential of Wegovy-induced weight loss. SELECT is a big trial, 17,500 patients that allows us to look at those comorbidities, looking at cardiovascular comorbidities, but also other comorbidities. Going back to Mike's point about precision medicine or looking at sub populations that will allow payers to relate to obesity without heart palpitations, 70,000 -- 500 patients will allow us to also identify patients who are at risk and who can have comorbidities prevented. So a lot of benefit coming out of SELECT and a lot of excitement. This excitement not being listened by the fact that we now are confident that we will have approved a sufficient number of events to conduct an interim analysis already this year, specifically in Q3. This interim analysis will be conducted by an external body, a data monitoring committee, independent of Novo Nordisk. They will advise us whether to terminate the trial or to continue the trial depending on the data and assessments that have been prespecified. If we terminate the trial, we will have the full termination and the data available around the turn of this year. If we continue the trial, we'll have the full data set available and the data available to you during 2023. So really, really exciting. Equally exciting, we have decided to extend the SELECT trial to look at the legacy effect of weight loss. So we'll continue the SELECT even after the original trial and the regulatory submission. More of that later. And now over to Camilla and how are going to use all of this?

Yes. Thank you, Martin. So based on everything you've heard today, it's clear that the opportunity with obesity is big. And on that background, we've also decided to change our strategic aspiration for 2025. So as you will recall, it used to be strength in obesity leadership and double current sales from 2019. And we have decided, based on the background that you've heard today, to update that to a strategic aspiration of more than DKK 25 billion in 2025, so more than DKK 25 billion in 2025. And based on everything you've heard now, it's clear that there is a large unmet medical need within obesity. You've heard about expectations to Wegovy in the U.S. And you heard a little bit about the update on product supply also. We talk about the pipeline. Wegovy being our second offering, but not the last one. And then we also talked about SELECT and the exciting interim analysis potentially to come this year. And then finally, the update of our strategic aspirations. So maybe that gives rise to questions or need for a dialogue. So I'd just like to invite the rest of the speakers up here together with the guest.

All right. And as my colleagues get on stage, then you know the drill, one question per person. And I think we go all the way to the sunshine with Pete Verdult at the window.

Pete Verdult. One question for Doug. I know we're only 8 months into the launch, but can you provide any data as to what's happening to those Wegovy patients that have gone through their co-pay card in terms of the -- how many of those are you losing or transitioning to full co-pays? Anything? I realize it's early days, but any data you can give in terms of what's happening to patients once the 6-month co-pay card is exhausted.

Peter, it's a good question. I think we're still in the middle of that. As I communicated at the end of the year last year, we had a couple of hundred thousand cards out there and about half were initiated. So we're still working through that, and we're still working through exactly what happens at the end of that expiry. So more to come on that.

All right. Then Florent?

Florent Cespedes from Societe Generale. Quick question for Camilla. On the diabetes care prescription online, could you elaborate a bit on could be -- what is feasible on this front because we all know that the severe sufferers have a lot of comorbidities. And also, we all know that more than in any other diseases, obesity, you need some support to make sure that the patients stick to the treatment. So if you could elaborate a bit on what is feasible on this front.

Yes. So when it comes to stay time, we know today that for obesity treatment, this day time is relatively short if we measured it within a year and only 25% stay on the treatment for longer than that. So what we can put in place are also support programs for people to understand when they are initiated on Wegovy. What it means to be on such a treatment, what do we expect? We are also working on indicators that can give them an impression of how would they develop when being on this product. But we also have, and maybe I should let Martin talk to that. We've seen also data on Wegovy that shows that for people that continue on the treatment for more than 102 weeks or more than 2 years they see a continued weight loss. So it is clear that we would assume that it's more likely to stay on the treatment as long as you keep seeing a weight loss effect. And with that, of course, it gives us also a hope that the stay time can be even longer.

Great. Thank you, Camilla. Then we move into cyberspace. And we have Sachin Jain with us, Bank of America.

Apologies for not being there in person. If I could just add a question on SELECT. I may have missed it, Martin, could you comment on the powering of the interim, what level of benefit is required in the interim for successful stop? And then obviously, we get a lot of data and I wonder if Doug could talk to the payer implications of SELECT and whether it would substantially advance or see to reduce obesity act.

So somehow our virtual speakers sneak in 2 questions, but we'll go with it again this time, Martin or Doug?

Thanks a lot, Sachin. So as you can probably imagine, I'm not fully ready to talk about the powering of neither the interim nor the full study and our assumptions put into that. Goes without saying we're a little bit conservative in this space. So we are confident that the interim should not be conducted unless we have ample powering for not only the primary endpoint but also the secondary endpoints that are of interest to us.

Thank you, Martin. Doug?

Yes, Sachin, what I would say is we're pleased with the level of access today and really, we need that component of employer that I just talked to. So certainly, we'll be benefiting from SELECT given if and when it reports out and how it reports out, but I don't know that we'll use that in our armamentarium, but I don't know if that changes drastically where we are today with access. As far as TRO, we're hard at work with that. And certainly, that will just add to the benefit.

Thank you, Doug. Then we move to Michael Novod.

Yes, Michael from Nordea. Just a question to reimbursement outside of the U.S. So you see that the NICE in the U.K. gave a initial positive response already 5 months after approval in the U.K. Is that a good sort of benchmark for other countries in Europe? And relating to that as well, their reimbursement is with one comorbidity. And you said that 90% of patients in the U.S. have one comorbidity. So is that also representative for sort of the patient population across Europe and the U.K.

Yes. So I think the quick answer is, yes. It is one that we're watching very carefully. I think it's nice that it started with U.K. because a lot of the European -- and actually, ex-European countries are looking up to U.K. for some sort of guidance. I would say that depending on, of course, the budgets also through the chain we will see differences between Europe because sometimes the national body give you some sort of restrictions and gives you a certain access. But then the hospitals, then the CCGs and what have you in various different health care systems become the bottleneck. I am cautiously optimistic, but we have to be patient with this as it will go slow since the other side has to balance their budget with the total number of obesity patients that they have and then often those numbers are very large.

Thank you, Mike. Cautiously optimistic. Then we stay over here.

It's Harry Sephton from Credit Suisse. Just one question on the U.S. So you talked about the 11,000 current prescribers and targeting about 35,000. Why not target a broader prescriber base and what's needed to broaden that prescriber base? Is it more insurance coverage driven?

Yes. That's a good question. So right now, in the initial phase, we're -- the targeting is very specific to those that have shown a willingness to prescribe in the past. So we want to do that initially, so we'd have the most receptivity for the product over time, the intention is to always broaden that level of target and be more like in the lines of diabetes where it's 2x or 3x times that. So always been our aim. We just wanted to add launch targeted in the most likely prescribers in terms of who would see the most benefit or someone that already prescribed in the past, say, Saxenda.

Thank you, Doug. Then we move to the other side, Keyur from Goldman Sachs.

Thank you. Couple of questions. The first one is just the DKK 25 billion -- greater than DKK 25 billion that you're guiding to, what proportion of the market do you think that represents from a Novo product perspective? So I guess my question is, what are you assuming relative to the size of the market relative to your DKK 25 billion. And then linked to that, the trajectory between last year and DKK 25 billion, is that broadly linear? Should we think of it as a hockey curve kind of hockey stick curve once you get the CV outcomes data? Or do you think that will help but not needed in the near term?

Thank you, Keyur, for these questions. And clearly, we're making aspirations. For the medium term, signaling our commitment and confidence in a serious growth opportunity within obesity care, and that's our intention with the more than DKK 25 billion. Of course, a lot of uncertainties given it's an immature market for branded anti-obesity medications. But Camilla, any kind of component to it?

Yes. Exactly, Karsten. So as you heard, what we are trying to do is to keep unlocking this market on the -- with the factors that we just discussed. And I just want to add to what Karsten said that in reality, we have not seen what Wegovy uptake looks like when it's unrestricted yet. So there's still a number of uncertainties in this market, and we haven't seen it launched in the IO yet. So hence the more than DKK 25 billion approach to it. But of course, the more we can unlock the 3 elements we just talked about, patients seeking treatment and awareness, number of physicians able to prescribe and then, of course, the market access or the reimbursement. Those are the key factors that can unlock more and more of this market. And that's the journey we are on.

Thank you, Camilla. And then we go to Richard Vosser.

Richard Vosser, JPMorgan. Just in that DKK 25 billion, the pricing development that you've sort of assumed within obesity. I mean you've got the 2-milligram launching soon that's getting perilously close to the 2.4 for Wegovy in terms of dosing and diabetes pricing is a lot lower than or somewhat lower than obesity. So how should we think about that? And also with competition coming with diabetes, too.

Camilla?

Yes. So while we cannot give specifics on pricing as such for products that we haven't launched yet, I think you should think of the obesity market, of course, like what we've also seen in GLP-1 market as it expands more and more. It's likely that the price will also develop accordingly. So that's a way to think about how the pricing in the obesity segment might develop as more and more people get access. I don't know, Doug, if you want to talk about in the U.S., of course, we have 2 different channels in diabetes and obesity at this point in time as we don't have Medicare access.

Yes, I'd rather not get into how we may or may not price a product downstream, but I think you've answered it nicely.

Great. Thank you, Doug. Thank you, Camilla. Then we move on to Kerry Holford from Berenberg virtually.

Yes. Can you hear me okay?

Yes.

Excellent. Just following on from the point made, from you, Camilla, with regard to the acceptance of obesity as a disease. Are we any closer to seeing broader reimbursement for obesity therapies in the U.S. specifically at government-funded channel? Any new discussion reporting commentary here and if you'd single data readout. And if I may, as I'm virtual, I'd like to squeeze in a second quick question, it's just a point of clarification. The new target of over DKK 25 billion by '25. Is that for obesity as a whole or Wegovy alone?

Yes. So the first one is simple. It's for obesity as a whole. And then next question for you, Camilla, on reimbursement?

Yes. So I think I might defer to Doug. I know he is happy to talk about this being an all the -- former market access guy, and that is right down -- always a market.

No, I think, Kerry, it's a good question. We're hard at work, as I mentioned earlier, on both the state and the federal level. And on the federal level, certainly one of the vehicles that we're using is to treat and reduce obesity act. We've been hard at work there. We have more signatures than we've ever had. I think in the end, the way I'd characterize to that, it's more of an if. It's more of a -- we're going to get this done, I guess, is the bottom line. And we feel very, very confident. It's just a matter of when we do it, not if we do it.

Okay. Then we have a question, Simon Baker.

Simon Baker from Redburn. I'm just going back to the issue of coverage within the U.S. Doug, you said you're about 2/3, 70% of insurers and about 50% employer opt-in. Now notwithstanding the fact that 20 million patients is more than enough to blow through the guidance you've just given. Where do you see the easier progress on that. Is it expanding insurance coverage? Is it expanding opt-in as we go forward? I'm not going to ask you to give a number you'd like to get to because I know you won't give it, but any thoughts on just the dynamics of those 2 buckets and drivers would be useful.

Yes. It's a really good question. And then in the end when we're trying to unlock this disease. It's a combination of both, and I'm not trying to just give a simple answer, but it's going to be the continuation of how we work on both national PBM, local level, health plan level as well as the employer opt-in. So we're actually working simultaneously on both. And then again, as I mentioned, it's also a state component and a federal component, which downstream, the federal component would unlock potentially the Medicare. So all of that is needed, and we're working on all of that.

Thank you, Doug. Then we go virtual to Wimal Kapadia.

Great. Wimal Kapadia from Bernstein. So can I just ask about phentermine? So it still dominates about 80% of the obesity volumes in the U.S. So I guess, is there a scenario in 2030, for example, where that number could be 0? I'm just curious if you've made any assumptions in your guide in terms of market growth versus phentermine share decline? Just trying to get a sense if you can significantly expand Wegovy volumes without actually increasing the penetration of obesity drugs.

Great. So if I start out and then hand it over to my colleagues. So first of all, the premise for our more than DKK 25 billion in '25. The premise is that of a market expansion of the branded anti-obesity medication markets. So we're not out trying to gain market share. We are north of 70% global value market share in the obesity segment already. So this is a market expansion. And you saw earlier on from my commercial colleagues that actually, the majority of Wegovy patients are new to anti-obesity medication therapy today. So that's our go to. And all our reps are not going out, detailing against phentermine. Our reps are going out selling Wegovy on its own merits and with -- based on its own clinical profile and benefits and risk reward. So Doug, Mike...

I don't know if I could say it any better at than you just did, at least in my market.

No, I can only say that the market also does not see the 2 as competitor. There's a lot of safety issues. There's -- this is almost like comparing animal insulin, I would say, with Xultophy. The market sees that as very, very different segments.

Excellent. Thank you. And then we have time for one last question before lunch. So I'm sure it's going to be a really good question, anyone. Was that too much pressure? Or just a lot of hungry people here? Probably. All right. Then thank you to my colleagues for excellent obesity session. And now it's time for lunch, at least for the ones here in the auditorium and we'll be back 10 minutes past 1. Thank you. [Break]

Good afternoon. And it's a pleasure to be with you 2 years after I joined Novo Nordisk to talk about what is now called as Novo Nordisk Rare Disease, formerly known as Biopharm. I just want maybe, before we start, to talk about what we did in the background in the last couple of years maybe to reposition a little bit what rare disease is for the overall Novo Nordisk. If you remember this slide from 2019, we had 2 big objectives at that time: secure a sustained growth outlook for rare disease, but also strengthen and progress our pipeline. Let's see how we went with this over the past couple of years. And before I do so, I just want to maybe contextualize a little bit what is rare disease for Novo Nordisk. It's actually a 40-year legacy of working with rare disease patients. The first in line of NovoSeven -- what is now known as NovoSeven was an AT1 actually, 41 years ago. And since then, we believe that Novo Nordisk has built a long legacy in the world of rare diseases, with 3 pillars that are essentially important for what Novartis want to do. One, the fact that rare disease is actually a robust and important pillar of what is Novo Nordisk. 14% of sales, 16% of profit in terms of share of profit, 4% sales growth last year and 47% operating margin, a very different business model to what you might have seen with my colleagues beforehand, which are more on the primary care and larger markets business models. So it's an important pillar. Second is a strategic portfolio play for Novo Nordisk because as you know, we are very much active in the primary care sector. This is ultra-specialty care, different dynamics, limited number of patients, limited number of physicians and a very specific way to bring drugs, medicines, solutions to patients, very highly specialized and highly specific. And last but not least, it's also a platform, a platform to test new ideas in terms of health care, and that could be really helpful for the years to come for the wider Novo Nordisk. That's why we really believe that this is a strong element in the overall portfolio of Novo Nordisk, and that's why we decided to baptize it Rare Disease. And you'll see flourished this hashtag rare for -- dare for rare going forward a lot across all our interventions. I was mentioning that many things happened in the last couple of years. And I want maybe to stop 1 second on this slide because this really, in itself, summarizes what we've been doing and how we've been working hard through all the elements of the value chain from research to development to commercial to really change our profile, raise our profile, stem cell based on our DNA. The first thing we did was actually to change and slightly enlarge our strategic focus. We were mostly known for products in hemophilia, and mostly NovoSeven at the time, and products in the growth hormone deficiency. What we did, looking at what were our knowledge, our biology, our footprint from a commercial perspective, what we did was to look at which were the rare diseases where we believe we could have a chance to meet the severe unmet need, to be super competitive with our science and our footprint vis-a-vis other competitors in that field. And that actually led us to focus, to focus our work in rare disease in 2 domains: the rare blood disorders and the rare endocrine disorders. The rare disease world is a huge world, 5,000 diseases. But of course, we didn't want to spread our self too thin. We wanted to focus and make sure that in a thoughtful manner, we could actually play to win. Hence, the 2 big domains you're seeing here, rare blood, rare endocrine, in which we then worked hard to understand which were the diseases within these domains that we should actually start investigating from a scientific perspective but also from a commercial perspective. And that's what you had behind me. Around 8 new families of diseases beyond the traditional hemophilia and beyond the traditional growth hormone deficiency, where we believe we can make the difference, leveraging all our scientific platforms: peptides, stem cells, genetic, silencing RNA. That's the first thing. The second thing is that, of course, we had to build a journey because you don't transform, you don't create a leader like this snapping fingers. And we went through this journey of creating 3 different growth horizon. The first one, the one that we are about to complete is the one to maximize our current portfolio with our launches with Esperoct, with Refixia, and we'll talk about that in a minute. But we're approaching the second horizon, the one where we're going to launch our new medicines, and that's why we'll have the pleasure later on to discuss with Martin about data and science. Before entering the third horizon, which is maybe the most daunting horizon in terms of science, is actually expanding beyond the core, and we're going to talk about that later on and all these new diseases you saw, with very selected -- carefully selected platforms and scientific endeavors that I'm happy to develop further. So all the elements of the value chain have been, if you want, raised and improved and the integration between all the elements of that has also been improved. So that now we have, if you want, an integrated governance from research to development to commercial. That's the way rare disease players are successful in the market. I was mentioning that we sort of worked and raised our level of efficacy across all the value chain. But I think it all starts with this one, this may be a commercial focus during the first phase. And that's what you see behind me. One of the premises was to return to sustained growth. And now for the third consecutive year, we've actually grown the rare disease portfolio. We've grown the rare disease portfolio. And we've grown it 4% in '19, 1% in '20 and 4% in '21. And interestingly, both from a geographic perspective, IO, as well as NNI, so Doug's and Mike's teams, but also on rare blood disorder and on endocrine disorder. So it's a very balanced, it's a very robust growth, which for me, makes me really believe that we've reached a point where we've really shown we could actually extract a lot of value from that kind of markets. Interestingly, our latest launches, Esperoct and Refixia have actually even been able to compensate what was announced to be the collapse at the time of NovoSeven, which, by the way, didn't really happen, to be fair. And this ability to launch will be essential as we're entering the second phase of the journey, the one that I'm going to now address with my good friend, who is also Mr. Select. You heard about him, he's also Mr. Real, and Mr. Explore and Mr. Frontier, a lot of misters in this one single person. And with a lot pleasure, I'm welcoming my good friend, Martin on stage.

Thank you so much, Ludovic. And now I have to try not to become too schizophrenic here. So we've already talked about it. We moved in areas of serious chronic diseases. We moved in areas of unmet needs. And what we want to do in rare diseases is obviously to develop and continue to develop distinct entities that improve patient outcomes, both when it comes to efficacy, but also when it comes to safety. We can do that by a focused approach we have, and I'll come back to that in just a minute, a strong clinical pipeline. Marcus and team, to Ludovic's point, are working towards stem cell based from that core towards what comes next. But we also have to acknowledge that we can help our patients even more already in the growth disorder space, maybe specifically in the growth disorder space and certainly also in the hemophilia space if we take the utilization of the digital health also into those diseases because we can help our patients. We can help them have an easier life and better outcomes by introducing digital tools. Now rare disease is also interesting from my perspective because when we expand, it's a unique possibility to test new modes of actions in terms of how we do drug development. Smarter, maybe a data trial design, use of digital tools in our clinical trials and new approaches towards regulatory authorities. This allows rare diseases to be not only a commercial growth platform but actually also a development growth platform, allowing us to become even smarter in terms of how we do drug development. And then obviously, we'll also take the approach -- and I think maybe specifically rare disease lend itself to that of maximizing the value of it in the individual molecules. You've obviously seen us doing that with semaglutide moving into more than 1 indication. But I think specifically, when it comes to some of the rare diseases, we can do just that. Sogroya is the first example of that in our current clinical Biopharm, already approved for adult growth hormone deficiency. Now we'll just finalize the growth hormone deficiency in children. And we are moving into several new indications as we speak, [ interestingly ]. This is super, super exciting. I sometimes get the question of why a once-weekly growth hormone? Isn't it just a convenience offering? Short answer is no. You can probably imagine, we go down to the age of 1 to 2 years of age treating patients with growth hormone deficiency. It's not just about height, it's also about other aspects. Height is just the easy-to-measure aspect of having growth hormone deficiency. But we know because of the daily hassle for patients, for children and their families of taking these injections, a lot of injections are missed. So poor compliance and thereby also poor outcomes for the patients. Imagine if we can take that into a once-weekly injection instead, again, going from 7-weekly injections to once-weekly injection, but also introducing digital tools to support our patients. We can improve their quality of life for the patients, for the families, but also potentially improving the outcomes of the patients. This is super important, and this is the purpose of Sogroya. So we just finalized a reasonably large study in this setting, 200 patients being randomized 2:1 to either somapacitan or Sogroya or Norditropin, which is currently the standard of care in growth hormone deficiency. It's important to remember that when we look at growth hormone, which is a titratable drug, regulatory authorities are asking us to do, again, just like in insulin, treat-to-target studies. As Ludovic alluded to, we have more than 40 years of experience with growth hormone treatment. That basically means that we know the balance between safety and efficacy. And the regulatory requirement is, therefore, because we believe we found that balance, is to show not inferiority to what is already out there. And that also means that some of you have said that's a little bit boring getting done, and for our sake. No, that's actually super exciting because without that, we would not get the drug approved. So I'm somewhat happy and excited to show that coming out of the REAL 3 study, we showed exactly that, not inferiority on high velocity, not inferiority on secondary endpoints and not inferiority on safety. So the upside of Sogroya is clearly going from 7 weekly injections to 1 weekly injection. Less painful injections, better device, better digital support and potentially better outcomes for the patients. So I hope you can use that.

I can definitely use that. And why is it so important? It's important because as you can see over the past couple of years, we've really continued our journey of leadership in growth hormone. We're now reaching more than 36% in terms of market share in that market, and that's only with Norditropin. Just imagine what the arrival of a new drug can actually do in that leadership overall for 2 reasons. One, because there's still a huge unmet need. Martin mentioned it, roughly 20% of patients do miss at least 1 or 2 injections a week, huge unmet need. Many of the indication we're going to work in terms of growth hormone disorders beyond the kids across among disorder like SL, like IGS or FSA will actually open a second 50% of that market. There is still potential to grow here. And last but not least, not all markets will go to long-acting growth hormone immediately. We know that for some markets, we'll have the 2 components. And I think the best offer in each of the short-acting and nonacting class is certainly the best way to make sure that we maintain our leadership, again, in an underdiagnosed therapeutic area. But I think it's time to move to maybe the other big chapter, and that is the rare blood disorders. Martin, sorry to bring you back on stage.

Yes, please. And I'm not going to repeat my spiel on unmet needs, but maybe taking us back to -- and I see my old boss in the room. Back in the days when we did performance management, you could either be on par, you could exceed expectations or you could be outstanding. You could also be worse. Lars, at one point, taught me that I could maybe be somewhere between exceed and outstanding. And I told him that exceed expectations, that was sort of a weird denomination, so I got the outstanding, that's good. What I'm talking about now is actually -- we expected something that maybe exceeded the expectations, but I actually hope to convince you that it is really, really outstanding. And we've received actually a lot of questions on Mim8, that is what we believe is the next true shot on goal. We received previously a few questions from you guys in terms of concizumab. Maybe, again, the potential for exceeding or being outstanding. So I'm actually super happy to be able to share some of the results from the just finalized concizumab study with you. Concizumab is, as some of you may know, an anti-TFPI antibody, enabling thrombin generation by binding TFPI and thereby clotting. We've conducted 1 study. It's a complex study, covering both patients with hemophilia A and hemophilia B. In this specific section, we are talking only about hemophilia A and B with inhibitors. There's still an ongoing study without -- in patients without inhibitors. What I'd ask you to look at is arm 1 and 2, which is patients who come from on-demand treatment and are randomized to either continuous on-demand treatment or prophylaxis treatment with concizumab. Now we had 2 additional arms, 1 arm where patients come from our Phase II study with concizumab and continue on concizumab treatment. And 1 arm where patients come from other prophylaxis treatment and are then being switched to concizumab prophylaxis treatment. Now we can discuss whether we are, at the very least, exceeding or being outstanding. But this has certainly exceeded our expectations. What we see is in all of the 3 prophylaxis arms, a median ABR of 0. This is to be compared to something else that is also out there. We see a mean ABR of 1.7, which is actually numerically better than what is out there, reflecting that 64% of the patients had no bleeds. This is truly, truly impressive.

Can we say flabbergasting?

We can say but only with Lars' permission, so can -- we can say flabbergasting, we'll say flabbergasting. What is obviously even more flabbergasting is the safety profile. That looks attractive. And will -- if we can expand this into patients without inhibitors, it'd be a really, really remarkable drug in and of itself. It has a broader reach because it also reaches hemophilia B patients. But with the efficacy and with the safety data that we've seen so far, this can actually be a true game changer in and of itself. We are looking towards, obviously, submission -- sorry, maybe I should just go back 1 slide. We're looking towards submission of this specific trial already this year in what we call a rolling submission. So starting out, we're getting the regulatory approval in hemophilia A and B with -- in patients with inhibitors. But then obviously finalizing the already ongoing trial and submit that. So we'll also cover the patients without inhibitors during the course of next year. Now Mim8 unique mode of action. This is, again, a bispecific antibody. It is the site to have strong activity, only aside of bleeding or of injury and not in circulation. That in and of itself carries then the potential of a very safe profile. What obviously concerns us in hemophilia treatment is if we overdo it, and we start to see clotting events. Mim8 should have an inherently lower risk of developing just that because of this specific feature. Thanks to Marcus and his team, it also has the potential of being, at the very least, a once-daily -- sorry, once-weekly, but potentially also a once-monthly offering. And they promised us it would also be super, super efficacious and have a high potency that would allow us to put it into a nice, easy-to-use device with low injection volumes, allowing us to have low injection-type pains. You know what is currently out there, it's being administered to the tune of 0.8 to 3.2 milliliters per injection. That's actually painful in and of itself. And if it has to be given in a syringe that is larger than 20 70, then it also hurts in and of itself. So Mim8 sort of had the potential of out-of-the-box efficacy, out-of-the-box safety and really, really nice convenience and low injection-type pain. That was a good promise. And Marcus always keeps what he promises. So what we see in our just finalized Phase I and II program. And as you know, we did single ascending dose, we did multiple ascending dose. I think that bored you to death with the design of that study, and you have asked me for the results. Now comes the results. First of all, the PK profile is crystal clear. Very, very nice exposure, very, very nice correlation between dose and exposure. Super predictable, super flat profile. To Marcus's point, a nice once-monthly profile and a very nice once-monthly offering. Thank you for that. We also looked at markers of efficacy or pharmacodynamics. Shown in this slide on the right-hand side, peak thromb. First of all, we see, again, very, very nice dose response, but we also see a potency comparing plasma concentration to the peak thrombin response. That is 15-fold higher than that of HEMLIBRA. Someone in Marcus's team predicted just that. This is a textbook example of going from preclinical into clinical and demonstrating not only a very robust PK profile, but also a very robust PD profile. And then I received a question from more than one of you, will we see as some bleeding data? And to be honest, we always said, no, you won't because the numbers are not big enough for us to really be looking at that. I have to sort of retract that a little bit because we did actually have the possibility to look at bleed data, and this is what it looks like. You probably see that in the 4 doses where we have higher doses of Mim8, either in a once-weekly or in a once-monthly setting, we see a very low risk of bleed. So we basically exceed 70% of patients having no bleed. So even in this small, not dedicated study, to look at this, we already now have a clear indication that Mim8 has the potential to be best-in-class in terms of efficacy. We also have a clear indication that it was safe. We know that the 15-fold potency will allow us to do small-volume treatment. We know that we can give it once monthly. So on safety, on efficacy, on convenience and on injection site pain, we think we have something that is super competitive. So Ludovic, you asked for at least 1 best-in-class drug. I think we've given you 3. And now it is up to you to talk about Sogroya, concizumab and Mim8 and their commercial potential.

Thank you very much, Martin. And again, as you see, so no antibodies detected with Mim8. It's really, really stunning from a biological perspective. So why is it so important? Well, it's important in the world of rare blood disorders for 2 reasons. The first reason is that the hemophilia market, maybe contrary to what we believe, is not finished at all. This is not the end of history in the world of hemophilia. You still have a huge unmet need. Only 15% to 20% of patients are actually getting into prophylaxis. You have still a lot of -- even people treated with FHLs, so short half-life as well as plasma. So the market is expanding. The need for new agent is quite high. And as you can see, something which is very, very important, there is a huge trend for individualization of prophylaxis. In other words, the market is very likely to remain quite fragmented between all sorts of new therapeutic approaches, not 1 single winner. So just imagine the power of a player that has an FHL, an HL, a mimetic, an anti-TFPI and maybe tomorrow, gene therapy, and I'm sure that at some point, Marcus, will also keep his promises, we'll talk about that, I hope. Having a portfolio matters, and this will help us being really the leaders we aspire to be. Our current market share on A is around 4% to 5%. And likewise, on B. Just imagine the avenue for us in terms of growth if you really bring these products well to patients and to physicians. And we've proven we could do it with a Refixia, with a Esperoct, so I really believe we can do that with this great portfolio as well. I would like maybe to finish off with one single word. We discussed about the commercial arm. We discussed about the development. What matters is the future. Exactly the same line as what Marcus alluded to this morning, we've already started with his team to think about not tomorrow, but the day after tomorrow. With all the platforms available, ranging from silencing RNA to gene therapy to peptides orals in these therapeutic areas, we have candidates coming in with a newly created rare disease research unit, combining internal innovation as well as external. And if you put these 2 efforts together and with the increased throughput that Marcus' team is really realizing right now, we're really confident we can achieve our objective to be a leading player in the world of rare blood and rare endocrine disorders by the second part of the decade. I hope I've convinced you that the change is real. And of course, I'd be very happy to answer any questions you might have during the Q&A. Let's now move to something completely different, exactly, out of serious chronic disease. Martin is back.

This is really becoming schizophrenic. I apologize for that. But now we are changing gears, moving into cardiovascular disease. Just want to give us more piece of advertisement. When we move into other serious chronic diseases, we can talk cardiovascular, we can talk NASH, we can talk chronic kidney disease and we can talk Alzheimer's. We decided to focus this session on cardiovascular disease, but Camilla and I will have a breakout session where we'll also cover Alzheimer's and NASH. So I want to take you back to our aspirations. If we are to succeed, and you've heard that during the day, we need to also succeed in what we still call other stage chronic diseases, maybe just like with rare diseases find a new name for it at some point. But for now, we call it other serious chronic diseases. Going from a research, from a development, from a commercial, from a production perspective into new disease areas, we've already received some questions on that. It is obviously an undertaking. Our approach is to build what Marcus also talked about earlier today, the knowledge that when we talk about the cardiometabolic space, starting maybe with obesity, diabetes, but certainly also cardiovascular disease, there's an underlying pathophysiology, there's an underlying clinical understanding that allows us to leverage on what we already know and what we already have. That makes it easier for us to move into these spaces. And obviously, again, from a clinical -- from a medical perspective, there's a huge overlap in patients suffering from obesity, suffering from diabetes, but certainly also suffering from cardiovascular disease. Now we oftentimes get the question, what can Novo Nordisk do specifically in cardiovascular disease? It's a super-crowded space. It's important to remember that cardiovascular disease is not one disease, it's several hundred diseases. And what we are obviously, again, doing is to leverage where we think that we can be good. Where there is an unmet need, where we have the biology, the pathophysiology, the medical, clinical understanding to move into those spaces. So even within the space of ASCVD or atherosclerosis, we defined for ourselves 2 spaces where we think we can make a difference. One obviously, as alluded to in this slide, being oral PCSK9. There's still an ultimate need for high cholesterol. It's still a crowded space. We acknowledge that. But again, bringing in as the first oral offering to this space may make a difference. I'll not go too much back into that. But we also see a tremendous unmet need in one of the underlying pathophysiologies for ASCVD and that is inflammation. We know that high level of inflammation is one of the underlying causes for developing atherosclerosis and for developing the poor outcomes that we see in these patients. No one has been able to address that unmet need, in part because we let a little bit of the efficacy that are actually reasonably efficacious drugs out there at a cost of safety and tolerability issues. In the heart failure space, specifically in heart failure, we'll preserve ejection fraction, there's really nothing out there. So again, a tremendous unmet need and a place for us to use our research, our biology, our pathophysiology understanding to step into that place. We specifically, obviously, are looking at our ATTR asset in cardiomyopathy. But Marcus also talked about our cell therapy ventures and specifically Heartseed and being able to start something already now in that space is obviously super gratifying. We have been in this space for more than 10 years. Again, we're not new to this. We have new development, have conducted cardiovascular outcome studies for the last 10 years. And we are actually now among industry leaders in terms of how to do cardiovascular outcome studies and doing the development in this space. We've also discovered that our GLP-1 assets, starting with Victoza, but followed on by semaglutide, actually had a cardiovascular benefit. We've not only ruled out cardiovascular risk, we established cardiovascular benefit. And then obviously, again, going back to the maximizing the value of semaglutide caused us to do more than just that. So we are conducting a plethora of outcomes trials with the semaglutide molecule, starting obviously with select control that we just discussed, but we also have flow, STEP-HFpEF, which is obviously in heart failure with preserved ejection fraction. And the STRIDE slide I mentioned previously, which is for peripheral artery disease. 4 years into a new R&D strategy, we also have clinical late-stage assets that are not based on semaglutide. We had the SU trial, we have the oral PCSK9, and then we have our ATTR asset as well, really, really exciting to be on this journey. And that basically means that we believe that we have a good chance of meeting our own internal aspiration that I obviously now shared with you, namely having a novel asset on the market somewhere between '24 and '28. We believe that we can do that. And obviously, this has to be a first-to-market, maybe first-in-class, addressing an unmet need. Pursuing, and this is Marcus's take, an innovative mode of action. And obviously, also, we had to -- maybe we cannot do all of this internally from a research perspective, looking towards the outside for inspiration and potential acquisition of assets or maybe stem cell based on our externally acquired platforms. This also means that when you look at the pipeline, you still see semaglutide-based assets in our pipeline. This is important. This is maximizing the semaglutide value. But we also have a lot of novelty in there. A lot that looks at new motivations, being first in addressing tremendous unmet need in Phase I, in Phase II and in Phase III, really, really exciting. I think in the progress of 4 years, quite impressive. Few words on the ziltivekimab molecule. I mentioned the balance when we talk about inflammation and treating inflammation between safety and efficacy. It is actually possible to suppress inflammation or address inflammation, but it has always the risk of infections. Introducing neutropenia, thrombocytopenia, potential liver impairment potential dyslipidemia. This is what we've seen in other modes that have been looking at these assets. Ziltivekimab is an anti-IL-6 antibody. It has been investigated in Phase II, where we saw a 90% reduction in the proxy for inflammation, namely CRP, in the 2 higher-dosed arms. That's pretty impressive in and of itself. But what we also saw was the safety profile that was super attractive. So no increased risk of infections, no clinical neutropenia, no clinical thrombocytopenia, no liver impairment and no dyslipidemia. This obviously is maybe a little bit of a higher risk than what we normally do, but we did take the decision based on those data to go into Phase III. So we are already now in the recruitment phase of a Phase III outcomes trial. This is a midsized Phase III outcomes trial, 6,500 patients being randomized either to ziltivekimab or placebo, midsized because we are looking at a very diseased population of patients, obviously, with cardiovascular disease, with inflammation, but also chronic kidney disease. And we expect to see an event rate that is substantially higher than what we normally see, explaining the slightly lower sample size than what we normally have. Very, very exciting. Do also want to spend 2 minutes on heart failure. This has historically been a place where we could not help the patients. Heart failure is today divided in heart failure with preserved ejection fraction, where there's really no treatment out there. And heart failure with reduced ejection fraction, where we actually see treatments out there and therefore, a place where we've decided not to play. But in preserved ejection fraction and specifically also with cardiomyopathy, we have already now 2 shots on goal, one going into Phase I, which is the Heartseed cell-based therapy for heart failure. Marcus already alluded to that. But for ATTR cardiomyopathy, we also acquired an asset from Prothena that allows us to go into the specific version of heart failure or what's it called? Yes, we call it heart failure. And again, I think broadly speaking, and I have thanked Marcus a couple of times during this session, but we are relying a lot on what he does to bring stuff from early research into development. I think it's impressive to see how we built a pipeline in a matter of 4 years, going even beyond the semaglutide molecule. But obviously, stem cell based on this semaglutide molecule in terms of stem cell based our capabilities and our progress into doing this. But with that, Camilla, I would like to ask you, what are you going to do with it?

What am I going to do with it? Yes, let's take it step by step, Martin and just explain where we're coming from with our entry into CVD. But just to get back why are we doing this in the first place. As you see here, and you alluded to it, Martin, cardiovascular disease is the leading cause of death across the world. And not only in developing countries, but also in developed countries. So many, many millions of deaths every year is due to this. And that's, of course, where we can hopefully make a difference. When it comes to the commercial perspective of this, it is -- we know that there are more than 100 products in development in the pipeline to address heart failure but also ASCVD. So of course, this is important. But on the other hand, we also know that, from a commercial point of view, the market is very different from what we traditionally know in diabetes as the top 3 players only make out 30% of the total market, whereas in diabetes, it's actually 2/3 that's made up by the top 3 players. So yes, it might be a crowded market, but there is still a lot of unmet need with this leading cause of deaths. So the way we are going to go about this from a commercial point of view, I'd just like to address with you in a couple of steps. So on the left-hand side here, you see our focus areas. So we will begin with expanding our presence with cardiologists from what we already have. So with our CV indications for our current products and what Martin just talked to, we will slowly establish our presence in this field over the coming years in the near term. Then in the medium term, we will be preparing for launching stand-alone assets in this field, and I'll just come back to the time lines in a minute. And then finally, long-term, new modes of actions that you heard from Marcus earlier on. So if you look at the right-hand side, you will see that in the next couple of years, based on the Phase III trials that Martin just alluded to, in obesity with semaglutide 2.4, we will be looking at HFpEF indication. Hopefully, looking forward to seeing the results soon. This will address around 13 million people potentially and be the first in class for this indication within obesity. Then in our semaglutide 1.0 milligram, we are looking at peripheral artery disease. We are likely to also get that to the market if everything goes well in the trials in the next couple of years. That can potentially address a much bigger population. And this will also be the first and only for type 2 diabetes. And then finally, on the more stand-alone, and these are just examples of what we would be doing, but just so you get sort of the 1, 2, 3-step approach that we are applying here, it would be in ATTR cardiomyopathy that Martin also looked into. Hopefully here, we will be able to reverse disease progression and not just stabilize. This has a little longer outlook, towards 2028. So this is the approach that we are taking and that we will be stem cell based on. If we talk to ziltivekimab specifically, we are, of course, also looking at what are some of the commercial opportunities and hurdles and success factors that we will need to be able to deliver on to get to the market in an organized fashion. And on the left-hand side, you see here the global number of patients with ASCVD and chronic kidney failure. And that sums up to around 15 million. But when we then also screen these for who have high inflammation level that can be addressed the high-sensitivity CRP above 2, then we will get to a potential of around 5 million to 8 million people. So that's what we are likely addressing with ziltivekimab in this indication. And to do that, of course, need to be able to work with the health care professionals, establish the relationship but also to be able to know who is who in this field. So to prepare for that, we have already now hired in people that have experience in this field, also from a commercial point of view, to make sure that we address it in the best possible way. And of course, we will be stem cell based on that as we progress this towards the launch. At the same time, we also want to quantify for payers what does this mean. What does it mean to be able to address this? And also, how can we prove the sort of relationship between the inflammation, weight and also a successful and socioeconomic relief of the burden. So those are some of the steps that we will be taking from a commercial point of view to prepare for the launch. And as I just mentioned, we are already embarking on this and having the right people on board. But of course, we are likely to expand more and more in a sort of trigger-based approach going forward on this. So just in summary on cardiovascular disease. We are entering a growing market that is still a big issue to society data. There's a big unmet need. We are focused to build a presence with the step-by-step approach that we just talked to. And then prelaunch activities are initiated and ongoing to make sure that we can benefit from the pipeline that Martin is working on, but also that Marcus is developing in the early part of the pipeline. So with that, I'd like to conclude this session and just invite Ludovic and Martin back for a few Q&As in case you have such.

All right. You know the drill. And I think this time, Mr. Vosser was the fastest one out of the gate. So over to you, Richard.

Just on concizumab, I think there was some -- you had to dose-reduce and you had some thrombosis risk. What exactly have you seen in the Phase III data from that sort of thing?

So you're absolutely right. It's really not unusual in hemophilia development to see that you have to tone down on your dosing and your dosing regimen, and we had to do the same thing with concizumab. So we had to change a little bit how we initiated the patients, but also how we allowed patients to adjust the dose based on a blood measurement taking 4 weeks into the treatment. Once we did that, we basically saw no safety issues. And that goes for both the explorer7 and the explorer8. Obviously, we've only seen the full data set for explorer7. Thank you, Martin. Then we move to Florent.

Florent Cespedes, Societe Generale. A quick question on your interleukin 6 on cardiovascular. Could you elaborate a bit on the profile of the patients you are recruiting on the cardiovascular outcome trial? We understand it's a more severe population. So why are you so confident that you will see some efficacy there, knowing that some competitors have failed with oral interleukins ? And also, could you share with us what the size of the population? You showed us some 5 million to 8 million people. So what's the size of the population from the outcome trial?

Absolutely. So maybe I'll take the first part and you take the last part. So the population we are looking at, to your point, is a very diseased population. They will have established cardiovascular disease, they will have established kidney disease, and they will have established inflammation as measured by CRP. That basically means that they have an increased risk of having cardiovascular events that we know from previous outcome studies that this will be to the tune of 50% to 100% higher than what we normally see. We had to acknowledge that moving into a new disease area with a new mode of action that is higher risk than what we normally do. The reason why we feel confident is, obviously, on the efficacy part we can decrease inflammation. And if you take, for example, the CANTOS study, which was an anti-IL-1 and not IL-6, they did have an opportunity to look at patients with increased IL-6 levels during the trial and patients who then decreased IL-6 levels and actually also CRP. And they saw in excess of a 30% risk reduction in those patients. And that obviously gives us some clinical confidence that this might work. In the CANTOS study, they also had safety issues. And these are specifically what we do not see, at least so far, in our Phase II trial with ziltivekimab. So we do believe that we have not only from the clinical space, but also from mendelian randomization studies and from the nonclinical space, good evidence that inflammation reduction will work. It has to be done in a safe way, and we believe that ziltivekimab can do that trick.

Camilla?

Yes, I heard the question. But yes, the population in the ZEUS trial, I heard in Martin, but maybe you normally know the...

Florent, could you repeat the last part of your question in terms of the patient population you're asking about?

Yes. I was just wondering as you are going for kind of severe population, is it something that is the same as the 5 million to 8 million people you were referring to?

Yes.

Short answer is, yes.

Then we move to Emmanuel Papadakis from Deutsche Bank, virtually. Emmanuel, audio. You're on mute, Emmanuel. Try again.

I'll try now. I don't think it's my end. Can you hear me now?

Yes, it works. Yes.

Okay. Apologies for that. And congratulations on the initial concizumab data. Perhaps I'll take the opportunity to ask the question I was going to ask in the initial session, which is kind of technology platform related that ties it pretty closely with what you're trying to do more broadly in rare diseases. You called out genome medicine, gene therapy as 1 of the 4 key technology platforms, but you gave it very little air time in your prepared remarks earlier this morning. We've certainly seen some challenges for gene therapy space recently. I think you've extended your collaboration with bluebird 270 on the genome editing, gene therapy side. Perhaps you could just talk a little bit about your intent there and how important that is over the coming years. And it was very interesting to see you mentioned lysosomal storage disorders as part of your rare diseases portfolio envelope, perhaps you could address that in particular.

I think the 2 questions are actually related. -- the LSD, lysosomal storage disorder part is actually a part that is quite filled with competition as we speak. However, if we can find the right approach from a gene therapy, then that could prove to be a very attractive space. One thing which is important to answer your question, Emmanuel, is that we are really focusing on gene editing i.e., you cultivate second, even third generation, if you want, of gene therapy. We believe far more in that technology. Hence, the partnership we have with bluebird bio. And as you know, we are working very hard with this partner now in the hemophilia A component, where we are bringing the best of both scientific knowledge on the platform on the one hand and our knowledge on the hemophilia A. This is actually going according to plan. And we are -- and I don't know whether you're addressing that later on Marcus. I think Marcus address this later on in the breakout. So you'll have all the answers to that. But it's certainly a pivotal element for our journey, let's say, late part of the decade and early part of the 2030s in the rare disease space. More on the gene editing than on a gene pure therapy.

Thank you, Ludovic. And a nice commercial for the upcoming breakout. Exactly. So moving on to Simon from Redburn.

Just going back to ATTR cardiomyopathy, a couple of weeks ago, AstraZeneca said that the true incidence is probably understated because of misdiagnosis those huff puff. I just wonder if you've got any perspectives on that and what the degree of misdiagnosis is to give an idea of what the real opportunity is.

So these are early days. And to be honest, the diagnostic tools to look at this have been wanting. As we improve both the diagnostics, the availability of diagnostics will become wiser and recent data suggests that up to maybe 13% of patients with heart failure has a level of ATTR cardiomyopathy.

Thank you, Martin. Then we have a question down here from Keyur.

A big picture one for you, Karsten and Ludovic. Given the progress you've made on the pipeline in the rare disease business from 2019 to now, your strategic expiration for that business hasn't changed, which is advancing the pipeline. So why are you today not being bold and giving us some commercial strategy objectives around that business? Why are you shying away from that?

So Ludo, if I start out and then you add on. So Keyur, I think the first premise of your question about the progress of our rare disease pipeline, you're perfectly correct. We are very excited and very satisfied with the progress we've seen in our R&D pipeline on the rare disease. So a lot of credit to the teams across commercial, all the way to research. So good progress. It's still early days. And those of us who have been around for quite some time, especially in the hemophilia space, I think it's not like a 90% or 80% probability of success. So we would like to see a little bit more data. Bear in mind that Mim8. It's Phase I/II data where we're looking at. So perhaps when we see Phase III data, we can talk about formalizing, even shop on our commercial aspirations. But rest assured, we are not holding back in terms of optimizing the opportunity at hand.

I think what matters is that this pipeline gets stronger and stronger. In the world of rare disease, as we know, the pipeline has a different logic as what you can actually observe in the more primary care for diabetes that we see. And we need to see that pipeline growing stronger and stronger. What we can tell you that all the elements or the building blocks are in place commercially from a development perspective as well as from a research perspective to create a leader in the red blood and rare endocrine disorders. But that has to be built on the go. And of course, as we go and as we move on and as we launch these new medicines between, hopefully, in the next couple of years, we'll then be able to formulate that maybe in a more, what you could call a, bolder fashion. That's another question, I guess.

So just a follow-up then. Is it fair for us to assume that growth rate for this business, 21% to 25% is going to be higher than what you've delivered for the last 4, 5 years.

I think we're not doing forward-looking statements, right?

So Keyur, I think, first of all, when you look at the Mim8 time lines and the Phase III trial for Mim8, then Mim8 is not going to benefit our growth trajectory in rare diseases towards 2025. So what we're going to benefit from is Sogroya as well as concizumab. And Ludo covered those opportunities. And clearly, we are going to benefit from that. So what you're seeing is we've seen erosion on some of our legacy products. And then we're driving growth and benefiting from our new launches. So clearly, in a good place now, but whether we're going to grow faster than 4%, I think actually 4% was something that we're really happy with last year. And if we can keep driving at that level, then we'll be very happy.

Okay. Then we move on to Sachin Jain from Bank of America.

Just a follow-on question on concizumab where the data you framed is outstanding. I have 2 questions. One, I wanted to understand what has changed from Phase II to Phase III in the inhibitor population where the ABR has gone from -- working from my memory, 3, 4 in Phase II to the 0 rate. So what's driven that? And then related, how is that driving your thought process in the bigger non-inhibitor population. Martin, when we've spoken before, you previously discussed the excitement predominantly in heme B. But does this data make you much more excited about the heme A setting.

So I think Ludo will answer the latter part of the question. From our perspective moving from Phase II to Phase III obviously as we just discussed, we optimized the dosing regimen. And that is maybe in part why we see even better results in Phase III than we did in Phase II. I think it's fair to say it changes a little bit the way we think about the hemophilia A part, but Ludovic is -- will get to talk to that.

Concizumab is a medicine that is actually valid given its mode of action in MA, MB with and without inhibitors. So the 4 quadrants. And indeed, at the first place, we thought that MB with inhibitors might be the best spot to be because there was no other alternative. When you look at that profile, and when you -- I really understand the fragmentation of the needs of patients, the fact that some patients want really a short life protection, high protection throughout the day, you can clearly see that there are many patients in patient groups, even in hemophilia A, without inhibitors that could be interested about what concizumab has to offer. Those who want a very high level protection, to be sure about its protection certainty are necessarily patients that could really enjoy with a very easy device to use that could enjoy the protection of concizumab. We clearly believe the portfolio play will be an important one. And that's why we indeed are revising a bit or, let's say, not revising -- reinforcing the idea that this could actually be a very good medicine across all type of hemophilia.

Then we have a question from Carsten Lønborg, SEB.

The Mim8 Phase I/II data, you showed 5 cohorts. Isn't it for a number of bleeds? Isn't somewhat of a concern that you see most bleeds on the lowest dose expected but also on the highest dose?

I think this is a function of a very small story, which is also why we were a little bit apprehensive in actually showing the data because this will happen. One patient who started out by having more than 50 annual bleeds a year was driving these data. And you'll always have that outlier that's easier to absorb in Phase 3 than in a very small Phase I and II trials. I've been educated by our hematologists [ at Nordisk ] and externally that this is what we always see. And there will always be that patient.

Then we have a question from Pete Verdult.

Pete Verdult, Citi. Just a quick one on nedosiran. I realize you didn't buy Dicerna for that asset. But just with that Phase III data hardly saying the word [ length ], I just wanted to know what your go-to-market strategy there and your commercial expectations. And then if I could squeeze one in, extra, Ludo or Karsten. At the last CMD, you made it clear that you're very actively looking for BD opportunities. Where are we now for biopharma? Is that still a strategic priority? Or are you just being opportunistic as it relates to supplementing your growth outlook inorganically?

Shall we start with the second one, maybe?

Yes, absolutely.

The easy one. We are still looking for opportunities. I think we cannot actually think about developing a proper rare disease army if we're just walking on 1 leg. So we'll be walking on 2 legs, one external collaboration. But it's true to say that the quality of our internal pipe has significantly improved over the past couple of years. So we'll be working in a balanced manner, both in -- with the support of our platform teams as we did with Dicerna. We're going to talk about it in a minute. But also in earlier -- maybe early clinical stage assets where we believe there is real value in the market. So it's going to be a 50-50, 2-legs strategy. On nedosiran, as you said, it was on the table when we did the Dicerna transaction. It's a drug, maybe for those who don't know about it, that is treating a very rare renal condition called hyperoxaluria with 3 genetic variants. But actually, the study was positive on the first one, the biggest one, variant, hyperoxaluria type 1. And we are definitely moving ahead to try to commercialize that asset. It's also a way for us to understand how to best design smart commercial models for such diseases. And it's -- I mentioned earlier on that it was a nice work for Novo Nordisk with rare disease to test new ideas. We'll definitely go ahead with this one and try to see how we can build smart way to commercialize such assets. We believe that these kind of assets will multiply in the next couple of years. So it's a very good way to start with actually, again, the compound that is fundamentally helping patients. We often forget about patients, but the unmet need is big. And this is really changing the life of patients. So there's absolutely no doubt we should move in that direction.

Then we have a question from Wimal Kapadia.

I am going to go ask you about the Sogroya franchise. How easy would it be to transition from Norditropin to somapacitan? How big should we think about the opportunity in the adult population just given your sales in the pediatric setting? What indication do you see the most upside potential for a weekly product given the adult population is somewhat slower? I can only assume because of the growth franchise with it.

Yes, Wimal, it was a little bit hard to hear your question. I think your microphone is pointing the wrong way or something like that. So perhaps if you could just restate it briefly, it was a transition from Norditropin to Sogroya, but please restate.

A transition from Norditropin to somapacitan. And then just thinking about the adult opportunity just given the sales, the majority of your sales in the pediatric setting, which indications do you see has the most upside potential for a weekly product? And can we assume growth for the franchise from here?

Do you want to?

Yes. Or maybe talk about the trials we have on that to extend the population and then I can talk about that.

So moving beyond growth on efficiency, we are planning to conduct Phase III studies in new indication such as small for gestational age, idiopathic, short stature, Turner Syndrome and maybe even Noonan syndrome. So building beyond and thereby maximizing the potential of Sogroya, if I understood the question.

The market today is split into 3 parts. You have essentially the adult deficiency, which is between 5% and 8% of the market. You have the kids deficiency, which is around 40% to 42% of the market. And the remaining 50% of the market are the other indications: short for gestational age and ISS plus the micro indications such as Turner, Prader-Willi and Noonan, et cetera. Right now, we are building a development program that aims to cover the majority of this indication, which means that we have somapacitan and we'll be able to cover a wide spectrum of indications. And that's why we believe that, that plus the fact that today, as I mentioned, only more than 22% of the kid patients actually do miss 1 or 2 injection a week. We believe there's enough space in the kids sector as well as out of the normal GH deficiency sector to grow. When it comes to the speed at which it's going to change, well, I don't think it's going to be 1 single speed. Because if you listen to physicians, some will tell you, "Listen, we're very well covered with the daily." Others will tell you, "We want to go to the weekly." It's very likely that the 2 will continue to coexist in many markets. Some markets will go fast. But I would assume that a great number of even mature markets will have the 2, short-acting and long-acting coexisting for the next few years. And that's why it's so important, again, to our portfolio and why our established position with Norditropin will continue to help us also in the growth of somapacitan. So definitely looking forward for growth in that aspect.

Thank you, Ludo. Thank you, Wimal. This concludes the Q&A session. Now we're moving into breakout sessions. A number of really, really exciting breakout sessions. And the way it works in practice is that for the virtual participants, you have to manage it yourself by clicking the right link on the session you want to participate in. And for the people in audience, you have it on your name tags which session you have signed up to. And then there will be people helping you understanding where to go based on this very simple graphic on the chart. So if you have any questions, reach out to Investor Relations. [Break]

We're ready to start. Welcome. This is the research technologies breakout, and I hope you're here in this room because you've chosen to be and not just because you couldn't find your way out. And if that is the case, then yes, there's still opportunity. So it's my great pleasure actually to not be on stage on my own. I've received a lot of attention personally already during a number of the talks also for Martin. But actually joined by 2 outstanding colleagues, Karin Conde-Knape and Lars Fogh Iversen. Maybe we should spend 20 seconds to introduce yourself.

Yes. Good afternoon, Karin Conde-Knape. I'm responsible for Global Drug Discovery and I have been with Novo for 4 years. Very happy to be here.

Hello, everybody. My name is Lars Fogh Iversen. I'm heading up Global Research Technologies. And this year, I've been with Novo Nordisk for 25 years.

It doesn't show. Congratulations. So what we will do, if we get over the forward-looking statements and our aspirations, which you all know by now, is actually to double-click on some of our technology space. We will present some data on certainly the protein and peptide space. We'll spend a bit more time on this, but we also actually do talk about gene editing. I'll start with giving you a bit more insight into what we're doing in cell therapy. Karin will actually focus on how we do drug discovery and what is changing maybe from the way we've done it before. We also actually would like to encourage you for active participation. So we'll spend half of the time that we have actually in a Q&A dialogue. So taking off from the broad technology space, which if you just remember the matrix, cuts across most, if not all, our therapy area. We're now able to execute on activating principles, agonistic principles on the outside of the cell in the circulation towards going into the cell, selectively with high fidelity-blocking targets to replace cells that are either damaged or dysfunctional and diseased. I think we -- hopefully, I can convince you that this is a very, very broad toolbox. And stem cells or cell therapies, which we should actually say because they're stem cell derived rather than being stem cells themselves, have obviously a very broad potential across a number of disease areas. And that actually is a challenge sometimes of choice. Where do we start and where do we want to engage? And we've, for now chosen a few disease areas, Parkinson's disease, heart failure, obviously, diabetes, how could we not do this and dry AMD, we're not talking about the latter. But it doesn't mean we're stopping there. I think that field is still evolving. On the right-hand side, you actually see, in a nutshell, the entire value chain from research to development to commercialization. And I try to allude to that earlier this morning where I said, well, of course, in the beginning of this, making the cells differentiating out of stem cells, either embryonic stem cells or induced pluripotent stem cells into the target cell of choice, that was really the art, and it was a differentiating factor. And I still think it's important, and we're learning more about which factors we need to actually get to the right cell types of use. But we feel this is actually something we get rather good at. And I think the industry is also evolving. The questions are then more actually on yield, on stability and on the quality of those cell preparations. And then we enter the mid- to long game, which is actually manufacturing, quality control, distribution and commercial models. And really, once again, this end-to-end mindset is where we feel, ultimately, we need -- we will decide which project will be successful, we'll reach many patients and which not. I want to show you 2 examples and don't get hung up too much on the very simplistic trial design here. One is our efforts with heart, Martin already spoke to it. This is actually -- and I think that was a small type. We're actually treating patients with reduced ejection fraction less than 40%, so really where contractility of the heart matters, yes, because we are actually giving cardiomyocytes, so the cells that are the muscle of the heart and deal with the contraction. Patients that are relatively sick. And I think I said to you this morning also in this first instant patient that actually undergo heart surgery for other reasons. And that also has made recruitment certainly not a simple play, to say the least. So we learn a lot about sort of our transplantation procedures. We learn about the scale of the cells that we need to actually get good output, improvement in ejection fraction. And we actually learn a lot about also the regulatory space. Maybe the first thing you have noted here is, of course, no placebo-controlled trial. And you also will not see healthy volunteers that undergo cardiac surgery. And I think maybe I'm stating the obvious. So we're entering actually a space where we're doing also different design of the trials than we've done before. On the right-hand side, on Parkinson, similar opportunity and challenge, direct CNS applications, specially made device or catheter. In some areas like outside of Japan, for example, they've talked about a sham surgery as a control in Japan, that is not needed. So we're actually also learning here in which regions do we -- which clinical trials and what is the particular outcome of those. We have 2 trials, one called is TRANSCEND 1 and TRANSCEND 2. The first one, you can think about like a run-in trial where we actually figure out which patient population might be more stable, which might benefit the most from such a treatment. And that, in its own right, is not a simple feat. Good news is, and this is where I want to leave you with here, both start actually in the first half of this year, if all goes well, of course. But that clearly is our aim. So we'll learn by the end of the year. And in next year, we will have learned a lot about stem cell therapies. But with this, I hand over to Lars to help you to get more insights into protein.

Thank you. You heard Marcus this morning talk about our endeavors in SRNAs. And you also now heard Marcus talk about cell-based therapies. And I'll talk about [ tenase-ing ] in a short while, and you might sit there and say, "Well, what are you doing about your core area?" You just saw almost a handful of wonderfully designed proteins and peptides by Novo Nordisk. Are we still investing, doing early investments in our early pipeline to still stay on top of protein engineering. And the short answer is yes. And of course, I have 2 purposes to stay on top of protein engineering globally. But secondly, that I will allude to in a short while, also to give us a momentum into the new modalities. But what you see on the left side is 2 major investments that we are doing to have world-leading protein engineering capabilities. We are designing, and I dare to say this is, one of the most challenging automated setups to do end-to-end protein engineering in the world. This will not be a classical platform where you can just do antibodies. This will be platform when you can do full recombinant proteins of any type, combined with peptide synthesis chemical modification in 1 end-to-end setup. It will allow us to do what we call multidimensional screening. So we'll screen all the needed -- all the properties coming from Karin's shop. In vitro screening, it will screen for how easy it is to produce these proteins and peptides, are they stable, can we formulate them? All that will be done in this automated setup, that will guarantee us a world-leading setup on how to do protein engineering. Clearly, with those amounts of data coming out of this setup, it will be above what we can handle as humans, and that's why we parallel to this, have set up a center of excellence in AI, Machine Learning and advanced analytics, and that is situated in CN. Those 2 investments will allow us to do the new molecules that we need for our protein and peptide strategy that will still be centered for Novo Nordisk. This is a substantial and big investments that will cater for those needs going forward. So I just want to be crystal clear that this is a really important area for us to stay on top of and it's really one of my big obsessions. Now this is all good, but I also want to bring you into that we can use these investments to do better gene engineering and also if we need be, mRNA engineering. Because whatever you would like to do with a gene, it actually is translated back to a protein. So in many cases, you do reverse engineering. So if you want to have a good gene then you need to know your protein and do the engineering, and I'll show this in a short while, why it matters. Likewise, with mRNA, it codes for a protein. So you wanted a good mRNA design, the need to do good protein engineering. So we believe that staying on top of being good at protein engineering will maintain our core business, but also will give us an excellent segue into doing gene editing and maybe also more mRNA therapeutics going forward. But let me showcase it by going in and talk about what we are doing in gene editing. So we have a collaboration with the bluebird bio now 2seventy bio, where they are a company that are really good at protein engineering. They understand how to do an excellent enzyme, the megaTAL that is an enzyme that cuts DNA very precisely and specifically. They do engineering on this enzyme better than nobody else. It takes one to no one. And we have collaborated with them to tailor the enzyme. We need to do a cut in a very precise place in our chromosomal DNA. So that's protein engineering done by 2seventy bio that we are collaborating with. On the other hand side, Novo Nordisk is responsible for designing the Factor VIII gene that we want to insert. We can only do that because we know protein engineering, because the AAV vector can only carry a limited amount of DNA, 4.7 kb basis and the full length of Factor VIII is larger than that vector. So for you to be able to deliver that protein, you have to engineer a mini Factor VII. And that is, of course, the core of Non Nordisk. So we have engineered the gene that can be delivered in the AAV. So here, you see the 2 component systems that we're operating with in gene editing. On the one hand side, we have an mRNA encoding for the megaTAL that is formulated in a lipo nanoparticle. On the other hand side, you see the that AAV that carries the DNA that we have engineered with the Factor VIII gene. Both of these 2 systems will be administered. And what would happen is that both of them will be taken up by the hepatocyte. The mRNA will be translated in the cytosol into the full enzyme that will diffuse into the nuclei of the cell. And the AAV will do its job by delivering the DNA cargo always also into the nucleus of the cell. So when you have those 2 components in the nuclei of the cell, the megaTAL would do its precise cut in a safe harbor place in the gene. And the gene of interest here, Factor VIII, will be inserted and will stay there forever. That means that this has the potential to be a lifelong correction of hemophilia A. Throughout our life, our hepatocytes divide. So if you don't have integration of your DNA into the chromosome, you see that your plasmid, if you have episomal plasmid, will dilute over time. And that will not happen when we go in and do gene editing. So I want -- with these 2 slides, I want to highlight that gene editing is connected to protein engineering. Likewise, we will be with mRNA. But I will show you 1 slide more that will show you the preclinical results in a mouse model of how this has actually worked out. What I described for you just on the previous slide, we have now strong preclinical data that show us that this can be done. What you see on the right-hand side panel is that the integration of the Factor VIII gene and the control that is just episomal expression of Factor VIII gene. And what you see on the outermost panel is the normalization of bleed time in the tail part of the mouse model. So actually, it's looking very promising. It's very, very early days, but it goes to show that this can actually be done in a preclinical model. And that's why we are fairly optimistic around this model. This is all good. But Karin, we need some more targets to use all these wonderful technologies within. How do we do that?

Thank you, Lars. And as you have seen, we are taking opportunity of leveraging the technologies with very well-known biology in the case of Factor VIII. But the reality is that the challenge that we have today is much larger. And throughout the day, you have heard really the wonderful molecules that we have. But still the fact that there is a significant unmet need, certainly in the areas that we work, but specifically in the cardiovascular and metabolism space. So how are we going to be able to deliver the next generation of innovation with the challenges that we have? So the trick here is that we have the opportunity and the responsibility do deep understanding of the diseases and the patients that we're looking to treat in the 10 years to come. These patients will no longer be the same ones that we're treating today. Why? Because the standard of care has given us an advantage to a certain level, but the reality is that patients continue to progress. So it is defining what is the residual risk in these individuals where we can actually identify ways to help. And the way that we are going to do it because we have a significant know-how in the biology of diabetes and obesity, but starting to get as well in the cardiovascular and other areas. It's by taking this opportunity to leverage the data that exists today versus the data that we are building and getting access to external collaborations to be able to integrate and understand better deeply what are the drivers of this disease. So by utilizing not only circulator at the biomarkers, but also looking at the level of the cell, the level of the nuclear, the level of the position of the cell in a particular injury and also mimicking this or pairing this up with genetics, to be able to identify really what are the causal genes that are driving the disease. This should give us the opportunity not only to stay in the monogenic diseases in the case of rare diseases, but also potentially ambition to be in a situation where even polygenic diseases can be treated with a novel technologies and then, eventually, we can offer a cure. But let me take you and deep dive into how are we doing this in the case of obesity. We heard a lot about today about the different patients that we have, the responsibility and the opportunities that we have here. But the reality is that we cannot look at the individuals as being all the same. We already know today, by studies that have been conducted by different groups around the world, that certainly there are different types of diabetes. And at the same time, there are different types of people living with obesity. So if we take the opportunity to grab the patient and work with the patient in his or her journey as to the point when they are starting to see a physician, which we saw today as well that not many are actually getting to even this point. But when we start to really understand what is the journey from the physicians, from the diagnosis from the -- putting a patient on a diet or an exercise regimen, the challenges that the patient go in the cycle of weight gain and weight loss and, therefore, still not achieving with the medication, what they need, if we pair this knowledge because this exists already, with circulatory biomarkers with the data that we collect from the different wearable devices, what the data that can be obtained also from behavioral components, then we can start to integrate the knowledge that we have about individuals and, therefore, define what is really the different type of patients that we are dealing with. So if you can just imagine that you will end up having those individuals that indeed are obese, but maybe have a different trajectory ahead of them when it comes to the level of risk to the level of progression into the weight gain, but also in terms of maybe retracting or keeping the weight off. At the same time, we will be able to identify those individuals that maybe today, they look healthy because they are also lean, but they already have a family history or other components in the environment and the society that are putting them in a trajectory that we could probably prevent. So by using this, we will be able to really define the best treatment for the best patient, but also very importantly, for the right time. And why are we different from the rest in utilizing AI and machine learning? Because we have the know-how, the historical background around diabetes and obesity. But then again, because we have the intention and the will and we are in the process of collecting the right data sets that will help us guide these efforts. So with this, I turn to Marcus to let us wrap up.

Thank you, Karin and Lars. This is really just a summary of what you've just heard from the 3 of us because we often talk about putting the patient in the center. I would argue here, it actually means putting the patient at the very beginning of a journey. So everything we do starts with data from our patients, big data and analytics. And I think that is a real game-changer probably in our industry. It will penetrate everything we do. It also will lead to a different view of our patient populations out there. And I hope I've also convinced you that we actually have the toolbox to then move from observation and hypothesis building to testing those hypotheses with the right molecular entities. Some of them are much more advanced. Others are newer to us. They are newer in the scientific world. But we're engaging with them, and we're learning about them as we speak. And I think I'll stop here and open up for questions from the audience, be it online or in the room, maybe we start in the room here. And Karin decides who gets the microphone exactly.

Dave Lashmet, Stansberry Research. I know that you're talking about adding something like health bands to watch people as they come off trials on Ozempic or Wegovy. Have you considered using like standard monitors for type 2 diabetes in regular obesity patients to get that kind of data like a glucose monitor?

I mean I think the reality is that we're trying to get access to as much data as we can, right? And there is a lot much -- a lot more that we can tap into these days with the technology advancing. So I think it is a matter of making sure that we are collecting the right data but also asking the right questions that can be addressed with that type of data, right?

Keyur Parekh, Goldman Sachs. Two separate kind of questions. The first one is, just as you kind of established a center of excellence on AI kind of machine learning, help us think about how you perceive where you stand competitively today relative to the rest of the kind of biopharma industry. How easy is it for you to kind of build that team up? What are some of the challenges there? So that's kind of one part of the question. And then separately, perhaps Karsten, kind of any specifics you can provide us on how much of your -- our budget is kind of towards this exciting stuff? How should -- how are you thinking about kind of your risk cost probability of success on these things versus kind of your more traditional R&D investments?

Lars, do you want to start with the first one? And I might even take a stab at number two, but Karsten, feel free to chip in, yes?

Yes. Regarding the use of AI and advanced analytics to drive our business, I think we had a good starting point. What you just saw earlier today around the Mim8 molecule that is looking pretty good is driven out of an automated endeavor with, you could say, low-key AI. This was done a couple of years ago. That was our foundation, our archetype project to do advanced design and that we have boosted since then. We have the center established just over a year ago. We acted very promptly when we saw the results coming out of AlphaFold to establish the group in AI. So I would say that we are on par regarding use of AI in protein engineering. But what we will see going forward, that is that we will be able to generate exclusive Novo Nordisk data to drive our AI, so we have an AI flywheel regarding the data we can produce in the LabDroid to guide us into even better protein design using AI. So we'd like to establish an AI flywheel in the protein design space, and that I think will stand strong. Regarding AI in other fields, we are basically trying to establish all these various parts where we can do it. And we have an approach where we both do quite high-level AI from the center of excellence, but we also have a lot of examples where we do bottom-up examples of AI and the use of machine learning.

Maybe I'll start on your second question. Maybe I even try to anticipate what you actually meant by it. I think the most important piece for us is with the budget that we're operating in. Our R&D budget is increasing gradually to put it to good use for the here and now, the projects that are live in our pipeline, but at the same time, to have the interest and the responsibility to ensure we stay relevant for years and decades to come. So I think the financial organization is, of course, a strong partner in this. I don't see that much less than a gatekeeper or somebody who tells us you can spend this much on earlier, risky or this much on later. And I think we're in total alignment here. If you look back just the last couple of 2 or 3 years, I mean, we've made not huge deals apart from Dicerna, but actually quite a broad spectrum of deals and many of them in early assets, partnerships and technologies. And I think that is the signal I would like to give to you is that we continue to be interested. We engage when it's right. We also put money on the table. We just had a very nice experience with Staten Biotechnology, where we tested an ApoC3 antibody. We had an option deal out of 2018 where we paid, if I remember correctly, EUR 10 million upfront and then running a Phase I study to give us actual data to see whether that antibody would deliver on its promise. And it didn't. At least not to what we thought would look like. And that's the kind of stuff how you can actually work through uncertainty and derisk some novel biology or technology. And I would say we are well-equipped in this, but, Karsten, feel free to chip in or add something.

So I think, first of all, I'll comment to it later on, but a way to think of it in a financial context, and you just saw the technology platforms. We have the table with therapy areas and technology platforms. And when we look at it, then we set aside a given the amount of resources for research. And then we have a discussion around -- basically on technology platforms. So what are the right allocation to protein peptides versus RNA versus stem cells versus the oral platform? And then it's basically a collaboration about all -- based on the scientific evaluation, about how mature are the platforms, what are the promises of the platforms and where do we invest ahead of the curve and where do we invest into pure productivity. So now we are maintaining our investments in proteins and peptides and then we are stepping up in RNA. And we did that based on our assessment of maturity of the platform and the 3 first human doses per year, as Marcus showed. And that's how we're assessing the platforms, whereas potentially on the cell-based therapies, we are investing less currently because we're still maturing the platform. And as we see it matures, then we double down on it. So it's -- I'd say it's rational investment decisions based on risk/reward.

And that's actually a beautiful segue in the question I got online, which is diabetes is an active area of investigation externally for stem cell therapy. Any thoughts on the Biosite and Vertex programs here and how Novo's approach is differentiated? I don't -- obviously, it's not for me to speculate on competitors' programs. What I can say is maybe we have -- and I see that in some of the commentary that you guys have written. On purpose, we have kept a lower profile. That doesn't mean we're not active. Actually, quite the opposite, but it's a complex area. And actually brings me right back to what I shared with you before. It's about the entire value chain. It's not necessarily about making beta cells. We all can do this, right? These beta cells need to be of the highest quality. Then you need to either encapsulate them to evade the immune system or you need to stealth them, so genetically engineer those cells so patients don't have to be on immunosuppression because I don't believe that is necessarily the future for a large patient population out there, that they should be on immunosuppression. But it actually gives you potentially a nice way into understanding how cells behave in a human body. So I applaud and I respect sort of those scientific advancements, but to think about a product in the long run, I think, will take many, many more aspects of this. And in particular, the game around devices, I think, is still a very active area of research and development, I think we're all in. And I think we're out of time. Is that correct?

We can take one more question.

We could take one more question? And if there's one in the room, then we take the room.

Can I be cheeky and ask 2 very quick ones then, please? Firstly, just what drove the decision with Dicerna to buy rather than partner? You've talked a lot about collaborations, but Dicerna, you bought in-house. What was different about Dicerna? And then just secondly, just on the duration of therapy. You've talked about cell therapy. You've talked about gene editing. What, in your mind, is the duration of effect we need for it to be viable? Or is there no such thing as a cure the only way?

Yes. So on Dicerna, and I tried to elaborate it this morning is we obviously had a very specific strategic collaboration on hepatocyte targets. And at some point in time, we could anticipate that we would have exhausted that target space, right? So -- however, we are actually keen, and we're seeing a lot of targets now coming through the target discovery engine out of Oxford, which deal with other parameters, dyslipidemia, diabetes, obesity. So our ability to address adipocytes, muscle, cardiomyocytes even has become really, really important. And if you read everything that's in the public domain, you will know our going-in position was not one to say we need to buy you. It was one to say, how can we strategically expand our partnership. How can we actually work better together to bring our competencies together in a synergistic fashion? It ended up in the acquisition, but it wasn't necessarily the first step. Then I don't know, Karin, do you want to take a stab at treatment duration in -- yes?

Yes, this is the key question, right, especially when we're talking about bringing gene therapy. So the challenge and -- I think is between the efficacy profile that you will be able to deliver. And as Lars was alluding to with the gene therapy for factor VIII, we know at least based on the science behind that with the approach that we are having with the integration, you will have much longer duration versus maybe other approaches that after 2 years are winding off. So I would say it's -- probably the easy way to say it is the longer the better, as long as you are able to deliver something safe. But I think that the jury is still out and if you're delivering value for 5 years or longer, I think you will have to take it like this. And maybe at the beginning, it's going to be a period like that, that we are aspiring while you are able to deliver something for more extended period of time.

Thank you for the great questions, and thanks for your attention. [Break]

So thank you, and welcome to join the Research Technologies breakout. We know you have many choices and choosing this, hopefully, it's worth your time and attention. You know me by now, and I've been mentioned many times. It's not that I'm seeking attention, but hence, I've brought 2 fantastic colleagues with me, Karin Conde-Knape and Lars Fogh Iversen, and maybe you introduce yourself.

Yes. Good afternoon. Thank you for being here. I'm Karin Conde-Knape, and I am responsible for Global Drug Discovery.

Hello, everybody, and good afternoon. My name is Lars Fogh Iversen. I'm heading up Global Research Technologies.

Great. So what we're going to do is to do a bit of a deep dive onto both the technology platforms that I already alluded to this morning, but also in particular, Karin will actually tell you more about how we're doing drug discovery in modern age and in the future, which has a lot to do with digitalization and data. And I think that will be super interesting. I hope I convinced you that we have a strong play in our core capabilities. Lars actually will highlight some of our outstanding and novel protein peptide technologies and also will double-click on genome editing in particular. We've heard a lot about Dicerna. So I will actually want to start my presentation to give you a little bit more insight into the stem cells, which is an interesting area, not only of research, but actually as a novel potential therapeutics. And as you can imagine, when we have the ability, which we do today, to either generate a differentiation from human embryonic stem cells or induced pluripotent stem cells to make nearly every cell type in the human body, and potentially to do this at scale, you're actually ending up in a situation of choice, yes? But I think it's also fantastic to see that there's an opportunity space out in a number of disease area, where it's very clear, if you were to place a dysfunctional or destroyed cell type in the human body, you actually make a fundamental difference to those patients. And that ultimately gets us very close to what we would call curative. And we had a question in the previous session about duration of treatment or duration of effect, that obviously is a very important consideration. But the value proposition of stem cell is that the duration is long. We're talking years. This is not a frequent injection, operation or administration. What we have settled on for now is diabetes, making beta cells, and that obviously shouldn't come as a surprise to you, us being who we are. We're actually working on heart failure. And Martin actually showed you some nice teaser on the stem cell collaboration. We're also working on Parkinson's disease, which is -- actually came up through a long-standing collaboration with the University of Lund in Sweden, a small company called BioLamina and we're also working with University of Cambridge on our device. And the important piece here on the right-hand side for me is what you're seeing here is, in a way, simply the value chain of drug discovery, so from making the cells, from differentiating those cells from stem cells to actually a scalable version. For many of us, that has been a big challenge for years or even decades to find those right protocols to truly make beta cells or dopaminergic neurons. I don't want to say this is easy today. There's still an art in actually making those cells very precisely and make them stable, but it becomes much more of -- and I don't want to call it a commodity, but something that is actually firmly established in science and medicine in our industry. So the attention needs to turn towards how can we actually turn those cell preparations into something that looks like a product. How can we manufacturing them with the highest quality? How can we ensure quality over and over again? These are living cells, right? It's not that easy to control them. It's not a chemical manufacturing process. And at the end of the day, and I think, Lars, you actually alluded to it is, what kind of commercial model do we then see. Are there treatment centers? Are there different ways of how we're actually getting those treatments to patients? And I fundamentally believe that this is important piece to focus on. It's not whether we can go quickly into a first time in human testing or not or whether those cells can be made but actually, how close are we in defining this product. And I want to give you 2 examples and also 2022 will be really exciting year because we are, if all goes well, starting 2 clinical trials, both in cardiovascular space and heart failure but also in Parkinson's. One with Heartseed, our partner in Japan. Really interesting collaboration because they brought a competence to us that we didn't have on induced pluripotent stem cells. They're working with cardiomyocytes, the cells that ultimately go missing in heart failure with reduced ejection fraction. But they also brought an opportunity for us that there's a product that could actually go rather quickly to market if all goes well because this is a patient population with significant unmet medical need. One thing I do want to call out here is the kind of clinical trials that you may be used to seeing from us is not necessarily what we're seeing here. This is about severe patients. There are no placebo arms in this, yes? There are no human volunteers that actually undergo cardiac surgery just to receive placebo. That doesn't happen, yes. So they're all on trial. And then I think it's for us to find out, in dialogue with the regulators, how to best define success actually out of those cell preparations. Similarly, on the right-hand side, you see we're going to do our trial in Parkinson's in Japan but also in the rest of the world. Some regulators would like to see some element of control, which is a sham surgery, which is, by the way, not a full surgery, but close to it. Others don't. And I think that is also a learning journey for all of us in the industry to see how we're actually moving this space scientifically forward in a very responsible and ethical way, of course, but also trying to find out which biologies ultimately fulfill their promise. So interesting space. Two new starts of first human trials in the first half of this year, COVID permitting, with patient recruitment, and we're very optimistic about this. Over to you, Lars.

Thank you, Marcus. So you heard Marcus this morning telling about our investments and development in SiRNAs. Now Marcus has told you about our approach in cell therapy. And in a short while, I'll talk about gene editing. So I just want to spend a little bit of time here to highlight the investments that we are doing in our protein and peptide platforms in the early stages. One purpose of these investments are, naturally, to be world-leading in protein engineering. I think you saw almost 2 handful of good -- or not good, excellent designs of proteins or peptides and we want to maintain that leadership to supplement the core with good designs in protein and peptide space. We do that by having a fairly substantial investment in what we call the LabDroid in a few kilometers here in our labs in Måløv. And that is an end-to-end system where we can do any type of protein or peptide fully clinically modified and screen it in a multidimensional space, whether it's in vivo -- or sorry, in vitro screening, by physical screening, can it be produced and such, generating a fantastic amount of data that we can utilize in AI to pick out the right models. So this will strengthen our core business. But what I also want to highlight here is that it will also propel us into the new modalities regarding gene editing, but maybe also in mRNA design. And I will show you that a little bit later. Remember that when you want to design a gene, it will translate into a protein. So designing a good gene means that you need to understand the protein that you're catering for. And that we do by being good at protein engineering. Likewise, if you want to design a good messenger RNA, then you need to understand the protein it is coding for. And that's why staying really sharp on protein engineering will allow you also to good at gene design and mRNA design. And let's look at it because we used it in what we are doing in gene editing. We have teamed up with the bluebird bio, now 2seventy bio, to engineer a fantastic enzyme, a megaTAL that can do precise and efficient cuts in DNA. bluebird bio are really good protein engineering company and it takes one to know one. And they are really top-notch in designing these precision enzymes. It will manifest itself when we deliver it to the patient as a messenger RNA, but the core of it is protein engineering. Now the other part in gene editing is to design the gene of a factor VIII in this example. The factor VIII gene is way too large to actually be fitted into an AAV vector. So you need to engineer a mini factor VIII for -- actually to fit into the AAV. Hence, without protein engineering capability, you'll not be able to engineer the gene going into the virus. So these 2 things have been protein-engineered, will exemplify them as an mRNA and a piece of DNA. The mRNA will deliver -- be delivered in a lipid nanoparticle and the gene will be delivered in the AAV virus. Those 2 components will be delivered to the patients in the final end. Here, we will show data from a mouse model. And both of them, both components will deliver -- be delivered to the nuclei of the hepatocytes. When we have the enzyme that can do the cut -- precise cut in the DNA and the gene of interest, it will be inserted. It's hard to see on the cartoon, but it is the red dot up there and then will be inserted and be there forever, so to speak. Hepatocytes divide throughout our lifetime. So if you have a piece of DNA that is not integrated in its chromosome, it will be diluted over time, but that will not happen here when we have edited the genome and inserted the gene. The data in the mouse model, you can see on this slide. So what we see here is actually a fairly nice integration of the gene. Using the MegaTAL and our factor VIII gene design, what we see here is roughly 25% of the normal levels of factor VIII. The control is episomal DNA that you might know, that gives you a slightly higher level of factor VIII expression. But what you see on the outermost panel are the bleed time in our tail vein transaction model, where we see a total normalization of the bleed time within these beta mouse. So this is actually a fantastic set of results that really show promise that we can bring this to humans. I would also like to say that this surrogate model with all the components is as close as we can get for this -- the design that we will bring to man. But we have all these wonderful platforms. Karin, what can we put into them?

Yes. Absolutely, Lars. And that's the key question. Right now, you have seen how we are leveraging technology with very well-known biology. But the challenge that we have is to raise the innovation bar in all the areas that we're working on because there is already significant advancement in standard of care. So in cardiovascular metabolism, especially, we have the opportunity to drive human-centric innovation here by accessing the data sets that we currently have internally but also those that we have been able to do -- to access through collaborators. We are going to be looking at having deep understanding of disease, meaning, what are the key drivers that are really making a patient progress in their journey of a disease or, even worse, in their comorbidities. In the cardiovascular metabolism space, we have really to understand what is a residual risk. And therefore, by focusing on this, therefore, identify what are the next-generation treatments that we can deliver. And how are we going to do this? Well, there is plenty of data that we could access. But data as such is not necessarily very valuable. You need to think how you're going to utilize it. So we are in a space of technology where we can look at the single level of the single cell, single nuclei, localization in a particular organ and how does this match with circulatory markers as well as genetics. So it's no longer about talking about genetics as a stand-alone, but really marrying it with what happens at the deep level in the tissue, in disease versus health. And through this integration of data, being able to augment our possibilities to define what would be the patient populations and subpopulations that we would want to address. So if we take it one level down, just as an example, how are we looking at this in the area of obesity? We heard today our ambitions to address more patients, but also we heard from the patient that this is not necessarily an easy journey. So if we were to follow the patient in this journey, from the time that the patient addresses the physician, gets put on a diet, on an exercise regimen, goes on cycles of up and down in their weight, comes to medication, stay on time on medication, et cetera, et cetera, throughout this journey, now we are at the stage that we can collect so much information not only on the basis of the regular clinical chemistries that we do, blood samples, but also through the wearable devices, through behavioral interventions or data sets that could help us paint a picture of what is this patient. And more importantly, how is the journey and the progression or the prediction for our patient journey. Is this patient going to continue obese only? Or is it going to become more faster into the progression of comorbidities? We know already that these type of populations exist through different sets of data generated by scientists around the world. So it is about integrating all these data sets in order for us to define individuals that are obese and will progress, that are obese or will potentially stay in this healthy state for longer, or individuals are healthy today but with their history, their environmental factors or the societal components, have a higher propensity to develop further into their journey or in the disease. And by being able to do this, coming to the molecular drivers of the disease, we will be able to deliver better concepts, better targets and potential drugs to treat the right patient at the right time with the right drug. And with this, I will turn it to Marcus so that you can wrap it up.

Thank you. I'm good at wrapping. So if you paid attention, which you have, obviously there's nothing new on this slide that you haven't heard before today. But I think as Karin has beautifully laid out, the human data sets and the interrogation of all those data become crucial, but also our ability to ultimately ask very smart questions. And I think that is the piece. And many people ask me, why are we -- why we're different, why we're distinct, why could not other big computer companies do this. Because you need to couple it with biological questions and a deep biological understanding. And then you overlay machine learning, you overlay data analytics to this. So I think both of them need to come together. We're very serious about this human-centric approach and, you see, towards less and less with regards to animal testing because, a, it's the right thing to do; b, we believe that with computing power and more and more training, the models will be much more precise. And I had a discussion with one of you early on today, then those models also actually become decision-making, and this is when it gets really, really interesting. Yes, we're not quite there yet, but we're really much on our way. And then we want to change your mind a little bit to think from an all-comers population to stratified and personalized medicine and go beyond maybe an initial reaction, oh, are the patient populations smaller? Yes, but it actually also means that the value proposition for those patient populations will be, relatively speaking, larger. Yes, so I think that makes perfect sense. And we can learn a lot from some of our colleagues here in rare diseases, but also, for example, in the oncology space. And then hopefully, you're seeing some really cool examples and credible examples that we now have a toolbox of modalities to not only ask the question, test the hypothesis, but actually have molecules and treatments to do that. So we're building on the strong legacy. I think that is important. We're not doing anything that we feel is crazy. The new technology platforms are adding to this and they're filling a void, certainly, that we've identified. And we're actually driving de novo target discovery much, much more than we've ever done before. Thank you for your attention, and happy for questions.

Simon Baker from Redburn. Two quick ones, if I may. Just going back to hemophilia A. As you pointed out, the target gene is an awful lot bigger than the payload, about 25, 30x bigger. So given that there are a number of mutations that lead to hemophilia A, how much can you cover with 1 gene edit? And then secondly, on the LabDroid approach, that almost struck me as a sort of a small molecule level of structure activity relationship identification. I've never seen that before with proteins. So firstly, how differentiated is it? And secondly, how applicable is that? Because it strikes me that, that gives you a degree of precision on protein engineering, protein discovery that we've not seen before.

Thank you. The construct that we are making for insertion will cover all mutations because remember that any mutations in the gene is actually holding the expression of a functional factor VIII. So -- and the inserts that we are doing is functional. And so it will cover all mutations and all also spontaneous mutations that you see in that disease. So it's one that will be good for all in hemophilia A. Secondly, you're absolutely right. I thank you for noting this. What we have laid out here is something that we have never tried before, to do a full end-to-end automated systems that will cater for all peptide and protein formats. You've seen it sometimes for antibodies, which is relatively simple, I would say, but this layout is quite new, complicated, but it will generate us a whole lot of data that we anticipate to use for design but also for exclusive use for AI.

We have an online question here, and maybe also to you, Lars. One challenge to machine learning in pharma has been the lack of data, "negative trial results underreported." Is that no longer an issue?

It is definitely an issue. So I think for any types of AI and machine learning, the amount of the data you need is crucial. We will be looking into methods where we can use less and less data, but that's not where we are now. So for now, the more the merrier in terms of data. But since we don't have a quantum computer yet, then we need the data. And the day we have the quantum, we'll absolutely go out of needing that much data.

I wanted to ask you a little bit more on your cell therapy strategy because some of these diseases have reasonably high numbers of patients to go after with cell therapy. So just around the platform, if you have a bias towards sort of encapsulated versus maybe CRISPR gene-edited because it would seem that the devices have been difficult, the ones that have been tried so far and maybe a CRISPR gene-edited approach might be kind of more of a -- more broadly applicable. So just wondering where your mind's at there and whether it's going to be different for different diseases.

So you're absolutely right. And I would say, if we paint for a moment an ideal picture, then the cell therapy products that we are administering evade the immune system. And they stay for a very long time. I think this is what we need to aim for. And then there could be various innovation steps in this. It seems more likely to me. It's -- I wouldn't say it's an absolute trend, but more likely than not that this will be sort of a significantly gene-edited version of cells than having a device which needs to be implanted, maintained, maybe taken out and so forth. And you are right. It's been a field that I don't think anyone has cracked yet really to the level of reliability and scalability that we would like to see. So I think the long game here clearly is one of gene editing, and we're very actively researching in that area.

I just wanted to ask as an add-on to that. Do you have capabilities and intellectual property in-house? Or is that something that you would need to do through business development? I'm just sort of wondering what...

As you know, intellectual property in CRISPR is an interesting one, as we've just seen. We're building some of the competencies in-house, but think I also shared with you this morning, I would never exclude and I will most certainly not exclude that through partnerships, we will actually move ahead much faster than we would do if we were just to be on our own. And I would also think that there are many opportunities out there. I think it's picking the right partnership and the right modality for us. You also asked about choices of cell therapy product. It's not, at this point in time, an active decision-making process, whether it has to be encapsulated or can be directly injected like in the eye, for example, or in the brain, which sort of is immunoprivileged, as you know. But it's nice to see for us that we have a somewhat balanced portfolio in all of those opportunities. In that is obviously also the number of cells that you need for efficient treatment. Again, we see a wide spread. And I think we're in good shape right now to cover a broad space, yes. That was -- yes.

Evan Wang, Guggenheim. Can you expand a little bit more on your target identification efforts in cardiovascular disease? Was that related to your Apo3C (sic) [ ApoC3 ] decision recently? And can you talk about maybe efforts in terms of LDL-C, triglyceride-lowering strategies, what kind of modalities you guys are thinking about in that space?

Yes. So let me talk general around the target discovery efforts. And as I mentioned, especially in the cardiovascular space, we are very much interested in that residual risk. From the dyslipidemia perspective, LDL cholesterol, it's well-served. And as you heard also this morning, we have an oral PCSK9. And we are working on the other dyslipidemia, which is high triglycerides. But there is still beyond to be done, right? So the plaque, at the end of the day, is a very complex organ. So we are doing this also through collaborations, making sure that we are understanding the individual components in the plaque at the level of the single cell, at the level of the full transcriptomics, to be able also to pair that up with local and systemic levels of biomarkers to just help us understand much better, how are these potential drivers of the plaque instability or not. And this is, at the same time, marrying it up with genetics, which we know that in cardiovascular disease is actually quite strong. So I think it's, again, going after the right biology with the right technology at the end of the round. So we are, to some extent, agnostic as to the therapeutic modality. We first need to be able to get to the right driver of the disease and then decide which is the best approach to tackle that.

And I have an online question here, which says you made it very clear that you are aiming for 3 new products per annum from the SiRNA platform. Is that what you need to deliver for returns to be met? If not, how do you get to 3? So first, let me clarify, this is not products. And I'm sorry if that came through -- came across. It's 3 first time in humans, right? And that is still a fundamental difference. So there's still a journey to be had until we actually see a product out of the siRNA platform because 3 products per year, that would be very ambitious and even I wouldn't be as bold as stating this. So I think there's uncertainty. I hope I also actually made clear to you that this is a space where we're also starting to explore. And I think building on the question and Karin's answer to this, of course, the single, monogenic disease drivers, ANGPTL3, PCSK9, they're all obvious choices, and it's very clear. Although, having said that, even our competitors -- some of our competitors have failed in actually then using their modalities on some of those targets. So it's also not yet a slam dunk. The interesting part comes when we talk about multigenic drivers, polygenic risk scores and so forth. And of course, keep in mind also, SiRNA has the potential for combination therapy, right? Nobody says we only have to have 1 SiRNA. You could actually have multiple targets in a single preparation. So I think that actually holds a lot of promise. Of course, we've made a business case before the Dicerna acquisition, and it's largely around capabilities. And in that, we're also articulating a productivity metric. And of course, I'm stating a number here that we think is ambitious and helps us to understand the value of this platform. If there are no further questions, then it's the time for coffee break, yes? Yes. Thank you very much for your attention and great questions. Thank you. Thanks, Karin and Lars.

Thank you, Marcus.

Thank you. [Break]

With that, Mike...

[ Andreas ], you stay there. I think Andrzej can join you. We have already some questions online, but let's see if anyone has a question here. Raise your hand. We'll give you a microphone. Yes.

Emily Field from Barclays. I know that Doug mentioned in the broader presentation that he didn't expect the CVOT trial for Wegovy to dramatically increase access in the United States, but do you see that as being a bigger driver in obtaining reimbursement in Europe?

Yes. So I can say a few words and then Frederik, you can speak on behalf of Europe. I think the answer is very different than what Doug said for international operations. And the reason being, we don't really have the same level of access right now as Doug has in the U.S. But more specific to Europe, maybe...

Yes, a few reflections. I think a positive readout will be positive in terms of enhancing access. If we look towards the nice draft appraisal that just happened for Wegovy, it's based on a cost-benefit analysis that NICE do. If we put into that a benefit of CV, I do assume that, that will have a positive effect. And with that potentially also for other countries, but NICE and U.K. is often the one that is looked towards.

And I have a follow-up question from Michael Leuchten online. Going back to an earlier question on NICE, what countries are moving towards a better reimbursement set up in Europe? Frederik?

I think the ones we showed have come in, as you also alluded to, Mike, over the last 2 years or so, most are coming in. We have a number of other countries that -- where we have submitted application, but I don't want to speculate as to when and if they will come by.

You could look at the flags on the previous slide and get a good indication. Yes, back to the room before I go to cyberspace. Then I go to the cyberspace. And this could be for you, Andrzej, and then maybe you want to add on, Frederik. With more high-potent GLP-1 coming to the market, is there a risk that we might see some sort of tender for the class? I guess they're making reference to our competitor who are coming in. Do you see this played out in a tender-based setup or in a normal setup that we've had?

I think mostly, it will happen on a normal setup for sure for -- in Europe. And if I think about rest of EMEA market, which is the place where I have a pleasure to cover, GLP-1s, if reimbursed, they are mostly reimbursed on the negotiation -- price negotiation base. So there are no tenders organized. And...

I was also saying that. Completely, yes, I don't see it either.

Yes, and I think the main reason for this, as long as there's a couple of competitors in international operations and from a price point, they are very similar to one another, the governments do not go on a tender. Tenders typically happen when you have 5, 6, 7 players, a couple of local players who would like to gain market share at much lower price levels, then the government gets tempted for tendering. That's how we typically see it. I would say that even when you look at it on the insulin segment, we see tenders often happening on the human insulins, maybe from here -- from the -- [ none ] then on the modern insulin segment, but very rarely on the top of the next-generation insulins.

Very good. Yes, please.

Wegovy is approved in Europe, but you haven't launched yet. Could you talk us through the time lines and perhaps also most likely first markets to launch?

For a start, please.

Yes. So Wegovy in Europe is, of course, part of the overall global launch plan. And I think as was alluded to in the general session, first, we stabilize supply in U.S. And thereafter, we do -- continue the rollout. What we are foreseeing is an approval in Europe of the FlexTouch device for Wegovy as well, giving us more flexibility on supply. So whenever we come to the end of this year, it's probably likely that we'll see launches in Europe of Wegovy.

Yes. I can add a little bit more to it. The approval you're mentioning has to do with the single-dose device that has happened. As we ran, of course, into the supply-demand situation with U.S., we decided that it is meaningful for us to make sure that the demand of U.S. on that device is made before we add to the problem by launching more countries. So to give ourselves more flexibility, we are actually now, as Frederik alluded to, getting a registration for the secondary device to provide more flexibility for us as we go forward. And that has not come through. Our current best estimate is that towards the end of this year, we'll have a few, couple perhaps, launches and then move into '23 with more. Yes?

[ Anderson, BOS Capital ]. Yes, since last time we met the 2.5 years ago, yes, you launched this target of, yes, 6% to 10%. And yes, as you showed on one of the first slides, you have been nicely outgrowing and yes, I guess, the combination with the fit for market. But can you allude to why you have been able here to beat? And what has surprised you the most? And yes, and what to expect going forward, yes?

You want to do the 6% to 10%? You want to start?

I can start. And then...

I can join.

I think we've been doing extremely well with Ozempic, much better than expected or really outperforming competition. And Ozempic itself is really extremely well-recognized treatment across HCPs, doctors, patients, highly appreciated. So that's one. Secondly, we outperformed competition in insulin segment, especially in, let's say, my part of the world, insulin still plays a very important role. We are not market leader everywhere. That means with Tresiba, with Xultophy, we can accelerate growth. So we've been doing much better than we thought. So in overall market share, we gained more than we expected. So that's a good execution.

Yes. If I can add. So I think one is we just have wonderful products that we're able to launch and that gives us...

Recovered well.

Yes. But they are coming to fruition now in terms of Saxenda really picking up. I think we have improved the way we go to market. So we have had a discussion in IO management where we all said in terms of having a market-fit approach, in order to make sure that each and every country make their own portfolio, that has played off probably more positive than what we had assumed. Then the last comment I will make is obesity is continuing to surprise us in terms of the potential that we have in the commercial success. We're now getting Europe on board as well, and we did not had that -- we had that hope 2 years ago. We were not sure that was happening. So that's one of the things I see a change in the trajectory.

I think that last point is worth really noticing. For the last number of years, there was a sentiment, I would say, inside and maybe outside of the company that when medications are not reimbursed, you cannot sell them in Europe. Due to the social system in Europe, people expect that they pay high taxes and they need to get their medications free of charge. Therefore, obesity will never do well in this part of the world until and unless it is reimbursed. Two years ago, the country, Korea, as a single country, sold Saxenda more than all of Europe combined. And that, of course, was then the reason and the excuse. I would say that a lot of mindset change has happened that it's different with obesity. There's a massive patient pool with obesity. And I think Frederik and the team have really shown that firsthand, that we are doing incredibly well this year or last year on obesity. Countries like Spain, now U.K., I would say, Switzerland, Norway, Switzerland, they are leading the top 10 packs, in many ways, in international operations on obesity, so -- and that is only to come. And of course, with Wegovy and some of the things that we discussed on reimbursement, I think there's a brighter future than we had hoped just a few years back.

Yes?

Are you starting to see salary inflation and inflation on other input costs? And what are your options to deal with it?

The answer -- so in the context of Europe, I would say, less so, obviously because the inflation has not kicked in yet to the levels -- in the part that Andrzej is speaking to, yes, but it is selective. Maybe you want to speak to...

It is selective. And it's part of, let's say, regular business. When you look at the different markets and different countries, we've been dealing with inflation rates like Turkey for, let's say, last 10 years. I've been working in previous set up in Latin America, think about Argentina. This is ongoing business. We know how to handle this. And yes, it's part of the game.

So when you think about it in a broader context of international operations, we have had countries with hyperinflation, think about Argentina, Turkey, perhaps Venezuela, where we have had staff and we had to manage that and we do so. And then we have countries with high inflation, then we also do that. We pay our employees based on market benchmark. Often that market benchmark is not exactly covering the full inflation, but at least it's competitive. And that probably we will have to do as we will see where the rest of the inflation will take us.

But do you have any options in Europe to raise the price on the product?

Usually not, but we also have not had hyperinflation in Europe. If you think about Argentina, Argentina is very much used to that. Therefore, the government then gets much more receptive to a dialogue because I think everyone knows that this has to be a win-win situation between the manufacturer and the government. We understand that the budgets have to be managed. So nothing -- no one wants a bankrupt buyer, but they also do not want to see pharmaceuticals as a whole, not just Novo Nordisk, leave the market because they no longer can afford it. So those dialogue in Europe has not taken so much place because there has not really been a precedent for that high inflation.

Yes. I think I have another question here on icodec for you, Frederik, given Europe has never really paid enough for premium insulins. Is this a product for Europe?

I think Camilla was speaking to that we don't -- we haven't set the pricing strategy yet. We do believe that this is innovation that also will benefit European patients. So for sure, it will be a good product for Europe regardless of what pricing strategy we're going to end up with.

And that leads me to another question that maybe you could connect it again from Michael, it says that we didn't really speak about Xultophy today. In the past, you have referred to this product, you with me, in countries like France, is that still a driver? Has the market now moved on to Ozempic? And maybe you can speak to, of course, Xultophy in general and maybe France? But Xultophy also I'd like to remind people remember is one of our most, if not the most expensive insulin that we have, which we have been able to get the access that's needed to the question to the previous question.

I think Xultophy especially for the region that I'm responsible for is having a large presence in France. And Xultophy together with Tresiba actually led us to for the first time ever to be a base leader in the homeland of Sanofi that was a good movement for us at least to be able to and Xultophy play the key role in ensuring that. France also have a nice development in terms of Ozempic, but they are balancing probably more than some other countries both a strong basal insulin portfolio as well as the GLP-1 scenario.

I can a little bit add to it, Michael. And that is to say, I'm still a big fan of Xultophy. And as a result, I'm also a very big fan of the new Xultophy so the icosema that we are developing. But we have to recognize that it's probably more selective than a general product like Ozempic has been. We also have to recognize that the success of Ozempic and the ever increases of Ozempic and higher dose in a safe manners like the Ozempic high dose that we will be introducing will delay insulinization for us and for our competitors. So we would probably have to put that in context. There are a number of countries where Xultophy will do well. One of the places where I'm incredibly going to look for success is in China where they have a plan to launch that sometime soon. But it should not probably be seen as a general product that we will see in all markets. Yes. sorry. one, then.

Yes. go ahead. You will try on your business.

And it's a question about Rybelsus looking at efficiency, it should be a no-brainer to switch from DPP-4 to Rybelsus. But could you talk us through the main obstacles on that switch?

I can start from a European setting. The main obstacle is that not in every country are we able to do it in terms of access. So we are pricing Rybelsus as a GLP-1, and X is according to GLP-1, which often is a bit later in the process. So that's one of the obstacles. When that is being said, we, of course, are working in terms of, as I said here, replacing DPP-4 deeply before because we do believe that either if they're in combination with an SGLT2 or alone, Rybelsus should fit in there. Efficacy is something that of DPP4 any day. But of course, the pricing difference do in some countries play a role.

When the access is granted, then we actually see a huge uptake of DPP-4 switches to GLP-1, the graph I showed earlier on Japan, that 50% of that uptake is actually coming from DPP4. And if you mix them DPP-4s with SGLT2 combos, then so 70% of that graph is actually being sourced from other modern OADs.

A recent launch in Italy.

And the recent launch in Italy. That confirms exactly what Frederik is saying because we have managed to achieve access which is we can use Rybelsus right after metformin. So we compete head-to-head with DPP-4s an uptake is simply amazing. It's anecdotal because we've seen data for the first month, but we reached 5.2% market share [ MOEDs ], which is -- if we continue like this, that means that Rybelsus, as you say, is no-brainer. Everybody will.

With that I have to say thank you very much. Good luck to the next session, hopefully is half as good as this point. Back on that.

So after 2 breakout sessions. We're -- the best -- yes. So my name is Mike. I'm managing international operations. We have a deep dive on region EMEA. Region EMEA is managed by 2 of my good colleagues; 2 Senior Vice Presidents, Andrzej Popkowski and Frederik Kier, Frederik is managing north and western part of Europe and the European countries, and Andrzej does the rest of EMEA region. And then they will run you through their slides. Hopefully, we'll take about 10, 15 minutes through the slide and then we'll have the rest for your Q&A. I'm supposed to talk about this. We will talk about the future, and you know the slides, I will not speak too much on to that and pass it to you. Andrzej.

Good afternoon. We have a few slides, which will introduce you to the market, to the how we -- how EMEA is growing with in the market, EMEA and then a few slides showing how we perform against competition in the GLP-1 injectable segment in GLP-1 oral and. So starting from EMEA, we cover 30% of the population of the world. And we are very diverse region. As you can see, starting from Africa and on Russia and having the whole Europe West run by Frederik. That means different health care systems, different political systems, different economies, different purchase power of patients, different willingness from the payers to pay for innovation. So we have to maneuver and we have to apply our let's say, market feet approach, which means that depending on the market and affiliate we use our portfolio and we apply different tactics to make sure that we supply products to patients and outperform competition. What is very important that it's a big market where we have 160 million people with diabetes, 250 million people with obesity and it's growing pretty fast. 65% growth we foresee in within the next 25 years. For the time being, it's DKK 100 million market where you can see a big insulin segment where we've been supplying or we've been competing with insulin for almost 100 years. It's growing 3%. We are a market leader. But what's -- there are 2 segments which are growing much faster, where we want to be very -- very much present and have significant importance. First is OAD. It's growing 10%, but what's more important within the OAD segment, modern OAD is growing 13% -- 14%. And we have Rybelsus, which is our new oral treatment, which we are launching now across the whole EMEA region. Smaller segment, GLP-1, is growing 30%, but here we define what is the market growth because we are a market leader in our, let's say, appetite and our investments are growing this segment. So 8% total growth. How we are doing them as Novo Nordisk? We've been -- we have accelerated our growth significantly. We've been growing in 2017, 5% and now our growth is around 12%. Insulin, as I already mentioned, pretty stable. Same for rare diseases, what is driving the growth is GLP-1. And within GLP-1, majority of growth is coming from GLP-1 injectable. Soon, we will see acceleration in GLP-1 oral. And 18% of the growth is coming from obesity. It's coming from Saxenda. We've launched Saxenda in 40 markets across EMEA. And last year, we have grown our business by 66% within our region, right? So all in all, it's -- growth is coming where we expect it to come from because, of course, we -- I think 2 years ago already when we had pleasure to share our plans with you. We told insulin will be flat, GLP-1 will grow our business. Please have a look at GLP-1 injectable. We have launched Ozempic a couple of years ago, and now Ozempic represents 80% of share of growth. We -- from the first slide, we remember 30% -- this market is growing 30%. So on the very dynamic market, we are taking 80% of the growth. So I think it's pretty good performance. Majority of patients are coming from failure on oral treatment and on insulin. So that means -- that explains this graph. Since -- in the last 2 years, we have grown our market share in GLP-1 injectable segment with Ozempic growing pretty fast. Victoza, of course, dropping the share. But all in all, we are not cannibalizing business Victoza business. We are adding more patients, and we are almost 56% -- we have reached 56% of the market. So GLP-1 injectable, I think it's good performance. Now I'd like to ask Frederik to share with you how we want to repeat the same kind of performance in the GLP-1 oral and how we want to build obesity market.

Thank you, Andrzej. Did you click? I'll do it. Good. Welcome. So we are entering for the first time, the modern OAD segment with Rybelsus. EMEA, we present DKK 35 billion, growing by 14% and on your left-hand side, you see the uptake curves within that segment for the countries in which we have market share data. We are launched in 24 at this point in time. The uptake is what Doug said. We are pleased with we have encouraging feedback from physicians and from the patients. Where we do launch, we do it with an all-in approach, basically meaning that all our commercial focus is on Rybelsus during the launch phase. Each and everyone that are front-facing personnel are promoting that of Rybelsus It's being promoted as the most efficacious oral treatment that is out there with the intent of replacing DPP-4s. I should say that launching it during COVID has posed challenges to us. It's pose challenges on 2 fronts. One is the dynamic in the segment is not as we would like it to be because patients are now going and seeking change in treatment as normally. And secondly and probably more to us, we have not been able to engage with our customers to the extent we would have liked to do. It goes both for the indoors whom we've known for many years. But more specifically, we have added new customers to our target list, especially in the DPP segment to establish a relationship doing COVID has proven to be challenging. All these learnings both have to do this, but also how to further optimize the positioning, the targeting, we are building in, of course, into the newer launches, and we are in the middle of 2 very big ones, namely that of Spain and Italy. Two very big ones, Spain, is the third largest in Region IO. We are a few weeks in, and it's fair to say endomically, we are seeing positive momentum and good feedback as well. If we turn our attention to another huge growth opportunity, namely that of building the obesity market, it is an area I spoken to earlier today, huge unmet clinical need. In this region, we are 240 million people living with obesity, only a very small fraction of those namely estimated 350,000 are currently on Saxenda. It is also a market that is fair to say that's in its infancy. It's DKK 1.4 billion at this point of time. It has grown despite the last 2 years' COVID challenges. It has grown. And as you will see, the growth is coming from Saxenda more or less only. Mike spoke to -- for a general point of view, 80% is out of pocket. 20% is reimbursement. For our region, combined is probably more 75-25. When I look to my Western European, it's probably more 1/3, 2/3. In order to build that market, we've spoken to you many times in terms of investments, investments required. I'm not going to belittle that point again. But as you see, we are significantly increasing it in region EMEA, tripling the S&D investments. Equally, potentially even more importantly, I think has been that we have made dedicated business units in each of the affiliates. So basically, people that are only solely focused on obesity, people we have invited into the company who has experienced from selling out of pocket and have a different profile than our deployed [indiscernible] and also a group that is reporting into the General Manager in order to create full accountability. Mike and Camilla also spoke to sort of standing on 3 pillars, 1 of payers, 1 of patients, 1 of physicians. Let me just give you a bit more flavor into that from a regional point of view. Reimbursement is developing very nicely. We are right now having 10 countries in this region that are having reimbursement. The last one, and you can see we did not plan that for the slide. It came a bit odd. But we got Netherlands on Monday night, added to the list, and that is just a testament to what is happening right now. We see more and more governments taking responsibility for treatment and obesity. Two areas of improvement. One is we want that list to be filling the whole column. So more countries to be added on. Secondly, equally important is to expand the criteria upon which both eligible patients. So the BMI 35 can then be less 1, 2 couple of these could that be less. Secondly, also, in some countries, they are restricting the number of physicians that are actually enable to prescribe it. Can that be expanded? So these are the things we are working on in terms of enhancing the reimbursement. The out-of-pocket will remain important. It will remain important for European context and EMEA context for sure. Therefore, we are continuously optimizing the way we work with partners. Mike spoke to the [indiscernible] partnership in Germany. Here, I brought 2 U.K. examples. We could have done the same from Middle East. The two I want to bring is 2 very large pharmacy chains in the U.K. Boots are now part of their online offering are having weight management service programs in which Saxenda is part of it. Lloyds are having 1,400 physical stores in the U.K. Majorities of those are offering also a weight management service. They do it with in physical stores. Boots do it online. But these are some of the opportunities that we are pursuing in order to enhance the access. Activating patients, we spoke about that. We need to, one, increase the awareness of obesity; secondly, probably more important at this point in time to reduce the stigma. So a lot of public campaigns, many of you might have seen them either on buses, in printed media and TV or whatever. We are doing a lot of public campaigns in order to pursue this opportunity. But what we have found and Doug was speaking a bit to it and Liz was in the morning, it's difficult to find a doctor that actually either is not able or willing to treat obesity. Therefore, without maybe I'm belittling the point, but think of the HCP locator as a dating site. So what we basically are trying to do, we're trying to bring in success of these campaigns people into a website where they can say, "Oh, I want to search for HCPs physicians that have shown an interest are willing to treat obesity. So we try to bring them together in order to minimize these many trial and errors that they have going to the physicians. This is launched in 4 countries, 17 more are going to come during this year. And the last pillar is that of engaging physicians, a lot of focus on ensuring that we enhance the understanding of obesity with the physicians digitally, physically, you name it, a lot of efforts are going into this. We are also imminently launching an Obesity and Me campaign, which basically not only talk to the whole science, the whole physiologic about obesity, but are taking a more social angle in order to understand what is it that the patient has gone through when he or she meets the doctor for the first time so that they will have a valuable conversation instead of 1 where they will be completely going apart. So we're spending time on educating on science. But equally so, how do you have a good and proper conversation. With that, I hope Andrzej and myself have given you a bit of insight to the region EMEA, a very diverse one, a very dynamic one, many different market dynamics or state on track to become the most used GLP-1 with Rybelsus, we are entering a completely new segment, 1 that will give us a lot of joy for years to come. And last but not least, I think it's fair to say that this region is also walking into the establishment of obesity and the potential that it has. So with that, Mike, you will take charge very much.

So yes, I saw Pete first and then Michael and then yes.

Pete Verdult from Citi. Just could you just describe generally like given the growth we're seeing in GLP-1 just the reimbursement environment, is it sort of blowing hot getting better? Or do you get a concern that restrictions are going to come in? And then just for Saxenda, could you just give us a flavor of the top 3 markets in EMEA for those 2 products? Just can you give us a flavor what are the biggest 3 top markets? I know you're not going to disclose actual sales, but just give us a flavor.

Yes, you can call 1 after the other. I can start with the Western European from GLP-1 and answer is, no, we don't see it. We don't feel it either at this point of time that there is a general pressure either on prices or excess levels part of the word, especially that reimbursement in, let's say, my region is quite limited, very often we sell our innovation out of the pocket. And so patients they have to pay from -- but there are a few markets where reimbursement is available and saw from my graph, Pete, also that proportionately, GLP-1 is very small, both in value and volume. Payers typically start squeezing you when the size of the basket gets large, they have a lot of balls to juggle. They come after you when the ball gets bigger.

In terms of Saxenda sales, it would be without being 1 to 10, the largest 1 that will be Saudi Arabia. It will be Turkey, it will be UAE, it will be Israel. It will be U.K., it will be Switzerland. It will be Norway. So those would be some of the large ones.

Brazil and Colombia, then you have your top 10 relies?

At this point of time, it will probably be U.K. in absolute sales then we are seeing some of the new launches that are coming in.

We just launched in EMEA region. The biggest potential will be, as I mentioned, it would be Japan. -- to start with -- then it would be U.K., Spain, Italy. And then you will basically have to exclude the 2 usual ones that's Germany and France because we are not launching there. And then outside of these 2 gentlemen's territory, add again, Brazil and India, Saudi Arabia was mentioned would be the top 10 for the.

Yes. Good. Yes, Michael from Nordea, and then we go there or Yes.

So staying on the reimbursement side. So is there any sort of rational reason besides cost, why U.K. NICE decided to sort of cap it at 2 years? And is there a reason to believe that, that could be changed over time? And then secondly, to reimbursement, what is sort of the thing you hear from other countries where you're sort of starting the potential reimbursement process by sort of bridging from Saxenda towards.

I can start -- I can only speculate on your first one, but I'll give you what I have. So for the U.K., we are in a draft situation. And of course, the final 1 will come end of April, the beginning of May. Those are some of the discussions we have with them. We don't have a stocking rule on Saxenda. They are willing or want to have it on COVID. I do believe my answer to your first question will then lead to the second one. Namely, they are scared of the absolute budget impact and that's why they're putting a stopping rule. That is also often the discussion we have when we are starting new discussion. That is how big will this be and how it's going to turn my budget apart.

A quick question on oral GLP-1 Rybelsus. The -- your goal is to replace DPP-4. I was just wondering whether you would have a specific marketing campaign ready or when the DPP-4 lose their exclusivity, there is a specific time frame or that you have already in place to push for Rybelsus prescriptions and marketing campaigns?

I think DPP-4 are an obvious target to go after. In terms of volume, they're the largest -- and a couple of companies that have introduced them to the market are not really pushing through due to the LOE. So there is no secret that, yes, the strategy is to not replace but displace them. And ultimate aim is to eventually become a market leader in the modern OAD segment, which means the DPP-4s and the SGLT2. So the competitor, you could say, in somewhat is the SGLT2 as they are also seeing good growth rates. With regards to time lines, unlike our strategic aspirations, where we say by this date, we want to be that market share. We don't have that -- we don't have a very specific target that we externally communicate. But what we do say is that we need to basically year-by-year, make sure that we grow faster than the market and try to get to that leadership. So very similar to what we have done, and that's what we're doing. Now in '24-'25 is when DPP-4 will lose their exclusivity -- so we do hopefully see that there will be a bit of a jump at that moment as well.

Yes. Can I -- before I come to you, Richard, let's go to Wimal and then I'll come to you, Richard. Can I ask about obesity pricing in IO? At the last CMD, you talked about $6 to $10 for Saxenda, fair to assume that the same for Wegovy tied to that, what is the right price point for EMEA? Does the price needs to be the same as MSDs, I guess? And what feedback -- what feedback do you get from the governments and on obesity price?

Mid-single digits, yes. Yes. So does any of you guys want to say how do we price basically Saxenda because that's more or less public knowledge. And Wegovy, we don't have, so we can't talk about the price of it. Yes. The discussions we have with the authorities, of course, based that they do an evaluation of the cost benefit when we go to reimbursement. And what we are seeing costs that are in line with what's been stated here. It's -- there's -- at this point of time, we're going to continue having the dialogue with the authorities in terms of getting reimbursement for Wegovy and they will do the cost benefit analysis just as nice have done. And apparently, they figured that what we are bringing to the market with Wegovy and the price we are asking actually is a good cost benefit ratio. And hence, they actually had some pretty nice appraisal of Wegovy in the U.K. Yes. So exactly. As we get closer to the market, as usual, then we will disclose the prices of Wegovy. You could, of course, look at what has happened in U.S. for some inspiration because that has been launched, but I cannot go into more details of that. Richard and I currently [indiscernible].

Just on Saxenda and some of the ways of trying to sustain patients and increase their stay time. So how is the time developed over time? And then have some of these online tools meant that, that has increased just thoughts?

We have introduced several patient support programs, which are quite comprehensive because, of course, stay time was a big problem for us, and we -- in the markets where we have introduced this, we have seen significant improvement, like 20%, 25%, 30% longer state time than normal. And we don't play with price, but we play with the very precise education campaign for the patients. Why? Obesity treatment require longer stay and what kind of additional support they receive while they are using product only because before, when we were launching the product or we launched product, and we were just hoping that a single prescription will be sufficient. That was not playing off as according to our wish because, of course, patients, they lost a beat and then they were discouraged either by, let's say, price because, of course, majority of the sales are coming from out of the pocket or lack of support because like after 2 or 3 months of treatment, you feel like maybe I should discontinue because maybe I will not get further down. With this type of support activities, we see that patients they stay longer and they are really, let's say, the quality of the treatment and quality of life has improved.

And then maybe to add to that, and it is logical what I'm going to say. But the countries where we are having and getting reimbursement, we see a significant increase on the stay time as well.

I can actually a little bit to give you a flavor on that. The average stay time is around 3 to 4 months in international operations, which is substantially lower than if you would ask my colleague, Doug, in U.S. And the reason behind it is really the reimbursement. As humans, we feel the weight has to go down and down and down to nothing less. So after a while, like glucose like lipid, it stabilizes, but then we kind of feel like the product is no longer working. And if you're paying for the product, then you maybe you stop paying for it, and you forget that also if you would have stopped your statin, your lipid would go up. If you stop your insulin, your sugar goes up. But with weight, kind of there's an education element to that. So if you have to pay for it, then, of course, you kind of stop it a little bit earlier. The other thing I think you should consider as a possible upside to our business going forward is we clearly see that stay time with weekly products are much, much better than with daily products and there's some obvious math behind that as well. Carsten?

So the -- back to the U.K. NICE decision recommendation, it was obviously very, very interesting. But can you compare -- try to compare to some of the other times you have discussed with U.K. nice about Saxenda liraglutide or something whatever, what how is this discussing? Was it easier or harder? What did you feel from the discussion? And 1 more, if I can sneak it in. In Japan, the uptick you've seen so far with Rybelsus has it impacted Ozempic in any way?

I can start with the U.K. one. It's probably difficult for me to sort of the balance, was it easier or more difficult. What we are seeing is that following COVID and specifically Boris Johnson's please and request for having obesity being treated as a disease, and they are also moving a lot of resources in that way, it felt as if that there was a potential request also from the authority size to have a very efficacious product entering the market. So I don't know if it was easier or more difficult than -- but it came faster and given that they feel that the cost/benefit ratio is better than what it was before, the criteria has been improved compared to that of Saxenda.

Yes. And then to Japan, the data you see, of course, is from last year, where there's only 1 or 2 months of massive uptick post restriction lift off. In Japan, you have the first year restricted and then it opens up. We have to wait and see, of course, what happens this year. But having said this, 75% of the patients that we are pulling in from Japan are either on DPP-4 or a combination of a DPP-4 and SGLT2s. Then you could argue that at 1 point or the other, you're getting patients that are naive basically to GLP-1 coming into it. And that portion 1 could have argued we would have pushed through with Ozempic if we did not have a Rybelsus. And now, of course, they might favor going for an oral medication rather than an injectable one and leave the injection for a later point of time. What we don't often see is that when a person is on Ozempic, injecting once a week, then wanting to go back and taking a daily tablet, they're fine with their injection. It's just a barrier to injection that's much, much higher than when you get started. Time for 1 more One more question. Yes, please? I think you have to use the mic because of the hybrid.

Just a question on the -- during the day when you talk obesity, you talk about changing the stigma both with health care, personal and patients. Do you see any kind of difference in the way you address this education the effort you have to do as a company in EMEA/IO compared to the U.S.? Is it different.

No. No, not compared to U.S. I think compared to how we were all doing it 3, 4 years ago, I see a massive difference. Whatever we came into obesity because our diabetes product had a side effect. So we very quickly then thought we'll sell the side effect, i.e., for weight and anyway, it's adjacent to what we do because type 2 is connected to obesity. So we somehow kind of bundle everything together. And we try to sell obesity for a good part of the first few years similar to how we structure ourselves and deal with diabetes products. We very soon realize that if you think about patients first, -- these 2 patients are fundamentally different. A patient with diabetes is scared of their life and their future. A patient with obesity is ashamed of their life. Obesity has more in common with HIV Aids and Lupus than it has in common with diabetes from a patient level. So therefore, we actually structured it with different business units. We brought different people in than the ones that were just clever in selling diabetes and that has been a big part of the success on the back of being able to still grow 53% last year with Saxenda while we wait with Wegovy really, just a different selling model. I don't think it's so much different than what Doug is doing in U.S., but we all had to go for that learning.

And we have to build HCP pool. Many of...

I am not skilled or are not skilled or they were not skilled like 4, 5 years ago.

And I do think as we go forward, digital health telemedicine, online pharmacy will play a massive role in all of this. You will see that in wherever city you come from, most of the stores that 20 years ago were selling XXX large clothing are no longer there. It all has moved to online. The reason is the shame. The reason is the shame. People prefer to sit at home rather than go to a physician, sit, be watched by various different people. And then maybe the physician can help often not because they're not educated in it. So we do believe that all the examples you saw, the pilots that you saw with telemedicine, online pharmacies and what have you, is going to be helpful as we go forward in this therapy area, perhaps more than some of the other things. With that, I'd like to say thank you very much. Thank you. See you in the next day.

Yes. Thank you. of the path of physiology of Alzheimer's development. So combining real-world evidence, combining ICTs and combining preclinical studies, we basically came to the same conclusion. This is a big potential. It's also a high risk. But we are actually the only ones who are allowed to go into Phase III with clinical data to support our decision. Most others have had to rely on biomarkers. And this is why we are maybe a little more confident than what we would normally be in this high-risk space because we do actually have strong clinical data to support us. So we've designed 2 trials. I show only 1 up here because they are more or less exactly the same in design and in terms of endpoints. It is the same approach. We have an initial treatment period that caters to regulatory approval, the primary endpoint for that is cognitive function. And then we follow up because we want to look at hard endpoints for regulatory but also for payer purposes, demonstrating that we can actually decrease the risk of having a vascular dementia diagnosis. The difference between the 2 studies is -- and this is a good thing is in evoke+, we've been allowed to add 20% of patients with vascular dementia. So a different pathophysiology than Alzheimer's disease. -- regulators, both in Europe and U.S. acknowledging that this may speak very well to the mode of action of GLP-1 analogs and allowing us to have a broader label than just Alzheimer's disease, if we are successful. So super, super exciting. 2 starters currently ongoing. 2 years of treatment. Once we recruit recruited all patients and that basically also means it's going to hit. Camilla please soon.

Not Alzheimer as I hope you mean, but yes. So talking about potential, what you see here is around 70 million, we expect to have a mild cognitive impairment or mild dementia of the Alzheimer's type. And of course, again, the ability to diagnose and the ability to treat is what will make up the potential in the end. But these are some of the numbers that you can relate to. And again, to support the difference between the prevalence and the actual treatment rate, there is a little bit like in NASH also the preparedness of the health care system. We expect that this, of course, is an ADC that is likely to increase also over the coming decades. So this will have a significant impact on the workforce, but also, of course, on the health care system. So the understanding of that is what we're preparing for. The diagnostic wave is very important also, and we can work with that again with noninvasive tools. and education also towards primary care physicians because these are the first ones that often meet these people with mild cognitive impairment or mild dementia. And those are some of the same positions that we, of course, already see as part of our diabetes and obesity business to a large extent. And then on the evidence generation, what is the impact of delaying the disease progression, the role of new inflammation and the cost effectiveness around this is what we are already preparing for so that by the time we get the readout of the Phase III trials, we would be able to better document whether the effectiveness of this and the impact of actually making a difference here. So for both NASH and Alzheimer's, the disease impact millions of people globally as we just talked about. Often these are undiagnosed. That's why we are also getting into this because we can make a difference there with treatment options. Otherwise, there is no reason to actually diagnose to the same extent. And then, of course, we are focusing on specific patient populations here being F2-F3 in NASH and mild cognitive impairment and mild dementia in Alzheimer's disease. And maybe just to add that, from a commercial point of view, the way we are working with this is that we have now made sort of a 5-year investment outlook, what it means for us to be able to gear up to some of the things I mentioned here. At the same time, it's all trigger-based depending on the results and the outcomes that Martin produced. So the way we are going to approach this is already included in the way that we think about the time towards 2025 and what you have heard earlier today and what you will be hearing about later. So this is sort of the model that we are applying here. The very important part for both of us is, of course, that we have hired in people that are experts in these fields and then they will hire in the next people. So that's the way that we are building our presence from headquarter to regions to affiliates over time. But with that, I think we are ready for some questions and those that are online can also send in questions and I will monitor that here. I propose, Martin, then you can monitor the room if you want. I'll let you into the demo.

Yes, Michael from Nordea. So 2 questions to Alzheimer's. First of all, why did you go for the 14-milligram oral dose of semaglutide? Now we see it sort of being more the 25 and 50 you're testing. And there could also perhaps be lesser viability from injectable. That's the one question. And the second question, how do you sort of cater for not being in a situation as you've been with the [indiscernible] and uptake in supply? Because there's no doubt if this hits the market, then obviously, there's going to be overwhelming demand. So maybe you could just explain why you're -- how you're trying to safeguard that in 4, 5 years from now.

So on the dose, as with everything else, there's balance between efficacy and safety, specifically in Alzheimer's disease and in dementia. There's a concern with neurologists that we introduce too much weight loss. And we know that all of the data that we have, have been generated on the diabetes doses. So either with Victoza or with semaglutide, these have proven to be efficacious doses in the Alzheimer's space. So in order not to jeopardize any safety considerations, we basically choose the diabetes dose to be the right dose in this space.

Yes. And on the demand forecast, if I can just add on that. The way that we think about obesity and potentially also Alzheimer's that is different from, for example, diabetes or NASH also is that it is could be potentially, to a large extent, also a patient-driven or family-driven demand. And that basically just means that the uptake curve is likely to be different than what we normally see when people first have to go and visit a specialist. This person will then recommend a treatment. Here, if you see a patient pool, it's likely to be more of a concave curve, uptake curve rather than a convex that is more a traditional diabetes curve. So maybe that's one way to at least think about preparing for the supply situation.

Okay. And we have a lot of questions here. If you just start on the front row here. And then maybe you can test the microphone down the line.

It's Pete Verdult. Just 2 very quick ones. Just enrollment rates on ESSENCE and Evoke, any commentary as to how well or not they're recruiting. And then just a simple one on Alzheimer's here. You're asking Alzheimer's patients to take oral medication. It's not going to be the same as Diabetes -- as [ robust as I ] hope in terms of bit of water, hour fasting. Is that really a [ fly ]?

So on the recruitment rate in ESSENCE specifically, we have the metrics to compare up against them. And we're actually currently recruiting ESSENCE faster than any other Phase III trial in the NASH space, super nice. On the 2 Evoke trials, we are currently faring basically as according to our plan. We don't have a lot of benchmarking. It is a difficult area to move into. But so far, it looks good, and we've recruited approximately 500 patients. On the dosing side, yes, it is going to be robustness but what we're also looking at is a potential to be able to bridge to subcutaneous once weekly. So people basically get the choice. This is still in the making, but it would make sense to have optionality for treating physicians and patients and, to Camilla's point, their family.

Just a few more questions on Alzheimer's. How much confidence do you have that this is changing Alzheimer's pathophysiology rather than just preventing mini strokes and having an impact on dementia through that kind of mechanism? Second, in not showing your studies, do patients need a PET scan to get enrolled as early Alzheimer's because that would impact uptake curves? And then the last one, you've spoken about what you've sort of imputed as your sort of magnitude of difference between treatment arm just to help us understand powering and impact you might have.

Absolutely. So on the first one, the only data that we have, again, are clinical data, obviously, also a little bit on preclinical data. What we could adjust for in the original database study was actually vascular or cardiovascular disease. And when adjusting for cardiovascular disease -- back to your question on micro strokes, we did see absolutely nothing. It still is appearing to be a very robust finding, irrespective of vascular status.

But just for example, in this like dementia data that you have, you have no idea what percentage of that is confirmed Alzheimer's versus non...

I mean then we have to look at epidemiology. We know that approximately 60% to 70% of all dementia patients are Alzheimer's patients. So that sort of helps us a little bit. And these are obviously some of the discussions that we've had with the regulatory authorities. I have to remind now the next question...

So would the patients have a PET scan to be enrolled?

They actually don't need to. You probably know that in U.S., PET scans are the sort of diagnostic of choice. In Europe, it's actually a spinal tap. What we've been allowed to do is to basically have 1 of the 2. But with historical data, they don't have to have 1 new assessment as part of the enrollment into the trial. That obviously is our sort of trial conduct and recruitment, but it will also -- is what happens to the market. But going back to Camilla's point, even here, we will be looking towards less invasive, less costly diagnostics, supporting basically the validation of those diagnostic blood-based measurements of amyloid [ or tap ] so that it will become easier to find those patients.

Sorry, the last one was just what the estimated efficacy impact will be within your...

So for the primary endpoint, we're looking at CDR sum of boxes and a slowing down in reduction in cognitive impairment, and it's basically a 0.5 estimate in that. I think in the longer -- the extension part, we will be looking at -- and report to the tune of something that we've seen in our real-world evidence and our historic as it is.

Florent Cespedes, Societe Generale. Quick question on Alzheimer. Other cancer drugs demonstrated or were supposed to have an impact on inflammation and on Alzheimer's disease, glitazones or statins. And they also had at the time some clinical evidence of potential efficacy and, unfortunately, they all failed. So could you maybe elaborate a bit on why you are more confident with the GLP-1 and your product? And maybe a follow-up. Do you have any, let's say, subgroup analysis because Alzheimer's disease is supposed to be kind of heterogeneous disease. So maybe it's not one population, but different population, if you have already factored that in your clinical trial design.

Yes. So I think you're absolutely right. This is also why we say this is higher risk than what we normally do. That being said, we believe both on the inflammation [ pan ], we know that semaglutide works centrally. And we can see that central inflammation in the brain is being impacted by semaglutide treatment in our preclinical models. I think that makes a huge difference in and of itself. And I also believe the magnitude of what we've seen in the clinical data and the robustness in more than one real-world evidence, but also in our CTs and having the preclinical mode of action studies, it adds to the burden of evidence. Whether it's enough, we can only talk about when we see the readout from the Phase III trials.

And a subgroup analysis eventually?

Yes. We'll do that basically also because to your point, regulators look at clear Alzheimer's disease, clear vascular disease and a mix of the two. Then we know that there are also other dementias, lewy body dementia and so on. But if you just stick to Alzheimer's vascular or the mix of the two, we have been asked to look at subgroup analysis. And the regulators know both from a sample size. They have accepted that if we see the right direction, for example on vascular disease, where we don't have the full power, then that will also give us the label if everything else becomes statistically significant.

Martin, we are getting signs from Investor Relations that we're really out of time. But if it's very fast, and the answer is also very fast then I think we can go. Yes, you. Very fast.

I will be quick. Just on Alzheimer's again, you said about adding vascular dementia patients to broaden the label. Can I flip it around and ask -- have you -- does the statistical plan allow you to salvage anything if you see an effect in vascular dementia, but not in Alzheimer's? Or would it just be hypothesis-generating from your study...

That would be hypothesis-generating. I mean, it's 10% of the entire population. We need to see a directional improvement, but it will not be carrying in and of itself.

But there are prespecified endpoints on it?

Yes.

Great. Thank you very much. And now I guess you'll answer the next session somewhere in this neighborhood. So thank you, Martin. [ Break ]

Now I will start. And hopefully, you can hear me. Welcome to this super exciting extension of our Other Series Chronic Diseases session, where we will today focus on NASH and on Alzheimer's. I've just been told by David, that I speak too much. So if you see him waving, I will stop talking and then move on because we also want to get to a Q&A session and answering all of your questions. But obviously, we need to give a run-in on why we are at all here. You heard us talking about our aspiration, 2025 aspiration moving into other serious chronic diseases. These diseases have to be adjacent to what we already know and do, namely diabetes and obesity. And we've defined a broader cardiometabolic space as part of that. Very clearly, cardiovascular disease, chronic kidney disease, NASH are part of that. I get some questions sometimes on Alzheimer's because Alzheimer's is not immediately part of a cardiovascular metabolic syndrome or cardiometabolic syndrome. But just for your information, having obesity is associated with the doubling in risk of having an Alzheimer's diagnosis. Having diabetes is associated with the tripling in risk. And some even call Alzheimer's disease Type 3 diabetes. So this is why it actually fits very nicely into our strategy and the way that we conduct ourselves. It's still early days, which is why -- and now I get to sound like a broken record. It's super great to be in a place where we have a strong clinical pipeline, certainly in NASH, but also in Alzheimer's disease. And we are looking towards Marcus and his people towards a very strong preclinical pipeline, specifically in the NASH space. We are again, looking towards tremendous unmet needs. I think we can agree in NASH, in Alzheimer's disease, we are seriously talking about unmet needs. There's really nothing out there for NASH. And there's very little, if anything, out there for Alzheimer's disease. So big, big unmet needs. And we need to do our part in terms of changing that picture. When we talk about NASH, obviously, as with any disease, there are different stages of the disease, in NASH, they talk about F1 to F4, F1 being sort of the mild early stage of the disease; F4 being the more advanced, close to cirrhosis, stage of the disease. A metabolic compound like semaglutide is very nicely suited in the middle of the disease, so F2 and F3. But we do believe that if we are to serve patients with the advanced form of the disease F4 and we had to look at combination with other modalities. This is why we are now in our clinical pipeline and looking at combination with our own internal asset FGF21. And this is currently ongoing in Phase II. But we also have a strong collaboration with Gilead, who have been in the hepatology space, in the liver space for many, many years, who have assets in that space. And we are doing a combination evaluation. So in the Phase IIb setting of 2 of their assets in combination with semaglutide to see if we can serve patients suffering from the late stage of NASH. But our big shot on goal, and I'll come back to why that is, is F2 and F3 with semaglutide in monotherapy. Then obviously, also I'll come back to Alzheimer's. We are going directly from nothing, so not Phase I and not Phase II directly into Phase III. And I receive a lot of questions on why is that. And how do you find the courage to do that? And we'll cater to that in just a minute. The reason why we think a big shot on goal in NASH, F2 and F3 and semaglutide is basically our Phase II data. We decided a couple of years ago, almost 5 years ago to do a big, robust Phase II trial, almost 400 patients treated for 72 weeks. Those of you who know the NASH base looking at what comes from our competitors, typically 12, 24 weeks of treatment, very small sample sizes. The advantages is then to be in a situation today where we now have the most advanced assets almost in the industry based on these Phase II data that are robust and reliable, in part because of the [ and part ] because of a longer treatment duration. So what we demonstrated in Phase II was the regulatory requirement of a dual endpoint based on liver biopsy, namely reduction in steatosis or improvement in the NASH disease without increasing risk of fibrosis. And the secondary endpoint or the primary -- secondary -- yes, the co-primary endpoint, it's called was reduction in fibrosis. With semaglutide, we saw both. And we are basically the only company who has managed to do that in the Phase II setting. So we saw 2/3 of the patients experiencing an improvement in steatosis compared to 23% in the placebo arm. We saw a 75% reduction in risk of progressing to the next level of fibrosis. And these are really, really strong grade. And the good thing is you don't have to take my word for it. USFDA have looked at these data and they've done 2 things. They granted us breakthrough designation because they like the data. That sort of blue stamp of this is good and valid data. But they even took it a step further and said, normally, we require 2 Phase III trials to approve a new indication for a drug, you will be allowed to use this Phase II study and another Phase III study. So I don't have to go out and do 2 Phase II studies now, I only have to do 1 because these data in the eyes of the FDA are so robust and so convincing that they take them as part of the evidence generation that they will require from us. And that's good because that means you don't have to trust me when I say this is good and strong data, you can just look at how the FDA system. This obviously has made us very enthusiastic. So we have initiated a Phase III trial. This is a reasonably large 1,200-patient trial that will be conducted in 2 parts, and I'll come back to that in just a minute. Patients will be randomized to semaglutide 2.4 milligram of placebo. Now what we do is we look at 2 parts of the trial. First part is 72 weeks long, just like our Phase II trial. Primary endpoint is liver biopsy-based histology. Again, looking towards improvement in steatosis, improvement in fibrosis, but to support what we want to do going into a completely new disease areas, we also wanted to look at harder endpoints. This is good for regulators, this is good for payers, this is good for treating physicians. And we can do that by extending the trial -- so a full 240 weeks of treatment, 5 years of treatment will allow us to accrue data to look at liver outcomes, cardiovascular outcomes, harder outcomes than just the liver biopsies. So we'll get the regulatory approval after already 72 weeks. And if I tell you that we are currently mid recruiting, we have recruited slightly more than half of the patients already. It also tells you that with the 72 weeks of treatment, we will be seeing semaglutide NASH, hopefully, approaching the market very, very soon. We have then one more challenge, and I just mentioned that in NASH, there is no established not invasive diagnostic. The regulators, sometimes also the payers, are saying that they require a liver biopsy for diagnosis. And those of you who have tried this, hopefully, none of you knows that liver biopsies they hurt, they're dangerous, they're costly, they're cumbersome. It's not a lot of fun. So we're looking for something else. Get to that alone. We are working with consortia. We are working with academia, but we're also working with other companies who have these biomarkers available, but don't have the tools to validate their biomarkers. We can help them because we are conducting the clinical trials where we take liver biopsies, but where we can also measure those biomarkers. And then we can help others validate their biomarkers in the ongoing Phase II trial with FGF21 and in the ongoing ESSENCE trial. This gave us an incredibly strong platform when we get to the market if we succeed to have the diagnostics available. That's not going to be, I think, a commercial sort of win for of Novo Nordisk, but it is a pre-requisite for us to be commercially viable and then obviously, having semaglutide on the market.

If you click to the next slide, then from a commercial point of view, just to give you a few numbers on we assume around 22 million people are living with NASH F2 to F4, but the real sort of difference between those and those who will end up getting treatment is, of course, as Martin said, how many will end up being diagnosed and how many will get access to the treatment? And as opposed to Alzheimer's that we'll talk about in a minute, NASH is not really a disease that is on everyone's mind the same way. So the diagnostic tools has meant and the lack of treatment has meant that there is a low awareness of NASH. So that is a clear hurdle from a commercial point of view between the prevalence rate and the actual treatment rate in the end. And of course, that means that the 3 things we would focus on from a commercial point of view is to build a strong presence, of course. And that is with the endos, hepatologists and primary care physicians to inform about this. Once that we have, of course, seen what are the results from our clinical trials, we will be in a much better position to actually also give solutions to the market. But before we even get that, the whole potential of this can be either increased or diminished based on the actual diagnostic tools, and that's where the noninvasive tools becomes extremely important, both for screening and for monitoring. But finally, we also, of course, need to repay us to provide them with insights on is it cost effective to treat NASH? What does it mean? And just preventing that people move on to the next stages of NASH, what are the cost effectiveness in that? So those are the very simple things. It looks like that we are focusing on. But in reality, the clear drivers of success in this field. And then I would propose we move on to Alzheimer's. And following that, we will then take questions on both topics.

So very briefly. Oftentimes, we get the question, why did you go into Alzheimer's disease? And we didn't have Phase I. We didn't have Phase II, why don't we go directly into Phase III? basically, we did that because we conducted a retrospective data-based evaluation of what does it mean to be on a GLP-1 analog vis-a-vis having a dementia diagnosis. And what we saw was -- and this was a very big Danish database that we started. Looking 10 years back into various different diabetes treatment, we saw that being on a GLP-1 analog was associated with an 11% decrease in dementia risk if being on a GLP-1 analog for 1 year. Being on a GLP-1 analog for 2 years was associated with 25% risk. Now obviously, being a database study, a lot of confounders that we can't adjust for, a lot of things that we don't know about the patients. So you have to take that kind of data with a bit of a grain of salt. Danish database, so we knew more than we would from normal databases. And what we could adjust for what we did and we found a very robust finding. 1 year, 11%; 2 years, 25% risk reduction in having a dementia diagnosis in a tremendous area of unmet need. Then we followed up by 3 more database searches because you said to not trust us just 1 database. Again, there are cofounders that you don't know. All of them showed the same thing. Being on a GLP-1 analog is associated with a quite dramatic decrease in risk of having a dementia diagnosis. Again, acknowledging that there are limitations by doing database research, we then said, okay, we have some RCTs that we can look at. We have our own historical outcome strength with Victoza, with semaglutide. If we pull those proving leader to Stage VI, PIONEER 6, we get a big patient pool treated for several years with the GLP-1 analog and what does that show? Basically demonstrated a 53% decrease in risk of having a dementia diagnosis versus placebo. So quite dramatic. So we had sort of a good base to start on, it appears that being on the GLP-1 analog is associated with a decreased risk of having dementia. We then followed up, look at other prospective RCTs, demonstrating that being on GLP-1 analog is associated with, in some studies, improvement of -- slowing decline in cognitive impairment, improved brain morphology, improved brain metabolism. And we could then follow up in our pre-clinical space, also trying to understand what is the mode of action. Repeating the findings on cognitive impairment on tau pathology, which is an underlying piece of the Alzheimer's pathology, but also in information, which is the other underlying piece in Alzheimer's pathology. So all of a sudden, we had very strong clinical data. We had very strong evidence on the mode of action, allowing us to say, okay, we actually are sitting with the strongest evidence based that any industry have had in order to make a Phase III stop-go decision. Most of our peers have had to be looking at biomarkers to make their Phase III stop-go decision. Here, we actually have clinical data to support our decision. It does mean that there is 0 risk here. There's actually quite a bit big risk. Historically, Alzheimer's clinical development is associated with the 99% failure rate. So just taking that number into account there is risk and will never be little. But looking at a potential of reducing the risk of having Alzheimer's disease to the tumor somewhere between 25% and 50%, we felt that we had an obligation to at least assess this in Phase III. And this is what we're doing. We are conducting 2 very similar-looking trials, 1,800 patients in these trials being randomized to either semaglutide 14-milligram or placebo, with, again, a 2-tier approach or 2-part approach. The first treatment period catering to regulatory approval, looking at cognitive function and cognitive decline. The second period being put in place to secure that we have hard end points, risk of having a dementia diagnosis for regulatory purposes, but also for payer purposes. The only difference between the 2 trials, and this is a good thing from a regulatory perspective, regulators, U.S. FDA, EMA allowed us to in 1 study to have 20% of the patients being of vascular dementia. So not Alzheimer's disease, but vascular dementia. If we see a similar improvement in those 20% of patients, we'll get a broader label going beyond just Alzheimer's disease. This is obviously super attractive for us and potentially also for the patients. And we are currently in the midst of recruiting those 2 clients. And therefore, again, think about 2 years of treatment, this is something that is potentially being on the market very soon.

Yes. And again, if we look at the commercial potential, here, we just included patients with mild cognitive impairment and mild dementia of the Alzheimer's type, there is around 70 million people living with that. Very few are diagnosed and even fewer would be eligible patients in the future. The hurdles that they are between the prevalence and then getting the treatment, of course, recognition of the symptoms, it's also the testing of the diagnostics and then simple biomarkers and simple tests. So these are the same things that we will then from a commercial point of view, be focusing on. One thing is about with the aging population, with more people living with obesity that Martin just referred to, we expect that the prevalence of Alzheimer's is likely to increase in the future. So this will put a significant strain on the health care system, both in primary care, but of course, also in the specialty system. Then with that, we can help with increasing the diagnostic rate, but it has to be with simple tools. Otherwise, it won't work and there won't be sufficient tools in place to do that. So education around the screening -- easy screening tools for primary care that are often the first people who meet the patients would be important. And then, of course, the whole evidence generation about what it actually means of delaying the onset of the disease progression, that will be very important from a cost-effectiveness point of view. And of course, all of this, we are preparing for a while we are waiting for the exciting results of the Phase III trial that, of course, none of us know about yet. So in summary, as an Alzheimer's impact lots of millions of people, no real treatment available today. But the diagnostic tools in both cases will be extremely important to get people diagnosed. And then we will be focusing initially on NASH, F2, F3 and on mild cognitive impairment and mild dementia due to Alzheimer's disease. So with that, we are ready for some questions. If you have an online, you can also type in questions, and we would get those here on the iPad. Martin, I suggest you handle the questions?

Yes.

Keyur Parekh from Goldman Sachs. Two, if I may, please. Martin, the first one, I should know this, but I don't. So apologies. Did you guys try asking the FDA for an accelerated approval for sema in NASH based on the Phase II? If not, why not? And if you did, kind of what was the feedback?

So I can't go too much into detail with -- on our discussions with regulatory authorities. I think it's very, very clear that the FDA have been concerned about the failure rate in this space. They have also been concerned as I spoke a little bit to the very low data base that some sponsors have given to them very small, very short Phase II trials leading to failure in Phase III. So they've granted us breakthrough designation, but they want to see more data before they probably want to discuss accelerated approval time lines or stuff like that. I think that's absolutely fair. We have to raise the bar or what kind of data do we generate in this space.

Just clarification on that. But assuming your Phase III study reads out, that should just be normal approval, then it wouldn't be accelerated, right?

I think it's too early to speculate. We'll have the dialogue that when we've seen the data. Obviously, the disease is representing a tremendous unmet need, but also the FDA, again, wanted to see robust data. So we have to take the dialogue when we get there. We're not sort of in a position where we can say we do that now.

And then separately, Camilla, as you think about kind of the commercial part for NASH, obviously, big, you need the noninterventional diagnosis to get sorted for it to be a really big product. How do you assess the likelihood that we will get some form of nonintervention diagnosis before kind of the Phase III reads out that is approved by the FDA and kind of across the world.

Yes. So maybe I can start and then Martin can add on. So right now, we are looking at who are some of those companies that we could potentially be working with and who is it that are more likely to have this approved and not, and that's, of course, important for us. I'd like to say that ideally, we would not be sort of teaming up with just one company on this little bit like the same philosophy as we've had in the digital health space, where if we look at what is the best starting point for people living with NASH, it's not that we have confined ourselves to one single diagnostic tools only, but that there actually could be more available, and we could work with more partners on this. I think there is a win-win situation in this, we might have the treatment, someone else might be able to provide diagnostic tools. And from that, there could be a good collaboration, not necessarily just with one partner on this. So we're working with a gross list that we might soon some a bit on a view on that, but that's sort of where we are. But clearly, this is an important step for us to get solved, not necessarily having to do it ourselves.

Yes. I mean we need to get this right. If we can do it exactly at the time of launch, that obviously depends a little bit on our collaborators because they have the biomarkers and the diagnostics, but it also depends on the data. If they have very strict requirements for what they want to see in terms of a diagnostic specificity sensitivity, what we can help is validating those biomarkers. So we are taking the liver biopsies, which currently is the gold standard. And then we are also measuring, for example, we are using fiber scanner in our [ clinical ]. So we can help the manufacturers of those tests to validate their diagnostic tools. If we can do it within the time frame, that's clearly our aspiration, and it should be doable.

Two quick ones. one here. Just firstly, just going back to the NASH Phase I, I just want to be crystal clear. The FDA said you need to hit both primary endpoint for approval?

Yes.

Yes. So both need to be still significant and -- but that then is acceptable for regulatory filing without the follow-up? Yes?

Correct.

And then just with regards to the -- you talked about partnering collaboration just now for diagnosis, noninvasive tests. Equally on the treatment side of things, you've got a sort of a collaboration with Gilead and SELECT. But really that's as far as you've got so far, do you see it that you're going to get sema over the line before you then go broader? Or I guess, what's holding you back potentially here, trying to go broader in NASH, given that seems to be what most experts think is the way to get?

So we don't necessarily need to see sema go over the line. But what we do need to see is scientific clinical possibility that this combination could work. And so far, our collaboration with Gilead is the only one that has really made that mark. I think it's fair to say that we are looking towards other external partners, but we are certainly also receiving a lot of request for collaboration, some of which we are taking into consideration, some of which are honestly not necessarily meeting our bar.

Sorry, to be clear you [ have a Gilead ] but not...

No. No.

I'd like to ask about the blood pressure for Alzheimer's. So is that -- are you screening for high blood pressure? And are you using that as a secondary endpoint?

The answer is no, no. We do measure blood pressure, and we will have the data. But in order to not -- I mean the more in an exclusion criteria you have, the more difficult it is to recruit. And therefore, we have it as an important assessment. I don't want to call it a secondary endpoint but it will be assessed and we will be able to conclude on it.

Can I just better understand the Alzheimer's -- the Alzheimer's population in terms of the trial? Because obviously you set off with a -- and these are the number of patients that progress to getting [ reducing ] that number. And then you've recruited a patient population that is already showing some signs of cognitive impairment. So how confident you are that that's not already too progressed when we think about the sema treatment?

So I've got to realize over the last 25 years, I should never be too confident. But I think it's a really good question. I mean there is a level of you wanted to stop the progression of a disease, maybe rather than reverting an already existing damage. And specifically in Alzheimer's, we need to -- we believe -- we don't know, but we believe that we need to get to the patients early. So my cognitive impairment, early dementia. It is probably as early as you can get there. But we also know that the underlying pathophysiology probably has been ongoing for years before they start having those clinical symptoms. It doesn't necessarily mean that we don't want to see. I mean we had the same considerations in cardiovascular disease. Some said, I mean, once we had established cardiovascular disease, it was too late to reverse. We've shown with semaglutide that, that is actually not the case. So I mean time will tell, but this is, at this point in time, as good as we can do it.

Good. Any final questions here?

Just on Alzheimer's. Obviously, you're going to see a lot of Phase III data over the next kind of 18 months. Martin, from your perspective, how do you handicap kind of one or more of those studies kind of showing positive benefits on cognition? And then what -- if one of those studies does show positive benefits on cognition, what does that mean from a commercial perspective for sema given that the sema studies would have had a different standard of care?

So from a clinical and from a trial contract perspective, I really don't see a conflict we are talking. And also going back to the previous question. From our perspective, we need to go in early. We have a different mode of action than a number of the other players that are largely in the amyloid antibody space have. That means that we will have, hopefully, a good safety offering in an early -- a slightly earlier population than what has been investigated by, for example, Biogen and Lilly. But also a safety offering that is very, very well established where we know that the antibody treatment does have some safety issues. So I think from our perspective, we are maybe looking at slightly different populations. And we're coming out with an offering that from an efficacy perspective needs to be good, but also from a safety perspective, maybe have the upper hand.

[indiscernible]

I was about to say, I hope so. And it's going a little bit back to Camilla's point. I don't think that we have to be owning this space alone. Again, I think we're looking at slightly different populations. There's no treatment available out there. That means that there's no market. And we need to push each other on innovation, probably also on building the market.

Yes. So from this point of view, without making further analysis, it also reminds us a little bit about the obesity business where we're basically starting from there is no treatment. There is a great understanding in the population of what this actually means and what it feels like every day for families. So we also expect that this will be more of a patient or family driven sort of disease in the sense, different from NASH and from diabetes, for example, where it is a specialist driven sort of approach to it. So this might tell us something about and also the shape of the uptake curves by the time we get to launch. But clearly, efficacy and safety has always played the important parameters when we have to think about access and uptake. So the more we can prove and the more we can see from that, of course, will help us.

I was just wondering if these findings in Alzheimer's that obviously -- this is because it's post-op [ through ] data and finding out, and therefore, you test that hypothesis in the trials. Has that then iterated through to looking at Alzheimer's as Novo in the early research to try and better understand other mechanisms and therefore, iterated that way? Or is it a case of wait to see the data and then whether you'd want to investigate other disease?

To be honest, it's a little bit of both. First of all, we need to understand the underlying mechanism for semaglutide in and of itself. Through that, we'll get broader understanding of Alzheimer's disease, and that will potentially allow us to expand into automotive actions. It's also fair to say that this will not be, I think, Marcus' key focus area until we have some solid data because as he already alluded to, he has to be honest, a lot on his plate.

Okay. Thank you, Martin. I think that concludes our session. We -- I get the sign that time is up. And I think you will get a small break, right, before we have to be back in the plenum. Yes. Thank you.

Thank you so much. [ Break ]

Welcome back. Hope you enjoyed the breakout sessions, especially the 1 on EMEA. Now we have a deep dive on the 2 operational units that we have, International Operations as well as North American operations. I will do that together with Doug. If we take a look at our corporate strategic aspirations that we showed you back in 2019, then on the financial quadrant, there were 2 KPIs with regards to the 2 businesses. It was to deliver 6% to 10% sales growth for International Operations while we transform 70% of the sales in U.S. And we are doing quite well on both of those fronts and we will talk about how we are actually managing that. I'll start with the International Operations. For a number of years and decades actually, the world outside of U.S. was delivering sales growth of around 5%, 6%. And it was quite stable but it was no more than 6%. Then with the new launches that we actually embarked upon with some changes in the organization with a bit more focus perhaps with a new CEO, we decided to actually raise the bar and we were -- when we were here together in 2019, we showed you that in 2018, we were able to go a little bit above that 5% to 6% by delivering 7%, and our promise is now to do 6% to 10%. Lo and behold, we have actually delivered on that promise, and I would even dare to say we were on the upper end and sometimes exceeding the 10%. And then we, of course, last year had a record year with 14% growth. It really came by stabilizing and making sure that insulin continues to deliver low single-digit growth despite an ever increased competition from often biosimilars but really get the growth from the GLP-1, and there's been a lot of talk today about how we've done that with the Ozempic launch and what-have-you. And the geographical part, then you also see that we are doing quite well, regardless of which geography you're looking at it. 50% is coming from EMEA, another 22% from Region China and 27% from all the other countries. And the strategy, to a large extent, is similar but there are some minor nuances of difference. In EMEA, it is really about GLP-1 on the back of Ozempic and now more and more, Rybelsus. In China, it is about managing the VBP and the pricing while we enter and expand on the GLP-1 market that has not existed. And in the rest of the world is also really about making sure that insulin, which is a very large part of that region, continues. We add GLP-1 to it and we make sure where it makes sense, Rybelsus does incredibly well. And then I spoke to Japan, which actually is the largest Rybelsus place for us over there. Now it doesn't mean that there are no challenges. There are tons of challenges in this diverse and this first part of the world. If you summarize it, it really boils down to making sure that we manage competition best way possible and we outperform them wherever we are. And we have local competitors and we have multinational competitors in all the segments and we do that quite well so far. Health care reforms, price pressures, of course, quite often, that's synonymous with U.S. and what Doug speaks to, but it also exists, to a large extent, in most parts of International Operations, managing prices and managing health care reforms in a way that is a win-win situation between both parties is something that sometimes gives us challenge but we need to overcome it as we have done so. And then, it's really geopolitical instability and macroeconomics that drives the business or gives us a challenge. And the last couple of weeks, it has given us a challenge as you know. But we have not been new to these type of situations. Any given year we have an issue or 2 wherever you look in my part of the world. On the other hand, opportunities are really vast and much -- sometimes, much better to look at the glass half full if you're managing IO than to look at it half empty. With the GLP-1 segment that I showed you earlier on, we are just at the very beginning part of penetrating GLP-1 growth into International Operations and getting a fair market share out of that. Obesity is even larger than diabetes, and there's a patient pool. There are millions of patients out there that are in need and wanting our products, so we need to find a way through to them. And one -- of course, 1 way could be ever increase of the digitalization. The model historically for IO has been just put more sales force on the ground. Imagine if we can marry that with digitalization to cover this vast geography what we'll be able to do. And our projection on all of that then is that we will continue to grow. We will continue to deliver on the promise of the 6% to 10%, and I will personally commit to try and be on top of, of course, the 10% whenever possible. No one wants to do that better than me. But on the other hand, there will be years where we will have headwinds like this year with China, where all of a sudden, a government goes under sanction or all of a sudden, half of the world gets shaken. Then of course, that might interrupt our annual number. But as a whole, we believe that there's a lot of opportunities. And the opportunity pillars for us is really the 3 things that I have spoken to all the time. They haven't changed. The strategy is still the same. When I think about GLP-1, then I think what obviously penetrating much faster and much more with Ozempic and now Rybelsus. Obesity, we're waiting for Wegovy, we will have the first few launches at the end of this year, and then it's going to be really, really nice with Wegovy across International Operations. And really gaining basal leadership with Tresiba. Now we have it in some 20 markets and more to come and also going big, replacing Novo mix patients on Ryzodeg in places like China and elsewhere where a mixed regimen is needed. So this is, in a nutshell, the IO story but that's again just half of the story. So from 1 double-digit country or region to another.

All right, Mike. Thank you, Mike. Appreciate it. [ 14 ] has a certain ring to it for both of us, doesn't it? So earlier this morning, I talked to everyone about the performance and how it was driven through the diabetes portfolio and that growth that I showed. This is the overall growth in North America. So we have been on this journey for many years. And again, the aim was to always to slow the erosion, stabilize the business, bring it back to growth and then bring it back to what was step change in growth. And we've accomplished that and we're very pleased with that. 14% was a step change for us, and we saw it throughout the portfolio other than insulin, which we're happy about. Now like Mike, we're living in an environment that has challenges, risks, some threats and some of them are very real. I mean, I'm not here and I don't want to predict what's going to happen from a political standpoint, but there is this uncertainty around health care reform. Within that, if we peel it back, there's some good guys and some bad guys within that, right? A good guy may be Medicare reform, right? The U.S. health care system in a lot of ways is broken, we've talked about that. There's a tremendous amount of misaligned incentives. So it's not always bad when we think about reform, it may happen, although we do realize that some of that may be challenging. But wait to see what happens. We also know that with 340B, that's something that we had some tailwind last year. We won't see this same tailwind this year. But again, it's something that is uncertain in and of itself in terms of what may happen in the end. When we also think about the intense competition, as Mike talked about, we have competition in branded products. We have competition in biosimilars, but we also have these best-in-class brands. But the competition is fierce so people continue and companies continue to invest in these markets -- in this market and these brands. And then lastly, there is this element of pricing pressure in the U.S. The health care system is set up the way that it is, and we do have and will have continued pricing pressure. But we've also built sort of this exterior armor in a way to be able to mitigate that over the years and we'll continue to do so. So there's going to be risks and challenges and we've been able to mitigate those along the way. But importantly, there is significant opportunity, significant. We have these unbelievable products, and I talked to you earlier this morning about Ozempic itself and how well it's doing, taking market share in a growing market and we feel really good about that. As I mentioned earlier today, we're pleased but not satisfied with the Rybelsus performance. We know and we will continue to be competitive in that space. As I mentioned to you, back in 2019, I stood here and I said, we want commercial excellence, was something that Lars set out when he became CEO. And we took that to heart and we'll continue to compete in these markets and even though they're competitive because we have best-in-class brands and we have the science behind us to do that. So then it's our job to compete. And we have momentum so we're going to continue to fuel that. What we also know is that when we think about obesity, I could tell you that this is, in a way, it's one of these disease states that is touching when you hear the stories of Lisa. They're all touching, but when you think about this significant health crisis and maybe it's this last bastion of one of these categories, that's 100-plus million patients that need our help. Lars and I, we often talk about sort of the legacy of us being able to help as many patients as we can not only with our current products but with our future products and the pipeline that you've heard about. We take this very, very seriously. And there is, as Mike just said, there's no one more excited and myself and my team to get back and to fully promote again because we know what we can do with for patients and for our own business. And then lastly, if I think about it in terms of maybe chapters, chapter 1 was sort of this transformation of the North America or the specifically the U.S. business. And I think that chapter was a good one for us. If I think about this next chapter, chapter 2 and this is more for the mid or the longer term, it's sort of the evolution of the business. It's us moving into other disease states that we don't participate in today. And that's incredibly exciting when we think about it. So for us, we've committed to the 70% mark and if this will change. So we are committed to the 70%. Again, we completed the last year, 60% of the transformation, well on our way to completing the 70%. Now for the last many, many years, and I communicated this in 2019, we have set out in a simple framework, simple yet powerful because everyone in North America can anchor around it. And we made some investment choices, we made some strategic choices, some operational choices, some structural choices and a lot of other things went into that. But this is the simple framework. What we know over the near term is that we have to maximize semaglutide, period. We have a beautiful molecule and we know that we can do that. In diabetes, we know it's through Ozempic and Rybelsus, period. We know we have to commercially execute there. We also know that within semaglutide, within obesity, we have this game-changing product in Wegovy. And we're super excited to get back at that. So that is our focus when we think about our framework. It has been and will continue to be, over the near term, simple yet powerful. And everything we do is anchored around that. We have other parts of our business and they are important. With insulin, we have 3-plus million patients on our insulin products so critically important to us now and in the future. So how we mitigate that decline is critically important and we spend a lot of time and energy around that. And lastly, what was biopharm and rare disease. In the short term, we had 7% growth last year reported so we were pleased with the progress there, for sure. And we're looking forward to continuing managing through to get to these flabbergasting products that are on the way, right? So we're looking forward to that and what we can do downstream with that. So this is the simple and powerful framework and we're excited for the future. We really are because there's a lot to look forward to. And nothing can happen without products so I'd like to bring up the product master. Before I do it, I do have 1 closing slide. I'd be remiss if I didn't thank Mike again. I'm sorry. I'm sorry, I jumped the gun there a little bit. I do have a closing slide and I forgot about that. So I think what you heard from Mike and I throughout the day is that we've hit against our strategic ambitions. You've seen double-digit growth at over the last 3 years and a step change in growth last year for North America. Sorry, Mike, but it was. We also know, though, that we're geared up and ready for the future so we're excited about that. So with that, sorry for the -- Mr. Product himself, Henrik Wulff.

Thank you, Doug. Yes. So before the CFO of Novo Nordisk will consolidate the financials, I will try to consolidate the demands that you have seen today in technical operations, you can call it. You have, throughout the day, learned from early research into development and from my commercial colleagues, a lot of promising demands. I need to respond to Marcus' cell therapy adventure. I need to respond to 14% in IO and 14% in North America. I need to respond to the changing color of your columns, Doug. You just changed the whole business from insulin to GLP-1 more or less. I need to respond to rare disease area where we have shown promising results. So manufacturing do need to be not only in front of sales, we need to be in front of all demands across the organization. So how do we do that when we also want to drive operational efficiency as we have always done? How can we do that, and at the same time, invest and protect the full path of activities that you see across Novo Nordisk today? There's a lag on this. So first of all, we have an extreme solid manufacturing footprint worldwide. It's mature, it's well-placed and it's fully operational. We have all our technologies, all our competencies, all our capabilities. We have them for good reasons and from our history. We have that in Denmark, even though that the pick on the map is very small, we have all the capabilities here. They are extremely close to R&D activities, I will come back to why that's important. From here, we expand worldwide. And we have large-scale manufacturing sites in China, in France, in Brazil, in U.S. And we have also, in the recent years, established large API capabilities in the U.S. We have also -- we have touched upon it a couple of times today. We have also started our cell therapy adventure in U.S. This structure is despite geopolitical tensions, COVID-19 pandemics, pretty strong. Having said that, there is a constant alertness level from our side in making sure that we protect this setup while we are growing both in volume but certainly also in diversity of the products and the technology platforms. So with this, we are planning to respond with this, we are planning to defend this and we will expand it as we go along. Just taking a couple of very good examples that we have also looked into today. This is just an illustration of what is going on from my side when you look at some of the numbers that you have seen today. From 2019 to today, if you look at the active pharmaceutical ingredients, the big factories, we have -- we are now 4x up the manufacturing volume as we did in '19. If you just take the brand itself of Ozempic, we are 3x up in our fill finished area and that's global numbers here. So it's a significant increase compared to the good old Novo Nordisk of their insulin developments. And I will come back to what we are doing to defend this. Here, I'll try to illustrate what we also communicated in the full year that basically for '22, we are now at a pace of DKK 12 billion in CapEx. And the reason for that for this year is the announcement we did in December, where we are actually adding a new API facility here in Denmark to basically respond to the increased API demand within diabetes and obesity. We do also expect, in the years to come, to be around that number. Now we have shaded the area here between DKK 10 billion and DKK 15 billion because it depends on how good we are to use the synergies, what is the market development. As you can understand, the dynamics are bigger and broader these days compared to beforehand. I have tried to compile all the marketed products on the right-hand side here. We have touched upon many of them and what is the potential of those products. But I also stacked up the late-stage clinical trials that Martin talked to both within diabetes and obesity but certainly also within rare diseases where we need to be prepared for the future and the potential of these products. It's important for me to say, and I'll come back to that in a short while, that this is not isolated investments with no synergies. When we move our investments up like this, then we can see a lot of synergies. So it's not that it's a one-to-one investment and then we increase the risk for not utilizing this capacity in the future. So how is our manufacturing principles? So first of all, we need to ensure that we have sufficient capacity. Secondly, capacity without compliance up against cGMP, you cannot use that. And then finally, driving efficiencies across manufacturing. We will continue to expand our highly efficient internal capacity worldwide. We will -- we have touched upon it a couple of times today. We will see more devices in Novo Nordisk. We will utilize them not only for the single brands but as a technology platform where we will use that across our products, both within diabetes, within obesity and within rare diseases. We will also utilizing a very strong setup there is around the CMOs of the world. We will use the top-tier CMOs for respond up against the high volume demands but certainly also to have a broader and more higher flexibility when we respond to the pipeline. And finally, we are working with backup factories and safety stocks that also, together with all the companies in this area, has been under pressure due to the supply chain disruptions during COVID-19. But this is fundamental for us to work with them. Within quality, cGMP regulations is extremely important. We need to respond to that in all regions of the world. We are running a very robust quality management system, and we are constantly running a very comprehensive quality auditing system, both internally but also externally at the CMOs. Then 2 dimensions of efficiencies. First of all, actually a very, very important point is to stay close to research and development for them to understand how we can scale innovation globally in volumes, spreading the innovation throughout the world but also for us to understand what it needs to take that into manufacturing. It's very, very important and I have a lot of people working in that dynamic field between R&D and manufacturing. Then, of course, we also have the constant chase of lower unit costs than where we use tools like LEAN, et cetera. Let me bring a famous example of how we deal with the new supply chain. So here is the global framework for Wegovy. We have already API in operations, we've had that for a long time. It's a semaglutide API manufacturing and it's well positioned and it's in full operation. Within fill finish, we are working on 2 platforms. We're working on a single-dose device, that is the famous one with the CMO. And then we are also utilizing a huge global platform that is called FlexTouch that we have established many years ago that has a worldwide approach. We use this setup both within filling but also within assembly and packaging, meaning that we are able to assembly and pack both in Europe and in U.S. and other places over time, using -- utilizing this platform to increase the volumes. And the same goes for assembly and packaging within the FlexTouch platform. So we are going to utilize a new platform but we are certainly also going to utilize a huge global platform of FlexTouch. If I try to illustrate how we work with the unit cost, then, of course, you have on the left-hand side, you have an illustration of that the newer products, they have a steeper curve because there's a volume part in it, but there's also a maturity of the technology that we're actually working with. We touched upon generations of oral sema. I think you mentioned version 4.5 or something. I think I've only received version 1, maybe soon version 2, but they will come into manufacturing over time and actually cut down the unit cost of oral sema. You see a steep curve on that because that journey has just started. Then you can also follow the GLP-1. GLP-1s within the injectables also have a good steep curve while we are building volumes and learn how to optimize that. And then you see the older products where you can actually also take human insulin where we have managed to a very, very old platform. We have managed to optimize that and actually drive those unit costs further down. So we work on a technology platform and we do that constantly over time. And I mentioned the obvious things here on the right-hand side, the scaling technology upgrades and then simpler processes, et cetera. And I promised Karsten -- I was about to go back to the CapEx slide to give it to you, but I don't know which one you like the most, the CapEx slides or this unit cost slide, so you can decide, but now it's on this one.

Thanks, Henrik. Clearly, I like this slide the most, lower unit cost. That's kind of the CFO, frankly, type of slide, but it's also a very investor-friendly type of slide. So this picture that Henrik showed here and explained kind of the operational tactics in delivering this, this is super important for investors in Novo Nordisk. So first of all, this is the background for why we, as a company, can have gross margins in excess of 80%. Some of the highest -- one of the highest gross margins in the pharma industry globally, more than 80% consistently. It's also a driver behind why we believe that we can maintain a broadly stable gross margin towards 2025 because continuing to do so and drive efficiencies is part of mitigating the price pressures we heard from our commercial colleagues. So really, really important, thank you for doing that, Henrik. And talking about resource allocation. Now you heard our plans so it's actually pretty simple to allocate resources, so this is more or less like a summary, a financial summary of our plans. And when I look at our resource allocation in a more strategic top-down context, the starting point is what you heard from Lars in the morning, our corporate strategy. So this is our where to play. So we allocate, of course, our resources according to where to play as a starting point. Then secondly, the cornerstone of our resource allocation is driving growth, is driving growth in the short term, in the medium term and in the long term. And we have the opportunity to do so. We're in a unique position today and let me just go through it. You look -- you see it on the right-hand side. So right now, we have Ozempic and Rybelsus really driving growth in the market today. Clearly, we need to grab that opportunity, invest in it and succeed on that opportunity. Then on top of that, we have obesity care. You heard that from my commercial colleagues also. Obesity care, we have Wegovy, we have Saxenda and we have a significant unmet patient need on a global scale, 650 million people with obesity on a global scale. And we have a great product with Wegovy. And then further out, we have the rare disease opportunities. You heard about [indiscernible], you heard about concizumab, you heard about Segro. So clearly, a growth opportunity in the medium term for our rare disease franchise in the medium and long term. And within other serious chronic diseases, you heard about celsivecumab, you heard about NASH. You heard about Alzheimer's in the breakouts, so also fantastic growth opportunities for Novo Nordisk to invest in today, to benefit from in the medium to long term. And talking about the long term, that is where we started out this morning. With the growth momentum we have currently in the short term, in the medium term, we have the perfect opportunity to step down -- or step up our investments in R&D. And we also have the obligation, we have the responsibility to be investing in R&D today so we have sustainable growth not only in the [ 20s ], but into the [ 30s and 40s. ] And that's what, especially Marcus and Martin explained early on. So investing in growth today, investing in platforms today so we are able to drive growth after [sema LOE] that we do through our research technology platforms. And in terms of rare disease, adjacencies research technology platforms, it's important to understand and that was clearly explained today, these investments, they are not happy-go-lucky investments. These are carefully thought-through investments where we are looking at what are our capabilities and our infrastructure today, what disease areas are we in, what are we capable of doing and what's a risk-based approach in entering adjacencies in a rational manner. As the CFO, part of my job is also keeping score. So one thing is talking about strategies, talking about the future, talking about the [ 30s ], that's also important, but I'd like to kind of understand where we stand today. And so I had the team do this, I'd say, a fairly simple slide. And it's basically a benchmark compared to competition. Over the last 3 years, we pulled out the COVID vaccine manufacturers because kind of their numbers are significantly impacted the last few years. But when I look at our performance over the last 3 years, look at sales growth, 3 percentage points stronger than the industry at large. Our margin, 42% operating margin. And I think right now, it's also at the right point in time to remind you, these are based on clean accounting, so these are not adjusted core earnings kind of whatever kind of metric. This is a real deal. What you see is what you get. This is our pure operating margin, IFRS-based. And then our continued capability of converting our earnings into cash flow into capital allocation to shareholders, you see us returning 88% of our net profits over the last 3 years compared to [ 70% ] of that of the industry. So that's the financial discipline that's very, very important to us. And talking about financial discipline, then I would be remiss if I didn't talk about return on invested capital. I didn't put it on the slide. But just to remind ourselves, last year, return on invested capital, 69%. You benchmark that to whatever companies you're looking at, I think we're pretty competitive in that respect, if not a clear #1. And sorry, this might be a little bit too bragging but I just wanted to bring this 2 decades at least, I know Miss [indiscernible] is going to enjoy this slide, 2 decades of capital allocation to shareholders. Look at this, DKK 400 billion of capital allocation to shareholders over the last 2 decades. More than DKK 200 billion returned to shareholders just over the last 6 years. And assuming approved by the AGM a few weeks from now, our dividend per share will have increased, for now, 26 consecutive years. So just another testament to our financial discipline in terms of driving performance, focus on cash and ensuring that we return cash to our shareholders. And talking about cash conversion, you know our principles take our net profit last year at DKK 48 billion. Our free cash flow last year was DKK 29 billion. But of course, we had an impact from the Dicerna acquisition. So if you take the net cash impact from Dicerna and add on to our free cash flow, then you actually get to 100% cash to earnings conversion. And of that, we returned DKK 41 billion to shareholders. And our ability to do so is based on premise and that's a slight change compared to when we were here back in 2019. So now we're investing more in our pipeline also based on business development activities. And what we are doing in terms of ensuring continued allocation to shareholders in terms of cash, then we are able to access the capital markets through Eurobond issuances. So we continue with an attractive capital allocation to shareholders, then we take on some debt on our balance sheet. We took on EUR 1.3 billion worth of debt last year. It's the first Eurobond issuance in the history of Novo Nordisk, actually in the year that marked our 14th year on the New York Stock Exchange by coincidence. And we did so at an all-in interest rate of 0%. So clearly, also good from a WAC point of view. And our capacity in our balance sheet, and I didn't bring all the numbers, but do bear in mind, when you look at our gearing, then we have a net debt-to-EBITDA ratio of around 0. And with our current credit ratings of AA, then that yields substantial capacity for further business development activities without impacting our credit rating by S&P or Moody's. So you should expect going forward that when we do major business development activities, we will be accessing the debt markets and thereby also accessing an attractive cost of capital while returning capital to shareholders. But coming back to our resource allocation, now I'm just going to go through some of our main P&L lines in our P&L. So first of all, commercial investments, we call sales and distribution costs in our functional P&L. The very simple story is, as I said before, we have a fantastic growth opportunity ahead of us. So what are we allocating our commercial investments against? Guess what? Rybelsus, Ozempic, obesity, including Wegovy towards 2025. That's how we're going to drive our business. That's how we're going to capture the commercial opportunity with the assets we have at hand today. The investments we're going to do will increase at a slower pace than our top line, given the attractive top line profile we have. And as a consequence, you should expect, towards 2025, that our S&D ratio to sales will be gradually going down towards 2025 compared to the 26-point-something level we are at today. In R&D again, the main financing of our increased R&D investments come from the increased top line. So with the top line growth we are having, we are able to step up R&D investments significantly even without increasing the ratio. However, given the outlook we had and what I explained before, then you should expect us to -- actually to increase our R&D investments even further than our sales growth. So we will be adding more into R&D, investing more into R&D incrementally than we've ever done before. And we do so to create assets, to create opportunities and optionality for the long term for Novo Nordisk. And as I said before, this is not something we do in a happy-go-lucky manner. We have a very thoughtful approach. And just to reiterate, our approach is, in research, which is to the tune of 1/3 of our R&D investments. Of course, it's changing by year. But if you take our research investments, we have a very thoughtful approach where we look at the different technology platforms, whether it's proteins, peptides, RNA, stem cells, et cetera, and then we're looking at the premise and maturity of those platforms and the return they're able to give. So put very simply, and Marcus showed it, then that now is the time to step down on RNA. And the commitment is to have [ 3 first tumor ] doses on an annual basis from that platform going forward. So that was basically the rational premise for stepping up our investments on the Dicerna platform. Within development, the other 2/3 of our R&D investments. Again, we have a very rational, thoughtful risk-based approach where we have a staged gate approach. So it's not like Martin just gets the 2/3 of our R&D investments and then just run. So of course, we are making formal decisions at start of Phase II and at start of Phase III and basically assessing these investments when we go into -- whether it's our classic areas or adjacent areas, we are looking at the unmet need and the business potential and the cost and probability of success of going into these areas. So it's a very rational approach and it's also a very rational decision from our perspective to be stepping up R&D investments. And as you see here in this slide also, and you heard it from both Marcus and Martin, efficiency is not something that only happens in manufacturing. Efficiencies are also something that we're pursuing in both research and development. So in research, you heard Marcus talking about speeds from pre project into first tumor dose. You heard Marcus talk about reducing the cost for first human dose. And we have similar metrics for the development organization doing benchmarks on an ongoing basis compared to that of the industry in terms of what's the cost of running clinical trials and what's the cost per patient here in clinical trials. So efficiency is also very much in fashion in R&D. And talking about efficiencies, I just want to share just a couple of very concrete examples around how we drive efficiencies across the company. The first 1 is our global business shared service center in Bangalore and India. And here, we're showing the step-up in growth in terms of FTEs in Bangalore and India. So some of you noted the increase in employees in Novo Nordisk on a global scale but part of that increase happens in Bangalore. And that's, of course, a very rational way of running the company because that way, we're taking some of our core processes in the company, consolidating on a global scale, putting it in 1 place, standardize, automate, digitalize, ensuring a very efficient service delivery model across the company. Another way to drive business is through procurement. And what we've done over the past few years is that we have installed a, I would say, best-in-breed digital platform called Coupa. And this platform now we have of our indirect expense, which is pretty much all spent outside the spend going into products and manufacturing, which is handled in a different setup, all that spend -- 90% is now consolidated on that platform. And as a consequence, we have full spend visibility on the main categories, thereby ensuring that when we source whatever services or products, then we are able to make that in a competitive setting during RFPs and securing attractive pricing and thereby getting gearing for the investments and the budget dollars we have in our budgets across the company. And ultimately, that leads to, of course, attractive financials. And the best place to look at it is actually in our admin cost-to-sales ratio, look at that, 20 years and counting, reducing admin-to-sales ratio. Really, really proud about that. So to summarize, towards 2025 in our P&L, broadly stable gross margin, gradually declining S&D ratio, increasing R&D ratio, decreasing admin ratio and net-net, a broadly stable, clean accounting, operating profit margin. So in conclusion, perfectly linked to our corporate strategy, we are pursuing a growth-focused resource allocation. Our capital allocation is focused on meeting in-line product demand as well as maturing pipeline. Henrik spoke about our CapEx, step-up in investments as well as acquiring assets and technologies for our R&D pipeline. We intend to continue our consistent financial discipline in terms of converting earnings to cash and securing an attractive capital allocation to shareholders. And all in all, a broadly stable operating margin towards 2025. So that concludes the financial section. And now it's over to you, Lars, to moderate the Q&A.

Please go up, those of you who have just presented. Now just -- yes. Sorry. So we'll run a Q&A session now covering the 2 operational units, manufacturing and finances. And yes, Michael, do you want to start?

Yes. Michael from Nordea. Two questions. First to the launch of Wegovy in IO. So it is going to differ between countries in IO whether you're launching the single dose or the multi-dose? Because it seems like you are still considering to launch in some countries in the single dose. And then on the second thing on U.S. So Doug, at least in verbal comments last time you had a CMD, you said sort of 0 to 2% for some time in the U.S. and then accelerating growth. And now you don't really commit to a new growth target. And maybe you could elaborate a bit on where you see business going. Is it further -- not acceleration from 13%, obviously, but how do you sort of envision the growth track for the U.S. business?

So Mike, first on Wegovy launch...

Yes. I think the quick answer is yes, Michael, we're going to use both platforms. The message has been that the 2 platforms will give us the flexibility that's needed. That's not any different than what we have done for many of the previous launches within diabetes where we have the product in multiple devices. So that would be the case also. Country by country, we will -- we'll make that assessment.

And Doug, while we cannot guide on individual units, if you can maybe talk a bit to the sources of growth, how you see that develop over time.

Yes. So Mike, what's really important is we want to complete this transformation of 70%, and we aim to do that this year. We think the sources of the growth are primarily going to come from that foundational component of semaglutide, which is going to be in the form of Ozempic, Rybelsus and Wegovy. That is where we're going to drive our growth. We have strong momentum. We expect the momentum to continue into this year.

Good. Yes, maybe we'll take one virtual. Sachin Jain?

Can you hear me?

Yes.

Okay. Great. So one for Doug on Wegovy inflection in the back half of the year. I think you mentioned in your prior comments a couple of hundred thousand copay cards, of which really half were activated. So do you have a good understanding of why there haven't been activations as supply comes back? Do you think that could be a material driver in the back half of the year? Just noting that you've only got 125,000 patients on drug at the moment, so that copay activation could double that? The second one is a real big picture one, I guess, for Lars. I know you don't want to give top line guidance, but I'm wondering if you can just speak to the following. The top end of '21 guide is double-digit despite 340B, VBP, half year of obesity. So why shouldn't we be thinking double-digit growth for '23 and beyond?

So Doug, first on, what's left of activation card? How long can they be used? And is that something that will play into the second half?

Yes. Thanks, Sachin. That will not. We discontinued that program. So the cards that are out there that are out there, we'll honor that. And again, depending upon how many fills, that's a bit of an unknown. We should see that -- really, that should be completed within the next couple of months. And again, those are the cards that we used at launch for what we internally refer to as a bridge program. We still have other support programs. But the one that we used for launch was discontinued, and that should be -- that should wean itself out over the next couple of months.

And sorry, just to add on that, so the cards we're honoring are the cards which were initiated in 2021. So there are no new cards being initiated since 1st of January this year. That's not possible.

Yes.

Yes. And you know that we are not into guiding for '23 yet. But of course, we have tried today to give a feel for the drivers we have. We see tremendous opportunities still in GLP-1 based on Ozempic, Rybelsus, and we are not wholly concerned about impact from tirzepatide. So we think there's a continued growth momentum there. We are just getting going on Wegovy. I think, Mike, you almost said that we haven't seen what it could bring in IO. And of course, that will also carry into '23. We have a strategy of sustained growth in Biopharm. We are approaching a period where we'll also be launching products in Biopharm. Again, that comes, of course, small disruptions like we see with VBP in China this year. And with what goes on in the world right now, it is to be anticipated that there are headwinds from time to time, but we're really, really comfortable with the growth outlook we have over the short to medium term. But you'll not get me to comment on double-digit or not for '23.

Can I make a quick addition to what Sachin mentioned? VBP in China, Sachin, was announced last year but was not impacted last year. So you made a reference that last year, you had VBP, and this year, we had VBP. Actually, VBP in China is only impacting us this year and not last year.

Yes. And repeat next year.

First quarter of next year. Yes.

Good. Richard?

Richard Vosser, JPMorgan. Just you mentioned and referenced geopolitical issues, and they come along from time to time. Any idea of quantification for '22 from geopolitical issues in IO? And then secondly, on CDMOs, could you give us a flavor beyond Wegovy how much CDMOs you have today, where you would like to take that? I presume it's more downstream rather than API, but just some flavor of the proportion of products and how you look to take that in the future.

Mike, first on geopolitical.

Yes. So the geopolitical situations that I'm aware of, which relates to basically now Russia and Ukraine, what I can tell you is that the direct impact of Russia and Ukraine on our sales is around 1 percentage point. The indirect one, no one, I think, would know, and we have to wait and see. The rest of the geopolitical ones, honestly speaking, they come and go, so we've had different ones. So I don't want to start speculating what can possibly happen.

That was the potential direct impact.

And that's a potential direct impact, correct.

And Henrik, on use of CMO.

Yes. The short version of that is compared to the capabilities and capacity of Novo Nordisk, it will be limited, but it will be used for flexibility and high growth in certain time. And then we will consolidate over time with both internally and externally. But if you look at the totality of what we're able to do internally, it's limited capacity compared to our power of our internal factories.

Good.

And we also use it partly for API for clinical manufacturing purposes. So for some pipeline projects, we do use CDMOs.

I think we had a question here. Yes.

Keyur Parekh from Goldman. Two questions and a clarification, please. So the 2 questions are, Lars, as you kind of look at the bigger picture growth opportunity for you over the next decade, do you see obesity being a bigger part of the Novo Nordisk revenue based in diabetes? And if so, kind of how should we think about the time frame by when you get there? First one. Secondly, Karsten, you referenced kind of your firepower of kind of M&A capacity. Wondering if you can talk to as we think about you using that capacity over the next few years, what are some of the areas, some of the kind of stages of assets that you think would -- Novo would benefit from given where you are today, given Dicerna, given kind of the strong growth you have, over the next 2 to 5 years? So just kind of big picture references in M&A question. And then lastly, clarification, Henrik. Kind of when we look at the chart of the sliding kind of cost per unit, which is a phenomenal chart, and we've all seen it over 10 years, just wondering if you can help us think about how much of that is a function of lower fixed cost allocation per unit. Because obviously, your production units have gone up 3x to 4x, so part of that is that versus actual marginal cost benefits that you are driving due to either higher output or better kind of resourcing.

Thank you, Keyur. So we're really losing discipline here. Now we're up to 3 questions, and as a matter of fact, they are broad. And so we have now guided on obesity that we want to get more than DKK 25 billion by '25. And I'm not going to model over a 10-year period how this can develop. But of course, when you look at the number of patients, it's a significant number of patients compared to those who have diabetes. So it's a sustained growth opportunity for us. We have by far the strongest pipeline in the industry. We are building the market. So I'm really bold on obesity, but I'll not get in to comment on the relative size of our businesses. Karsten, on M&A capacity and how we look at that?

Yes. So overall, we have a strategy of what you would call a bolt-on type strategy. As you note, we have the capacity to do so financially. So the way we segmented this basically, as I said initially, we start with our core strategy, our where to play. So that's therapeutic categories that we've just been through during the day. And then we are filtering based on scientific merits of the projects we see within those categories. And of course, then we do evaluation both on scientific merits, financial merits and, of course, when they kick in, sales growth-wise. So with the momentum now, we are not out in the market to buy empty calories, if you will. So we're not out buying top line today or tomorrow. So we are out buying innovation, I would say, in the more early stages of -- for our pipeline in order to secure growth in the medium to longer term of -- for Novo Nordisk across the categories.

Thank you, Karsten. Henrik, on unit cost development sources.

Yes. So the short answer is it depends. But I will say within our core technology of API, process optimizations technology upgrade is extremely important for us. And this is a heavy lift within our unit cost in that area. And that is a close collaboration between our -- the CMC part and manufacturing. And that, we have done over and over during the years, and no one has the setup that we have. Infill finish is more volume-based except for the tablet that goes at the same path as the APIs.

Good. So actually, I'd like to close down this Q&A session, Henrik, invite the rest of the executive management up here because then we can continue, and you can ask questions to everybody. And while they get up, we play a small video. [Presentation]

Good. And with the full dream team onstage, we will continue the Q&A session. I think we had a question over here. Yes.

Carsten from SEB. I got the microphone before, so this is still a question for Lars.

But you can ask anyone, so we can...

Yes, yes. I know, I know, but it's a question to Karsten and the gross margin outlook. If we look 3 or 4 years back, you have had what could be a catastrophic case for gross margin, massive price declines in the U.S. insulin market, a bread-and-butter franchise. That is now gone. It's difficult to get that one more time. On the other hand side, you have the GLP-1 franchise thriving. We can see, Henrik, you reduce unit costs, and you'll be highly dependent on GLP-1 by 2025. So my question is, how will you manage to keep your gross margin down?

Well, so thank you for that question, Carsten, there. So the first part -- or the last part of your premises, we are not managing to keep our gross margin down. Henrik and I, we get up every day to drive our gross margin in the best possible way. And Henrik nicely shared the perspectives around quality, cost and delivery in terms of how we run manufacturing. So clearly, unit cost is a key premise, but even more important is quality and our ability to deliver. So looking towards 2025, the important part is to understand our starting point is north of 80% in gross margin. So we are already among the strongest in the industry of gross margins. And then when we look forward, then yes, we do continue to drive productivity in manufacturing, that will help. At the same time, we also do have a new factory coming online in Clayton, North America. We're just in the final stages before we're shipping products out of that factory. So of course, that will have some impact on our gross margins to have depreciations and operating costs from that factory. Then we do have price. As another example, VBP in China, so even though you could say, then we had low exposure in some areas, then we do have VBP in China. So there will still be pricing pressures in different geographies and then, as you say, yes, a positive product mix. So net-net, that's why we say we do see a continued broadly stable gross margin at this very attractive level in the first place.

Thank you, Carsten. And we'll continue virtually with Wimal. And you have your microphone down, I can see, so we should all be good.

Yes. Wimal Kapadia from Bernstein. So you mentioned earlier in the day generic entry of DPP-4s and SGLT2s would have an impact on the market. So maybe you could just elaborate on that a little bit, please, particularly in the U.S. So what is your base assumption for the impact to the GLP-1s, both injectable and oral from SGLT2 generics? And just curious if you think step edits is a likely outcome. Just given SGLT2s offer quite a number of benefits beyond blood sugar, and they'll probably cost about $1 a day, just thinking if step edits are likely. And then my second question, I know you didn't run the trial in obesity in children, but that represents about 20 million patients in the U.S. And given that it's best to reset the body weight relatively early, how does Novo think about obesity in that setting? I'm just curious what it is. I appreciate your biggest question is serving adults. But just curious to hear your thoughts.

Thank you, Wimal. First, Doug, on how do you see kind of pricing impact and potential stabilities from DPP-4s and SGLT2s in the U.S. context. And then, Martin, you can perhaps talk to obesity in children.

Yes. Wimal, it's a good question, and thank you for that. I mean I don't want to predict if there will be a step-out or not. I think we're too far out from that, I guess, and it could always be a possibility. Anytime there's a generic entry, it's certainly going to put some pressure on the category. But again, I think we have a portfolio of products, and we've learned how to weather some of these. So I think we'll be well positioned and ready.

Yes. And on obesity in children, I think I would like to share this one with Camilla because I mean there are 2 aspects. Obviously, one is being treatment with Wego in children. We're pursuing that as we speak, conducting a clinical trial. We do believe it to be very, very important. But maybe even more importantly in the long term is to look for prevention of obesity starting specifically in children. And maybe you want to put a few words on that.

Only that we have actually just started that, and we are working on finding ways to -- we talked about Latin America earlier, in countries where the prevalence is really high, to see what can we do to bring down obesity. And hopefully, that will have a spillover impact on more countries. So that's definitely something that we are working on, but both are important aspects of it. We also have, of course, now for adolescents, indications for Saxenda already. But we continue to pursue obesity in children because that is important for the future.

Good. Thank you. Yes, Simon?

Simon Baker from Redburn. A bigger picture question on the pipeline if I may first. How do you see the risk profile of the pipeline? And I don't mean risk in terms of likelihood of approval but likelihood of commercial success. You touched on something earlier this morning, Camilla, on moving into areas which are certainly more crowded but where you think you have differentiated offerings. So just to get your thoughts on the overall risk profile of the portfolio in the future compared to where it's been in the past. And then secondly, a quick ESG question since I don't think we've had one yet today. Going back to the pen return scheme, having looked at the website earlier, it looks like you're getting, what, about 23% return with no incentive. I just wonder why you didn't emulate the Danish bottle deposit scheme, which is one of the highest return rates in the world at over 90%, and if there's a scope for sort of doing with pens what Denmark has done with glass bottles?

Thanks, Simon. So Camilla, first, on pipeline and how we see the risk profile of what we're now aiming for delivering and then why not a return scheme with actually financial incentives on our devices.

Yes. So first on the -- how we manage the risk, so basically, what we are doing is to try and model what is it -- what are the investments required also from a commercial point of view the next 5 years in the new areas that Martin and I spoke to. All of these investments are clearly laid out and depending on trigger points. So we are trying to make sure that we invest sufficiently but not overly depending on when we get clinical trial results. Then at the same time, as some of us talked about in the workshops, we are -- or breakout rooms, we are, of course, looking at also how can we start already now collaborating on screening and on diagnostics because that -- in most of these new areas, very, very important for actually releasing the full potential. So we are working on all these parameters already. On the take-back program, actually, we've now started this in Denmark and rolled it out to full scale. It works with multiple partners in the Danish environment that all were happy to contribute to this, being diabetes care association, logistics providers and others. So there is already a multi-fashion partnership around this. What we would like to get to at some point is an industry solution, a solution where someone, probably not us, can make something out of making this happen just like you see with bottles or you see with cans because it's not worthwhile for us to run a take-back program as such unless it's an industry solution. So slowly in Europe, we are now embarking on that in European Industry Association to have a look at how could we possibly work together on something like this because this is in the interest of everyone and not just us, and we want it to be easy for people living with chronic diseases.

Thank you. Yes.

Eric Le Berrigaud, Stifel. Two questions. First, we end up the day with one major change into your guidance as being obesity coming from doubling in sales to over DKK 25 billion. The difference is about DKK 15 billion in about 3 years, and it's maybe difficult to understand how those DKK 15 additional billion in sales in 3 years are not translating into additional growth for the group or any additional operating margin. So can you help us understand how this is absorbed over the next 3 years in other lines like R&D or others? And the second question is on biopharma. In the past and still today, biopharma is having margins above the average of the group. With difference in mixes and new products coming, is it fair to expect this positive difference to stay if we put ourselves in '25, for instance?

Thank you for those 2 questions. So first, Karsten, the stronger growth in obesity, how does that translate into, say, P&L and margin?

Yes. So clearly, the increased outlook for our obesity care business with the step-up you talked to, that is, of course, additive to the growth outlook compared to 2.5 years ago when we had our last session. So top line, everything else equal, is stronger than 2.5 years ago for sure. And then you say, so what about our P&L and our margin? And there I'd say, so first of all, what we've seen in the last 2.5 years, first of all, we've seen additional uptake in international operations across a number of markets. And we've seen the profile of Wegovy from our clinical trials, which was not seen at that point in time. And we've seen the initial uptake in the U.S. of Wegovy. So based on those data, that has made us even more intent in terms of investing and driving and building the anti-obesity agent market on a global scale. So we will be investing more based on the current outlook, basically linked to the opportunity we have at hand with Wegovy and the market that we're seeing starting to unlock. So we are more bullish and thereby also investing harder than we were 2.5 years ago. And then we're also stepping up our investments in R&D, as I went through before. I think it's a key responsibility for this team to be able to build a pipeline that will take Novo Nordisk into the next -- to the coming decades. We'll be celebrating 100 years anniversary next year. And hopefully, 100 years from now, we'll have been having a fantastic ride with a fantastic portfolio.

That's a forward-looking statement. Ludovic, you showed some fantastic data, and you also showed that rare disease has a nice margin contribution. So how do you look that -- look at that going forward as we both invest more in the business but also have an opportunity to launch some exciting products?

Exactly. I think this kind of margins is typically the features of what you see in the super ultrarare specialty care or rare disease sector. So this -- you rightly pointed out that way. Now of course, we'll have some launches. We have to increase the level of our development. And you saw the plans from a development perspective. But I think it's fair to say that from a -- give and take, the highs and lows of years when you launch, et cetera, the idea in the long run is indeed to keep that feature, the very attractive feature of the rare disease business to the benefit of Novo Nordisk. But again, it will change 1 year on the other based on what we launch. And as you can see, we have 3 products to launch for the next couple of years. And that, of course, can generate some investment from a commercial and medical perspective. But long term, I think it's a fair assessment, it's a fair assumption.

Good. Thank you. Yes, a question here.

Harry Sephton from Crédit Suisse. Two questions, please. So the first is just on your plan to increase R&D as a percentage of sales. So if you do have upside to sales growth, do you expect to reinvest that in R&D? Or are you more fixed on your R&D costs? Or could we see some operating leverage? My second question is more on U.S. rebating. So I think from the data that we contract with IQVIA, you can see that you're already seeing quite high levels of rebating on some of the GLPs or on Ozempic. If you see tirzepatide coming into the market, what do you expect to see in terms of rebating? And could you see potentially some payers excluding Ozempic? Or is that something that you can envisage with payers excluding Ozempic? Is that a threat?

Good. Thank you. So Karsten, first, on the ability to flex on R&D spend based on underlying performance.

Yes. So first of all, it's not a simple mathematical that if you change one parameter, then kind of everything else is automatic, then we will have also a smaller finance function. So our starting point is, of course, that what we invest what in R&D, both in R and D, we invest in those 2 areas based on the premise that we believe we're able to generate attractive returns. So in reality, of course, it's a function of our investment capacity overall, but the core starting point is whether we believe we can make an attractive return on the investments we do both in R and D.

And Doug, on the U.S. rebating, first, the point that we're already giving a good level of rebates and the strong momentum in Ozempic. There's a competing product coming. Do you see a major change in, say, access environment because of that?

Yes, it's a good question, Harry. Thank you. So in the end, we -- as I mentioned earlier, we have 95-plus percent access for Ozempic. And that is enabling us to commercialize our products. So it's investment that we make every year in these annual renegotiations. And we'll need to continue to make investments so we can maintain the appropriate level of coverage. We've had a stable competitor in that environment. And I think from a Novo Nordisk perspective, we certainly believe in open access. It's better for patients, it's better for physicians and their choice, and it's certainly better for us, and we like to compete in that. So I'm not sure what will happen with them. Let's see when they're approved and what will happen in the marketplace. And it presumably will happen midyear. And so I don't know, again, what will happen, and I don't want to predict that at this point.

But we're clearly really pleased with the momentum of Ozempic, what patients get out of it. It's a go-to product for physicians. More than half of all patients on the high dose, which will be the medium dose so far. So it's really the product you can just as a physician go to, and it takes care of what you need, and there's room for intensification. So we're quite confident in our ability to compete based on that. Are there any final questions? Yes.

Victoria Campion from Varenne Capital Partners. Just a quick question on the Wegovy composition in gender. Looks like there are a lot more women than men, to the tune by 80% women. Just curious, is that a problem among uptake or among awareness in men? Is that something that might stop you from maybe reaching your total addressable market in the future? And is that maybe what your awareness campaigns are more focused on? I've noticed one in Paris, but it's definitely got a woman on it, not a man. So just curious.

Yes. Camilla, would you like to talk to that?

Yes. So when we look at the real-world evidence that we see now is, right, that around 80% are women, and at this point in time, that's not necessarily an issue or our biggest concern because as we saw earlier, the unmet need is so high, and there is an underlying need for this. But of course, the more we can inform people about that there is help to get them all without having any gender bias, I guess we will get to everyone at some point in time. So we do see that a lot of information is shared also on social media in the U.S. from people on what are their experiences. And this, of course, in itself is also a way that people inform each other. So not a primary issue or focus for us for now. We're still a long way from having -- getting -- have gotten to everybody, unfortunately.

Good. Is there a final question? Yes. Keyur?

Just kind of perhaps a big picture industry question for you. Kind of we've gone -- with everything going on, kind of you've almost forgotten COVID. But the industry has played a massive part in coming to the help of various governments around the world. The charts you guys showed earlier today showed insulin pricing down 86% on a net basis over the last 5 years. And yet from a public perspective, every time we hear about insulin, it's about how bad insulin pricing is. So just wondering if you have thought sort of big picture industry level what the industry can do to take some of this pressure away but also be recognized more positively for all the good that it does.

Yes. Thanks, Keyur. It's a great question. I think in general, in the, say, industry network and association work I participate in, I think there is acknowledgment of what our industry is doing also from politicians. I think there's been a lot of discussion, for instance, about intellectual property rights. I generally believe also policymakers understand that it's a fundamental requirement for innovation. Sometimes you hear rhetoric that comes out a bit different. But when you actually sit with individual politicians, I sense there is a general understanding of the importance of that. I think the same goes a bit for drug pricing also and, in particular, insulin pricing because when you sit down with individual politicians, you actually explain how the market works. The fact that we actually get less and less for our insulin in the U.S., the fact that our, say, overall pricing for insulin in the U.S. is actually similar now to what we get in the rest of the world, that's actually also acknowledged. But of course, if you're a policymaker and you are facing a hugely complex health care system, and the population expects from politicians that you can actually change the complexity of that in a way that it benefits patients, sometimes you have a need for articulating the problem as it's seen by the individual patient if you are in a situation where it's really, really hard for you to change the system. So I think some of the rhetoric that comes out from a political point of view is political, and it's talking to the population where actually, when it comes to making policy change, there's actually more, say, a fact-based approach to it. And I believe we will keep having intellectual property rights as an industry. And I also have my doubt that there will be major health care reform because basically, when you look at this deteriorating insulin price in the U.S., that comes from the backdrop of significant rebates actually being passed on into the system and is actually funding the delivery of health care. And if you instead pass that on to patients, there is a funding gap for the health care system. So it's hugely complex. Our role is then to make sure that we help the most vulnerable patients. So I feel really good about the affordability programs we have put in place and the patients we help. And as I think we heard earlier today, nobody should be without insulin because you can actually contact Novo Nordisk, and we'll help you get access to emergency supply. So then you can say, okay, why are we not getting that message across? Maybe we can do better, but it's not always what the political system actually wants to hear because that means that the task moves to them in terms of changing the health care system. I have to stop here because I can talk about this for ages, and then maybe we can do it over drinks later on. So I actually expect there'll be a relatively stable environment for us to conduct business in also in the future. With that, I'd like to thank my colleagues for great presentations and being with me here onstage for the Q&A. So please take a seat, and we'll try to wrap up the meeting. So our aim today was to share with you how we are making solid progress on implementing our strategy and in the form of delivering on the strategic aspirations we set out at the Capital Markets Day in 2019. And I hope we have gotten across to you that we feel we're doing good progress on these ambitions. There's a united strong team behind it, and we stick to our aspirations as they are with the only caveat that we are now lifting our ambition level on obesity. The previous ambition level was set before we saw the clinical readout for what is now Wegovy, and we have seen a tremendous uptake. So we lift that to more than DKK 25 billion by '25. Easy to remember. My aim was also that we should share with you the unique opportunity we have for driving short-term and medium-term growth based on our portfolio within diabetes, both for insulin and GLP-1 and how are we unlocking the obesity opportunity based on GLP-1. We have also put in rare diseases here. I hope you share with us the excitement of how the rare disease pipeline is moving forward. I think Martin used the word outstanding. We're really excited about what we have there. So that's going to fuel our short- to medium-term growth. And while we deliver on that, I hope you also sense that we have one of perhaps the strongest late-stage pipeline in the history of the company. I hope you agree that we are making thoughtful investments in advancing our core capabilities, expanding them, complementing them with new technologies, which really creates an opportunity for us to continuously build a pipeline for the future and in a thoughtful way of taking a few steps away from the core, also diversifying Novo Nordisk. So thereby, I will not promise for the next 100 years but at least having a really, really long perspective on how we deliver growth. And that is all about living our purpose, that is about driving change and getting to more and more patients, and it's all about being a sustainable company. So thank you all for your attention today. This will close the meeting, and Karsten will wrap up with a few practical comments. Thank you very much.

Thank you, Lars. And also a big thank you from me for all of you taking time to either come here in person or sit in virtually for a very long virtual session. So thanks for enduring that. We hope it was worth the time and investment on your side, and you're able to make your personal return from this. At least on our side, we truly appreciate your investment in coming here and engaging with us. On practicalities. So first of all, you will be receiving a questionnaire from Investor Relations about just the classic feedback on our CMD. What can we improve? Any observations you have? It could also be feedback to us on our strategic choices. That's one. And of course, IR is always there. In case there are any questions that were not answered today, then do not hesitate to reach out to Investor Relations. So that concludes the formal part of the program. And for the people in attendance, it will be our pleasure to invite you to a drink and a snack just outside here. And for the people not here, have a great rest of the day and hope to see you around on the road somewhere. So thank you so much.