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. 2.5 years has passed since our last Capital Markets Day in 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. We're also going through a period with first a pandemic and now war in Europe. 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. I would actually like to start this meeting by focusing in on a patient. I would like to invite you, Lisa, to come to stage here with me. Thanks for being here, Lisa.
Oh, thank you. Thank you
Traveling all the way from the U.S. to be with us today.
Thank you for inviting me.
You have been living with obesity a significant part of your life.
Yes.
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. It was difficult is an understatement. I had tried everything I possibly could to lose weight, gain back, lose weight, gain back, you know, the yo-yo everybody has heard about. I heard about the trial, and I got on the trial, and it changed my life. For the first time, I didn't feel crazy that I couldn't. It 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. Thank you, all of you, who had all to do with that trial because it truly changed my life.
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.
Mm-hmm
That would allow me to speak about such a personal, you know. Obesity, everybody sees it, but nobody talks about it. 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, you know, it's obvious.
Mm.
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. 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, but perhaps also a bit how, you know, the rest of the world..
Yeah
..looked at you?
Exactly. It took many years till I found a d octor who believed that it just wasn't a lack of willpower, that it was an actual physical, chronic disease that I have. Talking with her, she introduced me to the trial and very much supported and said, "This is a chemical. There's something in your brain that isn't quite right. This trial will help you with that." Part of me was skeptical.
Mm
because I didn't wanna put too much effort. I didn't wanna put too much belief in it because it was kind of the last straw. 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." Nine times out of ten, they themselves are obese. I'm like, "That doesn't seem to make sense, but okay.
Can you tell a bit about when you sta rted using?
Yes
You know, what did it do to you?
You know, it was as I said earlier, it was like a switch was flipped. 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. It was like, as I said, it was like something had
Mm
...had changed. Then when I went off the trial, and I was off the trial for probably two weeks, and I had a very, very emotional experience because I felt those cravings, and I felt that desire come back. I was like, "This isn't right. Like, I can't go through this again." So I went back to my doctor. I'm like, "You gotta do something." 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.
Yeah.
You know, 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.
Mm.
You know, I would hate to say normal, but I felt normal.
Sure.
That it wasn't such a big deal anymore. Using the drug has been beyond easy. Again, thank all of you for everything that you do, whatever role you play.
You can still find products in the U.S.?
Yes. It's been a little tough.
Yeah.
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. I like to. I kinda think like it's because of me that everybody is wanting it.
Sure
I will. It's slowly becoming more available, and I hope more doctors and more health professionals learn about it, and I hope more patients discuss it with their
Mm
healthcare professionals the possibility of getting on it 'cause
I can promise you we'll keep working.
That's nice.
hard at it.
I appreciate it. Again, it's just
Yeah.
It's wonderful. Thank you.
Lisa, thank you so much for being here and sharing your experience.
Thank you again, Ed, for inviting me.
You are a great inspiration to all of us.
This is truly an honor. Again, thank you all.
Okay. Thank you very much. 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. The notion of driving change is something that's really important for us. It's about both focusing 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 values, 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. This is a cornerstone of our corporate strategy, and we have these four 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 and building 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 do in Nordisk is biopharma. We said, "Okay, let's be a bit sharper on the terminology." Going forward, we'll call it rare diseases.
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. Then we have the other serious chronic diseases, areas where we, based on technologies, adjacencies, think that it's obvious opportunity for us to explore, to diversify into areas like cardiovascular disease, NASH, and others. At our Capital Markets Day in 2019, we introduced our strategic aspiration for 2025. 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.
Both when it comes to purpose and sustainability, when it comes to innovation, 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. I would like to share one slide about how we have managed to accelerate our sales growth since we were together in 2019. 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.
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. 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 four 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. Then in the afternoon, rare diseases and other serious chronic diseases.
We home in on the financials, how we're executing in our two commercial operations, what's our perspective on product supply, and what are the financials. You can see that throughout the day we have made ample opportunity to have dialogue with you. There are a number of Q&As. There are a couple of breakout sessions, and we end up with a plenum Q&A. 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 slides here. 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 preach.
With that, I would like to hand over to Marcus Schindler, our Chief Scientific Officer, because it's all about the science we have in the company. Over to you, Marcus.
Good morning, good afternoon. It's fantastic to be there. 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. It's fantastic to actually, you know, have you here in person, but also that 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 four years ago. Actually, initially, I came in to help lead external innovation and bring more collaboration, more partnerships to Novo Nordisk.
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. 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. 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. 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. 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. Obviously, we have advanced on this position significantly. 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 three pieces. One is detail our approach to drug discovery. There are things that, you know, remain and we continue, but there are also new elements that we're building 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. Last but not least, I'll share some commitments we'll make with you and some expectations you can have on us. Of course, everything I say is future-looking and might not happen in the way we anticipate. Why we're here, right?
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. 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. For those of you like me old enough to remember in the early 2000, it looked rather bleak for diabetes care. Since then, we have many, many more offerings. Look at those numbers. We are only serving a fraction of people who are actually in need of care, and I think that is something we want to change.
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. 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. I'm actually gonna 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. you know, we started out thinking that would be a powerful glucose-lowering agent, and yet it has proven to be, you know, 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?
That was our starting point, I would say, a number of years ago. It's been very successful. I think we understand much, much more about this molecule than we ever did before. I think it's also fair to say it has been an iterative process and one that has run probably the better part of two decades. What if we put this biological inquiry, this deep understanding of molecular mechanisms at the very start, and we make our discovery biology-driven?
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, you know, 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?" We'll come to some of, some of those examples later. 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.
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? I would say the results are mixed. Yeah. Some mechanisms actually translate beautifully, even in a quantitative way, but many also don't. 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. 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 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, you know, 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 hypotheses for drug discovery.
We're now in a position largely through computing power, but also through a collection of, you know, what everybody calls big data, to interrogate those systems much, much better and much more detailed. I am actually a great fan and very, very, interested in what we call polygenic risk scores. It's not a single gene that will drive whether you become, have a propensity to become obese or have 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. 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.
Imagine we start building 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 we're lucky we had pronounced defects, but sometimes we also saw a large heterogeneity in our response. Really strong responders, but also people who didn't. Let's try to disentangle this at the very beginning, make it hypothesis-driven.
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?" Of course, you all know us as a company that is leading in peptide and protein therapeutics, and that will not change. 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. We've also expanded our toolbox significantly.
We now have siRNA therapeutics to block intracellular targets, we're engaging in cell therapies, and we're making actually first steps in gene editing and gene therapy, largely for the benefit of rare diseases. Everything you see here has the potential. While 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. 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. Yeah.
We've, I think, been you know, very, very good to make precise molecules that do exactly that. Now, through some analyses, actually transcriptomic genetic analyses, we realize that this number of target is actually a fraction of the entire target space. The vast majority, 21,000, sits within the cell. We can't easily address that with our technologies of peptides and proteins. How do we deal with this? 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. Once it's there, it does a pretty cool job because with extremely high precision, it knocks down a particular gene.
This gene is knocked out for a very long time, three, six months after a single injection, but it's also reversible. We're not actually altering something fundamentally here in the genome. It gives you an opportunity to be safe, certainly well-tolerated, but also extremely long-lasting. 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. 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. This is a molecule that hits a specific receptor on hepatocytes, on liver cells. The siRNA molecules can piggyback on what we call GalNAc.
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. 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. We're doing exactly this. 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.
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. 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. We're actually making highly specific molecules for the cell type in question, right, which also don't burden the system as much.
I hope you can sense I'm very excited about this technology, and I better be, because we've made a commitment on this. It was also an interesting journey. We had a productive partnership, so we had nearly two years actually to get together as partners. I really want to call this out because it's important. It was not us assessing Dicerna only. It was vice versa. You know, can a small biotech actually work with us? Do we have the right attitude to partnership? Are our competencies in this partnership and collaboration actually clear? Are they tangible to the biotech partner? 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.
This is obviously something we will continue. Why we were productive, because we set out in 2019, and we actually started formally the first project early 2020. This year, those molecules were under clinical development and having first time in humans. Less than two 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 timelines 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. I think for every—if I can't think of anyone, every target—we made those molecules together. That's what I would call a scalable and reliable platform.
I would hope that you actually see this. Some might have called it a bold move. I think it's actually a logical move and a very rational move to complement our technology platform with this. Your next question to me might be, I mean, you've never actually integrated a biotech company in the last 20 years or something like this. You know, are you not worried that you're basically destroying the value? 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, I don't think we've talked about this a lot, is a concept that we call Transformational Research Unit. 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, you know, swallowed up or slowed down? Some companies choose spin-outs. We actually choose a spin-in. We created a unit with high autonomy, with a ring-fence budget, with very clear purpose and leadership, while being embedded in our purpose and our quality systems. 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. We measure them entirely on output. The output for the Dicerna TRU will be roughly three 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. I think we have good evidence to believe that this will be the case. Of course, it will penetrate and affect all our disease areas. Let me give you, change tack a little bit. I think a super exciting example of pro-protein or peptide therapeutics innovation. One question I think I often get also internally, are we done with insulin? I mean, is there really anything left to do? Right. You see on the left-hand graph, 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.
You all know insulin does its job to lower blood glucose regardless of where the blood glucose is. Right? It's a very powerful molecule, but somewhat unintelligent, right, if you provide it exogenously. That obviously carries the risk of hypoglycemia, right? It requires frequent blood glucose monitoring. What if we were building 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 normoglycemia and have a safety buffer built in that you're actually not dropping below normoglycemia. That is the value proposition of what we call the glucose-sensitive insulin. We've actually, after years and maybe even decades of research, now put the first molecules in humans. 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. You will, by the way, see more and more of this. We are not building 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. 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. Yeah. That will happen by the end of the year. I think by that, we'll have very exciting data to see where we take those molecules next. 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, you know, high-fidelity glucose sensor. It's actually not only a sensor, it is an active switch. Another example here in obesity, right?
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. In the early 2000s, many of our peers walked away because they felt obesity was so difficult. The regulators set this incredible hurdle of 5% weight loss. Yeah. We're looking back, and I think we're smiling a little bit about this now. Yeah, 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 a GLP-1 molecule.
Imagine for a moment we combine those two 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. To give you a bit more icing on the cake, we're not making that an injectable, but we're making it actually an oral molecule. That is a reality. 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. In the title, it's cell therapy and it's collaboration because I think it's really important. 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 wanna highlight two particular example, and we're gonna double-click on those in the breakout session a little bit, Heartseed, and BioLamina in Lund. 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. The world is open because these are pluripotent stem cells. In theory, and actually in practice, we can make cells 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, 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. 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. We're actually thinking about commercialization even today, about commercial models before we have the first time in humans. 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. I think this is the winning formula. Human data will be informative, we're learning, and it's exciting.
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. All right? This is where the place is. 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 learn from it. The next iteration will be to actually put this in a stent.
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. 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. This study will also start in the first half of this year. I hope you're seeing 2022 becomes a year of starting. Cool to even see results. 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 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 building a physical phase I setting, not far from here. This is the place where we will test hypotheses. We will spend significantly less time in a 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? I'm not saying that is true for all disease areas. It might not be a reality for everything what we do, but this is starting. Right, it's also starting for us. Making molecules as fast as possible, building new hypotheses, putting them in human, you see much higher throughput in first time in human testing. 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. 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.
If you remember what I shared with you about precision medicine, hopefully we're actually gonna load the dice and have a higher probability of success. 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 that we are building on our strength. 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. Yeah, we're not leaving that, but we're actually expanding this foundation. 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. It's not just hot air.
We will have concrete example this year out of our new technology platforms to substantiate actually the claim that they will be an important benefit for our future. Of course, with that comes an increase in research productivity, a significant reduction in timelines, cutting it to a third of what we're now having, and a significant cut in costs. 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.
Welcome to this session about ESG, environmental, social, and corporate governance. It's my pleasure to talk a little bit more to that together with my colleagues. 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. 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. That together gives us an opportunity to focus both on the short term, but also on the long term of driving a sustainable business.
What you see on the right-hand side here is the way that we focus on being a sustainable business. It really has three elements. Something we've 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. When we add that all up, that's what we call driving a sustainable business. That's what we will be looking into today. 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.
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. Then we'll be looking at how we drive our business as a sustainable employer. Finally, how we report on all of this, because that's a field that is developing a lot in recent years in terms of ESG reporting. With that, let's just get into it, and we will start with a focus on our environmental strategy. 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. Look at our environmental strategy. 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, 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 three buckets so that we understand how what we are driving and which kind of aspiration we are setting.
First of all, in this ever-growing world with ever-growing activities, we thought it was important to state what the end goal is. The end goal is basically to have zero impact on the environment. We want to do that both how we operate internally, but certainly also around us. We have put in sort of three dimensions here. What we call a circular supply is basically us and our surroundings around the company working with environmental activities. That means that we are working actively together with 60,000 suppliers through 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 ourself 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.
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 zero environmental impact solutions for all these compounds that we are using in a global operation. 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 three-tier approach. We are first of all also trying to have a zero ambitions on our emissions. The reason why we have put 2045 on this is that we want basically to have our entire value chain and supply chain to be a part of this. 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. Just one simple example I think we all understand nowadays is just all our company cars worldwide. They must go into CO2 neutral solutions, and that means that we are into a heavy push for electric 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. 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. We have also committed ourselves to help in that way. All in all, we have now seen a reduction since we were together last time in 2019 of 43% of our CO2 emissions, and we will continue this journey in all three dimensions when we move forward. 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. There is a significant activity surrounded by that to get to more sustainable solutions.
Yeah, exactly. Thank you, Henrik.
Yep.
Also on the plastic footprint, we are starting to work on how we address that. We are not as far as Henrik has 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? 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. We need to look at three different opportunities to address that.
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. Maybe over time it could or it would. That's why also we are putting some of these pleas 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. 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.
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? We've now initiated pilots in Denmark last year on taking our pens back, so that could be our FlexTouch, our FlexPens that now can be handed in at 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.
We are embarking on new pilots now in different types of countries, but primarily it will be U.K., Brazil, and also France. At the same time, we are also now expanding the pilot in Denmark to be for the full country. For those of you who live in Denmark, you will benefit from that now. That's a 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, that is defined in what we call Defeat Diabetes. It really has three 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.
We also understand that not everyone gets access to innovation immediately. 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. Based on that's a core element in our social responsibility strategy. Then when we develop the strategy discussing with NGOs and others, it's also clear that, one thing is to solve the problem has happened and much better thing is of course to make sure that the problem doesn't happen. 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.
Let me just give you a few examples on prevention first, and then we can move into access and affordability. 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%. 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 costs, 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 a 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 is access to healthy food, and that there is access to exercise opportunities also. This in combination means that we have very strong partnerships to execute on some of the opportunities to bring down the prevalence of diabetes and obesity. 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. In 2021, as part of our access and affordability program, we helped 5 million people with that.
One solution doesn't fit all. 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 one vial that lasts for about a month. A monthly insulin support to $3 per vial, and that basically means that we've 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 that 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. I think already this year we will be able to add very soon a number of new countries on this program. Just want to reiterate that for these children, there are no alternatives. They don't have access to any other insulin. In every country, there are groups of vulnerable patients that do not have access to medication. Those we are addressing by doing an assessment in every country, who are those vulnerable patients? Of course, they exist in all countries, even in the U.S., which I'll come back to also in a minute.
Finally, in the U.S., our suite of affordability offerings that grows 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. 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. We now have around 1 million people involved or in this program, but actually if we take in the other solution, co-pay cards and other things, it is even more patients that we are addressing with this.
Affordability is one thing for those that are not insured, but also in the U.S., for those that are actually a part of either commercial or private insurance or government insurance, we also have addressed how we work with our list and net prices. Here you see for insulin how over the last five years 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. If we do the same for the full portfolio, you will see that net prices are now index 40 compared to what they were five years ago, whereas list prices is, as you know, a completely different picture in the U.S., with index 122.
This is just to say that there is in the U.S., net prices have declined in the last five 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. 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 will 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. 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 building, education, reach and so on. This of course means that we can help build an infrastructure so that more people can get access to treatment. In summary, a lot of different initiatives because that's what needed to make sure that more people have access.
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. 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. Without our people, none of these ambitious plans would be possible. We are a purpose driven organization. Despite the growth in our company, we're now at 48,500 employees, we continue to have high employee engagement and high employee retention rates. One of the reasons for that is because we have an employee listening strategy. 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, you know, 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. What we're really interested in is making sure that we benchmark ourselves against the most engaged companies. What I'm gonna share with you now is how we fare here. 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 score 94 here, and this is in the top 1% of the most engaged companies. I think this is really a testament to our employees' commitment to our patients, and you know, 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. I think, you know, all in all, we are really listening to our employees, and that's why we get an 81% response rate. 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. 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.
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. That's the reason that we call out these three focus areas. 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 you know, 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.
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. Lastly, we want to be inclusive and diverse. 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. 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.
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. It starts with being an inclusive culture, where our employees have a sense of belonging and can deliver their best work every single day. 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 non-birthing 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. Not least, the most important area in the line of business is local action plans. 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. With this, I'm confident that we will be able to tackle some of the issues around inclusion. 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're incentivized on performance on an annual basis on STI, LTI, management incentives. If not IFRS like financial data, it's SASB, TCFD, and other types of standards we're adhering to when we report our ESG data, but we're linking to the outside world to report in a way that we all understand in a global setting. As a result, we're being recognized, you know, many of the third party raters, so whether it's MSCI, Sustainalytics, CDP, Access to Medicine. We are being performance managed, we're being assessed by third parties, and they assess us really positively. 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. 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. A lot of progress. Defeat Diabetes, Circular for Zero. 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. Then as Monique shared, 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.
With this, we're now moving into our Q&A session, so I'd like to invite my colleagues from the first two sessions on stage. To cover the logistics, during Q&A, I would like each person asking a question to restrain to one question per person, and please state your name and affiliation. Doing so, we should be able to get through the room. I think Michael Novod was the fastest down here.
Yeah. Thanks a lot. Michael Novod from Nordea. Maybe a question to Marcus regarding now you have an amycretin, 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 that also, how do you optimize so you can avoid the significant fasting state after taking a tablet containing either semaglutide or amycretin or whatever?
Yeah. Great question. 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 ago, a year and a half ago. This is what we call version one or simple SNAC, and this is, you know, 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. I might go as far as saying Generation 4.5. So we're seeing significant progress in moving the chemistry and the technology forward. Now, they're 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. We move to Richard Vosser.
Hi. Thanks. Richard Vosser, JP Morgan. Actually, also a question on the amycretin product, as well. 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? Thanks very much.
Yeah, I think that is a great question. 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 clinic. The combination product or the new molecule is superior to the individual components, of course, and we'll, you know, show those data when we're ready to do that.
Thank you, Marcus. We move to Florent.
Good morning. Florent Cespedes from Société Générale. Question for Marcus again. It's a question on the Transformational Research Units. Could you share with us what is the specificity of these units? You mentioned that you are already some which are available. 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? Thank you.
A fantastic question. We started those TRUs when we found science or technologies that didn't quite fit our, what we called, core at that point in time, which also then would meant maybe we don't have the efficient systems, governance setups, or metrics working to actually deal with those technologies. Cell therapy is a prime example. 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. They really think proverbially out of the box on what you can do with peptide therapeutics. We leave them this space to innovate without interruption.
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. Their task is not only to produce to the pipeline, but also to learn, test, and bring back to the larger organization, organizational ways of working. You know, how you give autonomy to more self-forming teams, how you can actually, you know, de-risk novelty in a very smart way. That's what we are actually learning from those units, which is a very important output for us. We'll try to use those concept whenever we see something which, you know, we think deserves, you know, 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. Now we move into cyberspace and to London, I believe. Over to you, Wimal Kapadia.
Oh, thank you. Can you hear me?
Yes.
Yeah. Per,fect. Wimal Kapadia, Bernstein. Apologies for not being there in person. We can blame COVID. Maybe just another one for Marcus. Maybe we come back to you in the breakout session. Just the glucose-sensitive insulin. Now, how are you thinking about the reception to this molecule? I know it's quite some time away, but you know, Tresiba reduced hypos, was met with some hesitation, at least from payers. The absolute rates of hypoglycemia, at least for Tresiba, are rated to be low. I guess my question really is a glucose-sensitive insulin that different? You know, is it a big enough step up in innovation in a commoditized market?
I can speak about the science, and maybe, you know, 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, based safest way we can think of. I would argue, talking to a lot of patients that actually hypoglycemia remain a concern for many people suffering from diabetes out there. It is our task. If not we, who else should drive this science forward to bring those novel molecules forward? Over to you, Camilla, on the positioning.
Yeah, exactly, Marcus. 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. How to get this balance right, of course, is a daily, you can say, struggle for people. Now with our connected pens, we have been able to provide the data on, you know, 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.
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. I think we have time for one last question, Keyur, Goldman Sachs.
Thank you. This is a slightly broad question, which is, Marcus, what you are suggesting today is a very fundamental rewrite of how Novo has developed products kind of moving forward. If you are indeed successful, my question is, what does that mean kind of for everybody else on the podium? 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 timelines? 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 over the injection. 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. I think Lars, perhaps taking it top down based on our operating model, moving into new disease areas and new modalities.
I don't see it as a complete rewrite. I see it as something we do on top of a very strong platform. I think Marcus also mentioned that. 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 oral route, we are building more choices to apply up against the biologies we know really well. I think the go-to-market, of course, if it's a stem cell-based model is quite different. I think it is also quite attractive because you can get to very few centers to reach patients. From a commercial model, it's much simpler.
I think largely speaking, we are leveraging the biologies we know and the market approach we know. We know that we have a really long tail on the products we have. 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. As we look at Novo Nordisk as a growing company, that's what we believe we can handle. It's not a fundamental rewrite. It's actually giving additional options on top of what we have.
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. 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 two sessions and the Q&A. Now it's time for a break. You will be able to corner us somewhere around the coffee machine, management. For the questions not asked, please reach out, and then we'll be back at 10:35.
All right. Welcome back to the diabetes session, which we will now get into. 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. With me on this session, there will be several colleagues, but we will introduce those as we go along. You will recall two 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. Both of these things, we've talked already about the innovation and the science, but we'll get further into some of this now. 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. This of course gives rise to a company like ours to say we have to do more about solving this problem. 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%-50% of people are not in good control of all the people that are being even treated for diabetes. Our approach to this is, of course, to continuously build our pipeline. 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. 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. Ozempic actually has proven in clinical trials to get 80% of people in good control down below seven 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.
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 on for several years in a row. 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. 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.
Then, of course, we have combinations of insulin for those that need more basal insulin in terms of Xultophy and also mealtime insulin in terms of Fiasp and Ryzodeg in the future. Early 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. Of course, the data provides much more information to patients and providers. We know that patients can get two hours more in good control on their insulin if they combine the data from the injection device with the glucose monitoring device.
We are now partnering with more than 99% of the CGM companies for this in a non-monetary partnerships that actually just work so that the data will be shared with the patients and the doctors. 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, the total diabetes market, you see here that between 2018 and 2021, there has been approximately a 5% CAGR on the value growth. 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, growth has been significantly smaller, but also we need to take into account that in the next couple of years, DPP-4 will lose exclusivity, so that's an impact that will also be seen on the total diabetes market. 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.
These are the three 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. This, of course, is around 6 million people treated. 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. Three percent being treated is still a relatively low number compared to the total potential. Here, of course, there is also a potential for continue to do that, and that is a big part of our focus.
To make sure that we just get into that, we will talk about our two operating units in a minute and how we do that. 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. You see here that we are now above 30% on market share, 30.3%, and we are progressing towards our strategic aspiration of achieving more than a third of the global diabetes market share. That is our aspiration. Now into a little bit more on how do we then drive that in our two operating units. Mike Doustdar, I will 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. 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. 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 insulin, 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. We had after 10 years of Levemir, only two market leadership in the basal segment.
We have 20 and ever-growing. Our aim, of course, is to take the 37.7%-50%, which then gives us that absolute leadership we have in the other segments of the insulin. We have Ryzodeg for the markets that have decided to predominantly give a premix 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 a quarter of our patients.
It's about a quarter of our diabetes sales in international operations. 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. It's also a market that gives us a lot of challenges with regards to the risks. We have seen some of that this year with the introduction of the volume-based procurement, the change of the healthcare system, which is taking 3% off of our growth rates in Novo Nordisk. In short, for those of you guys who are not familiar with the VBP, it is really a tender-based system where the government came and decided to reduce the prices of all insulins by around half.
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, which are not part of the so-called VBP platform. 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. 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% of the value of the diabetes market in international operations just a few years back, to now 14%. That is a good growth rate. 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. 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 two are.
That just shows the future for us in international operations. Of course, those numbers are pretty much low no matter which part of international operations, which country you look at. 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 years back. Then in IO, we are able to basically sell close DKK 9 billion of that two, three years after the first launch. We have never, ever seen that in our history. This is really exciting. 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%. We have played nothing, zero, 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 OAD segment, so these are the DPP-4s and the SGLT2s. That's really where we're working very hard to get leadership in due course. When you dissect it into countries, 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. Together with basically 12 other markets, so 13 markets all combined, they give you 70% of the business.
Those are really the 13 markets we are going to put a lot of investments and attention to. 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 good result 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 compliment before to the.
Yeah, it did.
Thank you.
It did.
That doesn't happen too often. Partner in crime. Five years ago, we started on this transformational journey of the U.S. business. North America, but specifically U.S. business. What we know we needed to do was 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. 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 gonna put on our GLP-1 tires. 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. It's been successful primarily in the form of our diabetes products. As you can see here, there's 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're 60%, so we're well on our way to achieving that 70% by the end of this year. 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. 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.
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 wanted to talk about commercial execution and being able to launch products. We had aspirations to get the blockbuster status, if you remember. Ozempic was the fastest product to blockbuster status ever. It's 3+ times that now. I'm going to talk to you a little bit more detail about that product because we're extremely excited. 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. Let me get into a little bit about Ozempic. Ozempic is growing the entire category.
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. It was the workhorse. You know 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. 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 patients on Ozempic today, and we're adding anywhere between 1,000 and 1,500 per week. This was a workhorse, will continue to be a workhorse. It's the product that is outperforming in a growing market of 30%. We're very, very excited about that. What it's also doing is it's changing the paradigm. It's not only putting more patients, and by the way, we eclipsed 1 million patients on this product. Super excited about that. What it's also doing, it's changing the paradigm. As we know, this is a, you know, it's a disease that gets progressively worse over time, and it needs intensification. Patients start on metformin, we know that, and that's what this blue bar represents. Then what happens, they make a choice when it comes to intensification.
What we know is about 15% of those, that choice comes in a non-generic form. Now, prior to Ozempic, 17% of that non-generic form came in the form of GLP-1. What we now know is as a result of Ozempic, it's now up to 25%. 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. 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. 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+ representatives. There's a significant amount of spend. There's been label updates and we did launch into a pandemic. Having said all that, we grew last year 142% year-over-year. This product was the second-largest contributor to growth at 33%. 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 $16 billion or DKK 100 billion. It's a sizable market. That's about a quarter of the value of the overall market.
What we know is we're positioning this product directly after metformin. You can see from the center of this, our positioning is paying off. We're seeing 90% of prescriptions come outside of the GLP-1 category, which is good. 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. Again, here we have significant market access. 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. 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. You heard throughout this morning us talking about us being in areas of unmet needs. 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. 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 with our 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, also need to optimize what we do with incretins. 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. There's still need for insulin innovation. You asked us about the glucose-sensitive insulin. We believe that we can take it to the next level.
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 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. This is specifically what we're aiming at. Across the board, looking towards integrated solutions. This is obviously why it's a little bit gratifying for me to stand up here looking at a very, very robust clinical pipeline. Marcus talked to what we're doing in the preclinical space, so there's more to come.
What you're seeing is across injectable incretins, across all incretins, we're providing innovation, transformational innovation that will take us to the next level. We are also looking towards maximizing the value of semaglutide, increasing our knowledge base so that we can really maximize what we know about semaglutide and how to use semaglutide. We are doing the same approach in the insulin space. Obviously want to maximize what we have, but we also want to take innovation to the next transformational level. We'll come back to that. 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 oral amycretin. 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 human dose. Marcus alluded to we'll get there this year. Next time we meet, hopefully we'll progress also oral amycretin 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 these data before. Later this month, we expect 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 mg or 1.0 mg of semaglutide are in good glycemic control, and they're in good glycemic control in a safe and tolerable way. They don't need any more.
A few patients needs a little bit more, and what we wanted to with high-dose semaglutide 2.0 mg is to provide just that. 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. The interesting thing is this is without compromising on tolerability and on safety. We can achieve even better glycemic control, even more weight loss without having to compromise on tolerability and safety. 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. 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 seven times 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 HbA1c. In the insulin space, that would be a first. Already there you see transformational innovation.
Thank you for that, Marcus. 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, not with icodec. What we've seen in phase II is that we can improve efficacy without, again, compromising safety. 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, in U.S. slang, because we have to be serious about the digital offerings that we want to put around our insulins, making it easier for patients to live their everyday life, but also to achieve better glycemic control in a safe way. In the development space, we are introducing digital tools through connectivity to allow patients to get to better glycemic 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, a 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.
Obviously also going back to our sustainability agenda, goes without saying, if you can do with one injection instead of seven injections, that's good for the environment. We believe, and again, I have to show this in phase III, that icodec holds a tremendous potential for being a transformational insulin. We design ourselves a very nice, very ambitious development program. It's focused across all aspects of type 1 and type 2 diabetes. 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 and requirements of treat to target. We are obviously doing it to inform patients and treating physicians. 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 gonna 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 studies will roll out over the course of this year. Building 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. 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 four studies will read out during the course of 2024 for the SOUL, the FLOW, and the STRIDE trial, and the FOCUS trial will read out in 2027.
Finally, I just wanna 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. amylin is not necessarily only for obesity. There's 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 slowing 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 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 read out positively, you will see us initiate phase III for CagriSema in both obesity and diabetes later this year. In summary, still a tremendous unmet needs in diabetes, not only because of adverse outcomes, but also because of an ever-increasing pandemic. 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 still left. Only 3% of the total diabetes prescriptions are towards 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. At the end of the day, through strong innovation, thank you, Marcus, but also strong commercial execution from our two friends in U.S. and IO, we will achieve the more than 30% or 33%, easier to say, of the diabetes value market. With that, I'll invite all of us to come up to the stage and ask Lars to moderate us in Q&A.
Yeah. Start here.
Hi. Thanks. Richard Vosser, JP Morgan. 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.? And is that the sole trial that could do that, or should we think about this as just general grind of market share gains? Thanks very much.
Thank you. Doug?
Yeah, I would put it in that category of general grind. I'll use your terminology. I don't think we're gonna see a hockey stick moment, but what we're gonna see is a progression of success in taking market share. 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.
Thank you. 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 CMDs.
I'm not sure if that's fair, but all right.
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's 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 gonna be in the future, where do you see the split of Ozempic and Rybelsus in the U.S.? Thank you.
Maybe it dovetails on the prior question as well. I think that, you know, we see the trajectory now as we see in Rybelsus. We're pleased but not satisfied. We think we can do better. We're gonna continue to take market share. It's well positioned. We continue to pressure test that, and we have the right promotional mix against it. We're gonna 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, you know, greater than 50% of NBRx, if you look at the injectable space, and gaining. I think that split will, not to get into exacts, but we'll see a bigger piece in Ozempic in the future.
Okay. Let's go to the virtual participation that we have. Emmanuel.
Thank you for taking the question. Hopefully, you can hear me okay. Question for Doug. Competitive risks in GLP-1. You talked about how well Ozempic has done, but of course, we have a potentially formidable competitor coming with tirzepatide . 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 are you hearing from payers about the risk of, for example, exclusive contracting, any potential escalation and rebating pressure? If I could, a quick one for Martin.
The phase II CagriSema that's 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 semaglutide for the combination at 20 weeks with a relatively low rate of discontinuations? Thank you.
We'll make one exemption since this was a virtual participant on two questions. First, Doug, on competitive dynamics, as we see more launches into the incretin category.
Yeah. 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 in this space have continued to expand the GLP-1. As you saw, it's only 8% of prescriptions. As Martin alluded to, we expect to hear back from the FDA at the end of Q2 with our own products. We have a portfolio approach, and I think we're well-positioned for any competitor. Let's wait to see what their label looks like.
Martin?
Yeah. Thanks very much. The data you saw read out last year were exclusively in obesity patients having no diabetes, so not a possibility to look at impact on glycemic control. What we're doing in the currently ongoing phase II study is to look at glycemic control more so than obesity and weight loss.
Thank you, Martin. Yeah. Pete?
Thanks. Pete from Citi. Just one question for Lars. You probably don't wanna 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 five years. Can I at least invite you to quantify whether sustaining growth is like that 14% or at least double-digit? You probably don't like the question, but I think it's the question to ask.
Yeah. Thanks for that, challenging question. Obviously, you know that you're not going to get a number. 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're also very encouraged by our opportunity in obesity. It's really, you know, short term, the growth that's fueled from the semaglutide. 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.
Not every year will be to the same magnitude. We're confident in the growth we can drive based on these dynamics. We'll get back to more of the underlying drivers of it, and Karsten will also talk to the financials later on. Yeah.
Thank you. Erik Berrigaud from Stifel. Maybe we're not there yet, but first idea about how you think about pricing icodec going forward, if we think about one insulin versus seven and if we think about annual price, what latitude do you think you may have to reprice, 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 insulin? Thank you.
Pricing without knowing clinical profile is always tricky, but Camilla, can you give some perspectives on how we look at that?
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, you know, six injections a week, with a profile that is competitive on glycemic control and also on safety is, of course, a very compelling thing to bring to the market. 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.
From a market share point of view, just from the profile of what we're hoping to see from the phase III trials, 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 a total basis segment. There is a great opportunity to bring a better and a once-weekly insulin to the market.
Yeah. Great hopes there. We take one virtual question. Wimal, please.
Oh, great. Thank you very much.
Mm-hmm.
Wimal from Bernstein. Maybe one for Martin. I mean, there's a lot of competitor data this year, you know, but in particular the tirzepatide, the dual agonist, and the Lilly triagonist. 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. Just curious, you know, for the GLP-1 glucagon combo and the triagonist, you know, why you have conviction that these are not priority approaches for Novo and, you know, any intention of moving in that direction? Thanks.
Thanks very much, Wimal. It's a super relevant question, and obviously something that we've discussed in great detail. In our hands, we are always trying to balance efficacy and safety. What we saw with specifically CagriSema followed on, hopefully soon by amycretin, 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 one organ, specifically in the liver, on glycemic control or 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 a safety profile. This doesn't mean that we don't wanna pursue, for example, a semaglutide GIP combination as a potential fallback should we see a less attractive profile of the amylin semaglutide combination. So far, we are aiming for better efficacy but also better safety.
Good. Thank you, Martin. Thank you very much.
Thanks.
Keyur?
Thank you. 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 want it to show, that the regulators are on the same page as you? 'Cause historically there's been a slight difference of them being happy to give intra-class superiority claims and as we all know what happened in the placebo hypoglycemia label. Your confidence on getting the superiority on efficacy and potentially, anything else you can see on the label if it does show that.
Thanks very much. Important to call out that from a regulatory perspective, superiority is difficult because the regulators ask us to do treat to target. First of all, we have to convince the regulators that we have done proper treat to target. If we then in that setting, and 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 gonna be a treat to target. It's gonna be real world evidence. The FDA have reviewed the protocol, and they will allow us to show the safety data, but not necessarily the efficacy data in that. The bar is from a regulator perspective high.
We have to show first treat to target and then superiority, but then we have a good chance.
Thank you. Question over here.
Hi, Evan from Guggenheim. Just a question for Doug. Can you talk about Rybelsus, how access compares to, I think you mentioned 95% for Ozempic. Now where is that in 2022 versus 2021?
Yeah, 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. 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'll 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 in your portfolio. You're all equally pursuing an artificial pancreas or similar using a sort of glucagon. Is this because you think it's just a stopgap measure and ultimately, you know, cell therapy, et cetera, is gonna get in there? Or, I guess why not consider glucagon and its role potential for that sort of type one? Thank you.
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 your great questions. We break for a short 10 minutes, so look forward to have you back here and discuss obesity. Thank you.
I worked here in Boston at Harvard Medical School, where I'm both a clinician and an investigator. We need to take action on obesity because it affects individuals with the problem, and it affects society as a whole. It makes us less healthy. It disrupts social interactions and the social fabric. It has a strong negative impact on economic viability and productivity. We need to rid the world of obesity or at least aim to do so over the next two or three generations. It'll take that much time even if we found a solution today, but that's what we need to do. We need better understanding and more ambition.
Welcome back to this session about obesity, 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 two strategic aspirations. One, strengthening obesity leadership and double our sales based on a 2019 base. Secondly, develop a leading portfolio of superior treatments that we would bring to the market. Today, we will give you some updates on this. Before we get into that, we will just like to start with remembering what this is all about.
You heard this morning from Lisa on what is like living with obesity. I also 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 more than 200 possible health complications associated with obesity. Needless to say, this also has implications for the healthcare authorities, for the pressure on the healthcare 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 healthcare budgets. The impact on the global GDP is comparable to the impact from smoking, just to give you an idea about what we're 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 a different interest from healthcare professionals to treat obesity. Policy makers 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.
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. That is all good, but we are starting at a point where too few are being treated. 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 were quite convinced that there is no help to get. Many have been visiting the physician. They've been told to go back home, eat less, exercise more. Everyone has tried that. It doesn't last, and it is not the solution to a problem if you're living with obesity.
That means that only 2% of those are being treated with anti-obesity medication. If we take a look at the right-hand side about our approach to this, then only 1 million are being treated with Saxenda, our first product in obesity. Only 25% of them stay on the treatment for more than a year. Compare that up against a serious chronic disease that leads to severe complications, then this of course has the potential to be improved on. In Novo Nordisk, you will see two boxes here, 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 healthcare priority, and that is understood, and on the other hand, 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. Under what we call the market development, there are three 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. The way we do that, I'll 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 healthcare 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 healthcare 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. There's a lot of opportunity in that can also minimize the burden on the healthcare system. 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. 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 two seconds about what it looks like in terms of supply for us now. 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. Later on, we will also see oral semaglutide 50 mg, and then CagriSema as you just heard a little bit about before also.
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. Henrik, you just give, you know, a very short update on that, and then we'll move over to Doug.
Yeah. Normally, I do not disturb my commercial colleagues in the middle of their presentations, but I guess I'm in between all the strategies of obesity and then Doug coming up and telling about the uptick in the U.S. This slide, that was slide nine, by the way, in the previous investor call that we had. Almost at least, the message is the same. It's very important for me to state upfront that our expectation is that we are back on the growth that you are providing in the second half of 2022 this year.
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 plans that the CMO that we are relying on in this phase, initial phase of this manufacturing, they are holding on to their plans. They will restart manufacturing here in Q2. Why do I know that? That's because within the coming weeks, they are starting their so-called media fill. For you that don't know of manufacturing within pharma, it's basically advanced test manufacturing, testing the manufacturing setup, making sure that everything is in order for commercial manufacturing. They will do that in the next couple of weeks, and we also normally do that, and then they will continue the commercial manufacturing for us.
Right now, we are still holding our own with 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 will 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 2023. Doug, what can you do with that?
I think a lot, Henrik, so let me talk about it. Thank you. Henrik, thank you for all that you and PS are doing. It's really appreciated. Simply put, we can consider this one of the best launches, if not the best launch, in the history of Novo Nordisk. 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 2015, about five years to get to 10,000 TRX. It took Wegovy five weeks. The highest level of TRX that we got to with Saxenda, and that took about six and a half years, was about 14,500 per week. With Wegovy, we're already averaging over 20,000. It has been called a game changer, and we really believe it is.
There's three pillars that Camilla talked about. I'm gonna give you U.S. context, which is getting more patients like Lisa to seek treatment. We need more prescribers, and then there's this element of market access.
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. Then lastly, she said it took her many, many years to find a doctor. We know that in the U.S., four in ten 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 healthcare professional. We know we need to activate more patients. If you think about this big number that I'm showing, 140 million patients with a BMI 27 or greater. Now we're breaking that down into different cohorts. Simply looking at it, 90% of them have a weight-related comorbidity.
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. That's also encouraging. 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. How do we do this? Well, we do this through unbranded campaigns, and Camilla talked about some of these.
You know, 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's a biologic component to this. We're encouraging them. We also have programs like one 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, right? Prescribers, excuse me. We'd like prescribers. 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 in its population, you'd think there'd 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. 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 recurring prescribers, and then we're adding about 1,100 per week. It's already eclipsed Saxenda, and that's encouraging. 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. It's important. 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. Then we also have a complement of educators and medical liaisons.
It's really important that we need healthcare 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. 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. 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 six months. Now, to put that in comparison, if you look at Rybelsus, it took about nine months to achieve the same level of market access as Ozempic.
It took Ozempic about a year to achieve the same level of market access as Saxenda or as Victoza. Relative to our other launches, we've done a nice job. This speaks to the fact that payers and PBMs, they do wanna tackle this. They are willing to put it on. Unfortunately, there's another element to it. Employers have to opt in. We're hard at work there. We look at the left-hand side of the slide, this really talks to the story. 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 into 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 one in five. What we have on the brand today is about 125,000 patients. In a lot of ways, that's good, and we're encouraged by that. In a lot of ways, we're only scratching the surface when you think about the size of this market. 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. 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 wanna unlock the potential of this disease, and it's gonna take all those efforts to do it. 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. I know my friend here in the other part of the world also thinks the same. Mike?
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+% growth the last few years. Actually, last year we grew 53% with Saxenda, which I'm incredibly proud. It is really coming from two of the three geographies, namely EMEA and the rest of the world. Number of countries have launched Saxenda already and are doing phenomenally well. You 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 medication 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, while only 700,000 people have been on Saxenda last year, the pool is very, very large. That, of course, gives me a huge opportunity and hope that if you do the right thing, if you get the right product, then we are able to, for many years, also drive growth out of this section.
As Doug 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 oncologist. If you have diabetes, you go to an endocrinologist. If your 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. 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?
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 professional locators, the truth about weight, creating communities, various different websites, bringing people together are some of those initiatives. Rose in Germany, LloydsPharmacy collaborations in U.K., Eucalyptus in Australia, 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 healthcare professional. We also are, of course, eagerly waiting for Wegovy because we need to really bring these types of solutions to our two 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 I today do not have opens up again through increasing the growth rates that we possibly 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. In every market it's different. If I have brought just two examples here, if you think about Australia, it's the GPs. If you think about Spain, it's the endocrinologist. It's much, much more related to mindset of the physician rather than the specialty of the physician. That's how we are really actually operating now.
At the same time, we realize that people are looking for a dedicated obesity clinic to go to. We're putting a lot of investments and our efforts in building those obesity clinics across International Operations, and you can see the growth on those numbers there. It is really about educating the healthcare professionals, connecting those healthcare 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. We have, again, a lot of collaborations with the pharmacist around various different countries. You see some examples here from Saudi Arabia, Australia, and what have you.
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. I say restricted because you can see from the three 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. We are making a lot of dialogues and deals. Can we try this for some subpopulation?
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 one comorbidity." In Israel, they say again, 30 BMI, but they have to have visited two dietitian before we can basically consider them. In U.K., BMI of 35 is really set forth. I think it's a really good start and quite encouraging. 15 countries that right now are benefiting from these so-called restricted reimbursements, eight of those have happened in the last two years. 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. That's, of course, what we're looking into. They need a very potent drug, and Wegovy brings that, so that gives me even more hope. Then I'm incredibly excited, of course, when the results of SELECT hopefully prove what we have been thinking for a long, long time. Who better to talk about SELECT than my selected friend and colleague, Martin.
Thanks very much, Mike. 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. To Mike's point, this increasing understanding of not only individual impact, but also societal impact is paving the way towards better obesity treatment. 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%-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.
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. Obviously, our aspiration is to take it to the next level, normalization. What 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 weight loss. We are already now, even though we are super happy 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 that. We have a good, strong pipeline. I'll talk about the SELECT. You heard us talk about oral semaglutide and CagriSema, and I'll go into a little bit more detail on that. Then obviously also here calling out oral amycretin. 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 GLP-1 agonist is not enough, we look toward combination of different modes of action.
The really, really interesting thing about combining amylin and a 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. They deserve 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 four weeks on the maintenance dose. Nevertheless, 17% weight loss. This is to be compared with the 17% weight loss we see for semaglutide in monotherapy in 68 weeks. I've promised Daniel 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 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. When we've seen combination with GIPs and glucagons and 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. We basically get the best of two 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 number 6. Some of you have asked about that. You will see that we don't achieve more weight loss with cohort number 6 than we did with cohort number 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 + 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 CagriSema. In obesity, hopefully also in diabetes. This is why we have designed a very, very focused phase III program, two trials for regulatory approval.
One in obese patients also comparing to the monotherapy of the mono components of the drug, and one in a combination of type 2 and obese patients. This is sufficient for the regulatory approval. Obviously, we'll follow up with more data in phase III-B and phase IV, including looking at cardiovascular safety. With the weight loss that we can potentially accrue with CagriSema, we believe it warrants a fast approach to market. You heard Doug 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 conduct this 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. 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. Again, talking 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 subpopulations that will allow payers to relate to obesity without hesitation. 17,500 patients will allow us to also identify patients who are at risk and who can have comorbidities prevented.
A lot of benefit coming out of SELECT and a lot of excitement. This excitement not being lessened by the fact that we now are confident that we will have accrued 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 pre-specified. 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. Really, really exciting.
Equally exciting, we've decided to extend the SELECT trial to look at the legacy effect of weight loss. We'll continue the SELECT even after the original trial and the regulatory submission. More of that later. Now over to Camilla on how we're gonna use all of this.
Yeah. Thank you, Martin. Based on everything you've heard today, it's clear that the opportunity with obesity is big. On that background, we've also decided to change our strategic aspiration for 2025. As you will recall, it used to be strengthen obesity leadership and double current sales from 2019. 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. More than DKK 25 billion in 2025. 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 talked about the pipeline, Wegovy being our second offering, but not the last one. We also talked about SELECT and the exciting interim analysis potentially to come this year. Finally, the update of our strategic aspirations. Maybe that gives rise to questions or need for a dialogue. I'd just like to invite the rest of the speakers up here together with Karsten.
All right. As my colleagues get on stage, then you know the drill, one question per person. I think we go all the way to the sunshine with Pete Verdult at the window.
Great.
Thanks, Pete Verdult. One question for Doug . I know we're only eight 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, you know, 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 six-month co-pay card is exhausted?
Pete, 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 200,000 cards out there, and about half were initiated. We're still working through that, and we're still working through exactly what happens at the end of that expiry. More to come on that.
All right. Florent?
Thank you very much. Florent Cespedes from Société Générale. Quick question for Camilla. On the diabetes care prescription online, could you elaborate a bit on what could be what is feasible on this front? Because we all know that the serious sufferers have a lot of comorbidities. Also we all know that more than in any other diseases where obesity you need some support to make sure that the patients stick to a treatment. If you could elaborate a bit on what is feasible on this front. Thank you.
When it comes to stay times, we know today that for obesity treatment, the stay time is relatively short if we measure it within a year and only 25% stay on the treatment for longer than that. 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 to expect. We're also working on indicators that can give them an impression of, you know, how they would develop when being on this product.
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 two years, they see a continued weight loss. 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. With that, of course, it gives us also hope that the stay time can be even longer.
Great. Thank you, Camilla. We move into cyberspace, and we have Sachin Jain with us, Bank of America.
Hi there. Thanks. My question is, and apologies for not being there in person. If I could just take a question on SELECT. May have missed it last week. Could you comment on the powering of the interim, what level of benefit is required of the interim for a successful stop? And then obviously, I wonder if Doug could talk to the payer implications of SELECT and whether it would substantially advance the Treat and Reduce Obesity Act. Thank you.
Somehow our virtual speakers sneak in two questions, so but we'll go with it again this time. Martin and 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're 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?
Yeah, Sachin, what I would say is, you know, we're pleased with the level of access today, and really we need that component of employer that I just talked to. Certainly we'll be benefiting from SELECT given if and when it reports out and how it reports out. I don't know that we'll use that in our armamentarium, but I don't know that it changes drastically where we are today with access. As far as trial, we're hard at work with that, and certainly that will just add to the benefit.
Thank you, Doug. We move to Michael Novod.
Yeah. Michael from Nordea. Just a question to reimbursement outside of the U.S. You see that the NICE in the U.K. gave initial positive response already five months after approval in the U.K. Is that a good sort of benchmark for other countries in Europe? 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. Is that also representative for sort of the patient population across Europe and the U.K.?
Yep. 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 a 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 gives you some sort of a restrictions and gives you a certain access, but then the hospitals, then the CCGs and what have you in various different healthcare 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.
Hi, it's Harry Sephton from Credit Suisse. Just one question on the U.S. 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?
Yeah. That, that's a good question. Right now in the initial phase, the targeting is very specific to those that have shown a willingness to prescribe in the past. 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 that. That's always been our aim. We just wanted to, at launch, target it in the most likely prescribers in terms of who would see the most benefit or somebody that already prescribed in the past, say Saxenda.
Thank you, Doug. We move to the other side, Keyur from Goldman Sachs.
Hi. 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 novel product perspective? So I guess the 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?
Great. Thank you, Keyur, for these questions. Clearly we're making aspirations for the medium term, signaling our commitment and confidence in a serious growth opportunity within obesity care. 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. Camilla, any kind of
Yeah, exactly, Karsten.
confidence to it?
As you heard there, Keyur, what we are trying to do is to keep unlocking this market with the factors that we just discussed. I just want to add to what Karsten said, is that in reality, we have not seen what Wegovy uptake looks like when it's unrestricted yet. There's still a number of uncertainties in this market, and we haven't seen it launched in IO yet. That's hence the more than $25 billion approach to it. But of course, the more we can unlock the three 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. That's the journey we're on.
Thank you, Camilla. We go to Richard Vosser.
Thanks. Richard Vosser, JP Morgan. Just in that DKK 25 billion, the pricing development that you've sort of assumed within obesity, I mean, you've got the 2 mg launching soon that's getting perilously close to the 2.4 mg for Wegovy in terms of dosing, and diabetes pricing is a lot lower than or somewhat lower than obesity. How should we think about that? And also with competition coming with tirzepatide too. Thanks.
Camilla?
Yeah. While we cannot give specifics on pricing as such for products that we haven't launched yet, then I think you should think of the obesity market, of course, like what we've also seen in the GLP-1 market. As it expands more and more, it's likely that the price will also develop accordingly. 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 two different channels in diabetes and obesity at this point in time, as we don't have Medicare access.
Yeah. 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. We move on to Kerry Holford from Berenberg, virtually.
Yes. Hi. Can you hear me okay?
Yeah.
Excellent. Just following on from the point there from you, Camilla, with regard to the acceptance of obesity as a disease, are we any closer to seeing broader reimbursements for obesity therapies in the U.S., specifically that government-funded channel? Any new discussion points, commentary ahead of your data readouts? If I may, 'cause I'm virtual, I might squeeze in a second quick question. Just a point of clarification. The new target over DKK 25 billion by 2025, is that for obesity as a whole or Wegovy alone? I may have missed that. Thank you.
The first one is simple. It's for obesity as a whole. The next question for you, Camilla, on reimbursement.
Yeah. I think I might defer to Doug because-
Sure.
I know he is happy to talk about this being an old former market access guy, and that he's right up your alley.
Always a market access guy.
Always a market access guy.
No, I think, Kerry, it's a good question, and we're hard at work, as I mentioned earlier, on both the state and the federal level. On the federal level, certainly one of the vehicles that we're using is the 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 it is that it's more of an if. It's more of a we're gonna 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. We have a question, Simon Baker.
Thank you. Yeah, Simon Baker from Redburn. Just going back to the issue of coverage within the U.S., Doug, you said you had about two-thirds, 70% of insurers and about 50% employer opt-ins. 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 or expanding opt-in as we go forward? I'm not gonna 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 two buckets and drivers would be useful. Thank you.
Yeah. It's a really good question. In the end, when we're trying to unlock this disease, it's a combination of both. I'm not trying to just give a simple answer, but it's gonna be the continuation of how we work on both, national PBM, local level, health plan level, as well as the employer opt-in. We're actually working simultaneously on both. 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. You know, all of that is needed, and we're working on all of that.
Thank you, Doug. We go virtual to Wimal Kapadia.
Oh, great. Thank you very much. Wimal Kapadia from Bernstein. Can I just ask about phentermine?
It still dominates about 80% of the obesity volumes in the U.S. I guess is there a scenario in 2030, for example, where that number could be zero? 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 know, you can significantly expand Wegovy volumes without actually increasing the penetration of obesity drugs.
Great. If I start out and then hand it over to my colleague. First of all, the premise for our more than DKK 25 billion in 2025 is that of a market expansion of the branded anti-obesity medication markets. We're not out trying to gain market share. We are north of 7% global value market share in the obesity segment already. This is a market expansion. You saw earlier on from my commercial colleagues that actually the majority of Wegovy patients are new to anti-obesity medication therapy today. 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. Doug, Mike-
I don't know if I can say it any more than you just did, at least in my market.
No, I can only say that the market also does not see the two as competitors. There's a lot of safety issues. You know, this is almost like comparing animal insulin, I would say, with Saxenda. The market sees that as very, very different segments.
Excellent. Thank you. We have time for 1 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. Thank you to my colleagues for an excellent obesity session. Now it's time for lunch, at least for the ones here in the auditorium. We'll be back at 1:10 P.M. Thank you.
With a condition called sickle cell anemia. My name is Jenica. I am an award-winning author of a children's book series about sickle cell. Growing up with the condition, I really would say that I felt like I didn't really understand what my condition was. I didn't really understand how it affected me and what impact it would have. With creating my book, the first book explains, like in layman's terms, what sickle cell is, and the next book in the series talks about, you know, visiting a hospital and what's involved in that. My wish for the future of sickle cell would be, less stigma and more awareness. The younger generation coming up living with sickle cell, I want them to have the confidence that I didn't have, the peace of mind that I didn't have.
All of the work that I'm doing is kind of to help the next generation.
Good afternoon. It's a pleasure to be with you two years after I joined Novo Nordisk to talk about what is now called Novo Nordisk Rare Disease, formerly known as Biopharmaceuticals. 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 a rare disease is for the overall Novo Nordisk. If you remember this slide from 2019, we had two 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. Before I do so, I just want maybe to contextualize a little bit what rare disease is for Novo Nordisk. It's actually a 40-year legacy of working with rare disease patients.
The first in man of NovoSeven, what is now known as NovoSeven, was in 1981, actually 41 years ago. Since then, we believe that Novo Nordisk has built a long legacy in the world of rare diseases with three pillars that are essentially important for what Novo Nordisk 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, in terms of share of profits, 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. It's an important pillar.
Second, it's 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. Last but not least, it's also a platform. A platform to test new ideas in terms of healthcare 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. You'll see flourish this hashtag Redefine Rare going forward a lot across all our interventions.
I was mentioning that many things happened in the last couple of years. Yes. I want maybe to stop one second on this, 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 building 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 was our knowledge, our understanding in biology, our footprints 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 footprints vis-à-vis other competitors in that field. That actually led us to focus our work in rare disease in two domains, the rare blood disorders and the rare endocrine disorders. The rare disease world is a huge world, 5,000 diseases. Of course, we didn't want to spread ourselves too thin. We wanted to focus and make sure that in a thoughtful manner we could actually play to win.
Hence, the two 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. That's what you had behind me. Around eight 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. We went through this journey of creating three 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 talk about that in a minute. 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. In all these new diseases you saw with very selected, carefully selected platforms and scientific endeavors that I'm happy to develop further.
All the elements of the value chain have been, if you want, raised and improved, and the integration between all the elements 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 maybe commercial focus in during the first phase. That's what you see behind me. One of the premises was to return to sustained growth. Now for the third consecutive year, we've actually grown the rare disease portfolio. We've grown the rare disease portfolio.
We've grown it 4% in 2019, 1% in 2020, and 4% in 2021. 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 rare endocrine disorder. 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.
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, Mr. Explorer, and Mr. Frontier. A lot of misters in this one single person. With a lot of pleasure, I'm welcoming my good friend Martin on stage.
Thank you so much, Ludovic. Now I have to try not to become too schizophrenic here. We've already talked about it. We move in areas of serious chronic diseases. We move in areas of unmet needs. 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 building from that core towards what comes next.
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 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 adaptive trial designs, 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. Then obviously we also take the approach, I think maybe specifically rare disease lends 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 one indication. 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 pipeline already approved for adult growth hormone deficiency. Now we just finalized the growth hormone deficiency in children, and we are moving into several new indications as we speak in phase III. This is super exciting.
I sometimes get the question of why I want 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 1-2 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. We know because of a daily hassle for patients or 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 seven 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. We just finalized a reasonably large study in the setting of 200 patients being randomized 2 to 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.
The regulatory requirement is therefore, because we believe we found that balance, is to show non-inferiority to what is already out there. That also means that some of you have said that's a little bit boring getting non-inferiority. No, that's actually super exciting because without that we would not get the drug approved. I'm somewhat happy and excited to show that coming out of the REAL 3 study, we showed exactly that. Non-inferiority on height velocity, non-inferiority on secondary endpoints, and non-inferiority on safety. The upside of Sogroya is clearly going from seven weekly injections to one weekly injection, less painful injections, better device, better digital support, and potentially better outcomes for the patient. I hope you can use that.
I can definitely use that. 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. That's only with Norditropin. Just imagine what the arrival of a new drug can actually do in that leadership overall. For two reasons. One, because there's still a huge unmet need. Martin mentioned it. Roughly 20% of patients do miss at least one or two injections a week. Huge unmet need. Many of the indications we're gonna work in terms of growth hormone disorders beyond the kids growth hormone disorder like SGA or ISS will actually open a second 50% of that market. There is still potential to grow here.
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 two components, and having the best offer in each of the short-acting and long-acting class is certainly the best way to make sure that we maintain our leadership, again, in an underdiagnosed therapeutic area. 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. I'm not gonna 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. Mads at one point told me that I could maybe be somewhere between exceed and outstanding. I told him that exceed expectations, that was sort of a weird denomination. So I got the outstanding. That's good. What I'm gonna talk about now is actually we expected something that maybe exceeded expectations, but I actually hope to convince you that it is really, really outstanding.
We've received actually a lot of questions on Mim8. That is what we believe is the next true shot on goal. We received precious few questions from you guys in terms of concizumab. Maybe again, the potential for exceeding or being outstanding. I'm actually super happy to be able to share some of the results from the just finalized concizumab study with you. Conizumab is, as some of you may know, an anti-TFPI antibody enabling thrombin generation by binding TFPI and thereby clotting. We've conducted one 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'll 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. We have 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 zero. 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 impressive.
Can we say flabbergasting?
We can say only with Mads's permission. 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, 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 one slide. We're looking towards submission of this specific trial already this year in what we call a rolling submission. Starting out, we're getting the regulatory approval in hemophilia A and B in patients with inhibitors.
Obviously finalizing the already ongoing trial and submit that, so we 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 designed to have strong activity only at site of bleeding or of injury and not at 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 choose to 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 once weekly, but potentially also a once monthly offering.
They promised us it would also be 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 no injection site pains. You know, what is currently out there is being administered to the tune of 0.8 ml-3.2 ml per injection. That's actually painful in and of itself. If it has to be given in a syringe that is large, larger than 27 G, then it also hurts in and of itself. Mim8 sort of had the potential of also past efficacy, also past safety, and really, really nice convenience and no injection site pain. That was a good promise. Marcus always keeps what he promises.
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 I've bored you to death with the design of that study, and you've 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' 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 thrombin. First of all, we see again very, very nice dose response.
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' team predicted just that. This is a textbook example of going from pre-clinical into clinical and demonstrating not only a very robust PK profile, but also a very robust PD profile. Then I received a question from more than one of you. Won't we see some bleeding data? 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.
Probably see that in the four 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. We basically exceed 70% of patients having no bleeds. 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. On safety, on efficacy, on convenience, and on injection site pain, we think we have something that is super competitive. Ludovic, you asked for at least one best in class drug. I think we've given you three.
Now it is up to you to talk about Sogroya, concizumab, and Mim8 and their commercial potential.
Thank you very much, Martin. Again, as you see, no antibodies detected with Mim8. It's really, really stunning from a biological perspective. Why is it so important? Well, it's important in the world of rare blood disorders for two 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%-20% of patients are actually getting into prophylaxis. You have still a lot of even people treated with SHLs, so short half-life, as well as plasma. The market is expanding, the need for new agents is quite high. 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 one single winner. Just imagine the power of a player that has an SHL, an EHL, a mimetic, an anti-TFPI, and maybe tomorrow, gene therapy. I'm sure that at some point, Marcus, that also keeps his promises, will 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%-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. We've proven we could do it with Esperoct. 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 in 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. If you put these two 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 endocrine disorders by the second part of the decade.
I hope I've convinced you that the change is real. Of course, I'd be very happy to answer any question you might have during the Q&A. Let's now move to something completely different.
This is really becoming schizophrenic. I apologize for that. Now we are changing gears, moving into cardiovascular disease. Just wanna give a small 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 also cover Alzheimer's and NASH. 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 serious chronic diseases. Maybe we'll just like with rare diseases, find a new name for it at some point. 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, 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 biology, 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. 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. 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. Even within the space of ASCVD or atherosclerosis, we define for ourself two spaces where we think we can make a difference. One obviously, as alluded to in this slide, being oral PCSK9. There's still an unmet need for high cholesterol, and it's still a crowded space, we acknowledge that. Again, bringing in the first oral offering to this space may make a difference. I'll not go too much back into that.
We also see 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 lacked a little bit of the efficacy. There are actually reasonably efficacious drugs out there at a cost of safety and tolerability issues. In the heart failure space, specifically in heart failure with preserved ejection fraction, there's really nothing out there. 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.
Marcus also talked about our cell therapy ventures, and specifically Heartseed. 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 in development have conducted cardiovascular outcome studies for the last 10 years, and we're 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 not only ruled out cardiovascular risk, we established cardiovascular benefit. That obviously, again, going back to the maximizing the value of semaglutide, caused us to do more than just that.
We are conducting a plethora of outcomes trials with the semaglutide molecule, starting obviously with SELECT and SOUL that we just discussed. 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. Four years into a new R&D strategy, we also have clinical late-stage assets that are not based on semaglutide. We have the ZEUS trial, we have the oral PCSK9, and then we have our ATTR asset as well. Really exciting to be on this journey. That basically means that we believe that we have a good chance of meeting our own internal aspiration that I obviously now share with you, namely having a novel asset on the market somewhere between 2024 and 2028. We believe that we can do that.
Obviously, this has to be a first to market, maybe first in class, addressing an unmet need. Pursuing, and this is Marcus' take, an innovative mode of action. Obviously also we had to acknowledge maybe we can not do all of this internally from a research perspective, looking towards the outside for inspiration and potential acquisition of assets or maybe building 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 modes of actions being first and addressing tremendous unmet need. In phase I, in phase II, and in phase III. Really, really exciting, I think in the progress of four years, quite impressive.
A 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 come at the cost of increasing the risk of infections. Introducing neutropenia, thrombocytopenia, potential liver impairment, potential dyslipidemia. This is what we've seen in other modalities 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 two higher dose arms. That's pretty impressive in and of itself. But what we also saw was a safety profile that was super attractive. 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. We are already now in the recruitment phase of a phase III outcomes trial. This is a mid-sized phase III outcomes trial, 6,500 patients being randomized either to ziltivekimab or placebo. Mid-sized because we're looking at a very diseased population of patients obviously with cardiovascular disease, with inflammation, but also chronic kidney disease. 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 exciting. I do also want to spend two 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. In preserved ejection fraction, and specifically also with cardiomyopathy, we have already now two shots on goal. One going into phase I, which is the Heartseed cell-based therapy for heart failure. Marcus already alluded to that. For ATTR cardiomyopathy, we also acquired an asset from Prothena that allows us to go into this specific version of heart failure.
Again, I think broadly speaking, and I've thanked Marcus a couple of times during this session, but we are relying a lot on what he does, bringing stuff from early research into development. I think it's impressive to see how we built a pipeline in a matter of four years going even beyond the semaglutide molecule. Obviously building on the semaglutide molecule in terms of building our capabilities and our progress into doing this. With that, Camilla, I would like to ask you, what are you gonna do with it?
What am I gonna do with it? Yeah, let's take it step by step, Martin, and just explain where we're coming from with our entry into CVD. Just to get back to 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. 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.
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 three players only make out 30% of the total market. Whereas in diabetes, it's actually 2/3 that's made up by the top three players. Yes, it might be a crowded market, but there is still a lot of unmet need with this leading cause of this. The way that 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. On the left-hand side here, you see our focus areas. We will begin with expanding our presence with cardiologists from what we already have.
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. In the medium term, we will be preparing for launching a standalone assets in this field, and I'll just come back to the timelines in a minute. Finally, long-term new modes of actions that you heard from Marcus earlier on. 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 in obesity. On in our semaglutide 1.2 mg, 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. This will also be the first and only for type 2 diabetes. Finally, on the more standalone, 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'll be able to reverse disease progression and not just stabilize.
This has a little longer outlook towards 2028. This is the approach that we are taking and that we will be building on. If we talk to ziltivekimab specifically, we 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. On the left-hand side, you see here the global number of patients with ASCVD and chronic kidney disease, and that sums up to around 15 million. When we then also screen these for who have high inflammation level that can be addressed with the high sensitivity CRP above 2, then we will get to a potential of around 5-8 million people.
That's what we are likely addressing with ziltivekimab in this indication. To do that, we of course need to be able to work with the healthcare professionals, establish the relationship, but also to be able to know who is who in this field. 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. Of course, we will be building on that as we progress 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?
Also, how can we prove the sort of relationship between the inflammation rates and also a successful and socioeconomic relief of the burden. Those are some of the steps that we will be taking from a commercial point of view to prepare for the launch. As I just mentioned, we are already embarking on this and having the right people on board. Of course, we are likely to expand more and more in a sort of trigger-based approach going forward on this. Just in summary, on cardiovascular disease, we are entering a growing market that is still a big issue to society. There is a big unmet need. We are focused to build a presence with the stepwise approach that we just talked to.
Pre-launch 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. With that, I like to conclude this session and just invite Ludovic and Martin back for a few Q&As in case you have such.
All right. We know the drill. I think this time Richard Vosser was the fastest one out of the gate. Over to you, Richard Vosser.
Thanks. Just on concizumab, I think there was some, you know, 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? Thanks.
You're absolutely right. It's really not unusual in hemophilia development to see that you have to tune in on your dosing and your dosing regimen. We had to do the same thing with the concizumab. We had to change a little bit how we initiated the patients, but also how we allowed patients to adjust that dose based on a blood measurement taken four 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. We move to Florent.
Good afternoon, Florent Cespedes, Société Générale. 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. Why are you so confident that you will see some efficacy there, knowing that some competitors have failed with other interleukins? Also, could you share with us what the size of the population you showed as some 5-8 million people? What's the size of the population from the outcome trial? Thank you.
Absolutely. Maybe I'll take the first part, and you take the last part. 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. We know from previous outcome studies that this will be to the tune of 50%-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, one, the efficacy part, we can decrease inflammation.
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 in IL-6 levels and actually also CRP. They saw in excess of a 30% risk reduction in those patients. That obviously gives us some clinical confidence that this might work. Now, 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. We do believe that we have, not only from the clinical space but also from Mendelian randomization studies and from the non-clinical 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.
Great. Thanks, Martin. Camilla, on the population.
Yeah, I heard the question, but yeah, the population in the SUSTAIN trial. I heard it, Martin, but maybe you normally know the-
Florent, could you repeat the last part of your question as, 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 5-8 million people you were referring to
Yes.
Yes. Short answer is yes.
Thank you. Thank you.
Okay. Thank you for that. We move to Emmanuel Papadakis from Deutsche Bank virtually.
Emmanuel
You're on mute, Emmanuel.
Emmanuel, you're muted.
You're on mute.
Apologies for that. Congratulations on the initial consensus update. Perhaps I'll take the opportunity to ask a question I was going to ask in the initial session, which is kind of technology platform related that ties in pretty closely with what you're trying to do more broadly in rare diseases. You called out genome medicine, gene therapy as one of the four key technology platforms, but you gave it very little airtime 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 2seventy 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. It was very interesting to see you mention lysosomal storage disorders as part of your rare diseases portfolio and blocks. Perhaps you could address that in particular. Thank you.
Yep. I think the two 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 you 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 when we are really focusing on gene editing, i.e., you could say 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. As you know, we are working very hard with this partner now in our 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. I don't know whether you're addressing that later on, Marcus. I think Marcus addresses later on in the breakout. You'll have all the answers to that. It's certainly a pivotal element for our journey, let's say, late part of the decade in early part of the twenty-thirties in the rare disease space.
Thank you.
More on the gene editing than on the gene therapy.
Thank you, Ludovic. A nice commercial for the upcoming breakouts.
Exactly.
Moving on to Simon from Redburn.
Thanks very much. Just going back to ATTR cardiomyopathy. A couple of weeks ago, AstraZeneca said that the true incidence is probably understated because of misdiagnosis as HFpEF. 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.
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, we become wiser. Recent data suggests that up to maybe 13% of patients with a heart failure has a level of ATTR cardiomyopathy.
Thank you, Martin. We have a question down here from Keyur Parekh.
A big picture one for you, Karsten and Ludovic. Kind of given the progress you've made on the pipeline in the rare disease business from 2019 to now, your strategic explanation for that business hasn't changed, which is advancing the pipeline. Why are you today not being bold and giving us some commercial strategic objectives around that business? Why are you shying away from that?
Ludo, if I start out and then
Go ahead.
You add on. 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. A lot of credit to the teams across commercial all the way to research. 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. We would like to see a little bit more data. Bear in mind that Mim8, it's phase I/II data we're looking at.
Perhaps when we see phase III data, we can talk about formalizing even sharper on our commercial aspirations. Rest assured, we're not holding back in terms of optimizing the opportunity at hand.
Exactly. I think what matters is that this pipeline gets stronger and stronger. In the world of rare diseases, we know the pipeline has a different logic as what you can actually observe in the more primary care setup diabetes that we see, and we need to see that pipeline growing stronger and stronger. What we can tell you is that all the elements, all the building blocks are in place commercially from a development perspective as well as from a research perspective, to create a leader in the rare blood and rare endocrine disorders. That has to be built on the go.
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 to formulate that in a, maybe in a more, what you could call a bolder fashion. There's another question, I guess.
Just a follow-up then. Is it fair for us to assume that growth rate for this business 2021-2025 is going to be higher than what you've delivered for the last four or five years?
I think we're not doing a forward-looking statement, right?
No. Keyur, I think first of all, when you look at the Mim8 timelines and the phase III trial for Mim8, then Mim8 is not gonna benefit our growth trajectory in rare diseases towards 2025. What we're gonna benefit from is Sogroya as well as concizumab. Ludovic covered those opportunities and clearly we're gonna benefit from that. 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. Clearly in a good place now.
Whether we're gonna grow faster than 4%, I think actually 4% was something that we're really happy with last year. If we can keep driving at that level, then we'll be very happy.
Okay, we move on to Sachin Jain from Bank of America.
Hi there. Just a follow-on question on concizumab, where the data you framed as outstanding. Just, I have two 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 memory 3.4 in phase II to the 0 rate. What's driven that? Then related, how is that driving your thought process in the bigger non-inhibitor population? Martin, when we've spoken before, you've previously discussed excitement predominantly in hem B, but does this data make you much more excited about the Heme A setting? Thank you.
I think Ludovic should 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. 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 probably more better to talk to that.
Concizumab is a medicine that is actually valid given its mode of action in hemophilia A and B with and without inhibitors. The four quadrants. Indeed, at the first place, we thought that hemophilia B with inhibitors might be the best spot to be because there was no other alternative. When you look at that profile, and I really understand the fragmentation of the needs of patients. The fact that some patients wants a really a short life protection, high protection throughout the day. You can clearly see that there are many patients and patient groups, even in hemophilia A, without inhibitors that could be interested by what concizumab has to offer.
Those who want a very high level of protection to be sure about it, 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 important one, and that's why we indeed are reinforcing the idea that this could actually be a very good medicine across all type of hemophilia.
Thank you, Ludo. Thank you, Martin. We have a question from Carsten Lønborg, SEB.
Thank you very much. The Mim8 phase I/II data you showed, the five cohorts. Isn't it for number of bleeds 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 study, 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 this data. And you'll always have that outlier that's easier to absorb in phase III than it is in a very small phase I and II trials. I've been educated by our hematologist both in and externally that this is what we always see, and there will always be that patient.
Thank you, Martin. We have a question from Peter Verdult.
Thanks. Pete from 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 setting the world alight, just wanted to know what your go-to-market strategy there is or commercial expectations. Then if I could squeeze one in extra for Ludo or Karsten. The last CMD 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? Thank you.
Yeah. Ludo?
Shall we start with the second one maybe?
Yeah, absolutely.
The easy one. We are still looking for opportunities. I think we cannot actually think about developing a proper rare disease arm if we're just walking on one leg. We'll be walking on two legs. One, external collaboration. It's true to say that the quality of our internal pipeline has significantly improved over the past couple of years. We'll be working in a balanced manner, both in with the support of our platform teams, as we did with Dicerna. We're gonna talk about it in a minute, but also in early clinical stage assets where we believe there is real value in the market. It's gonna be a 50/50, two 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 three genetic variants. Actually the study was positive on the first one, the biggest one variant, hyperoxaluria type 1. 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. I mentioned earlier on that it was a nice way for Novo Nordisk Rare Disease to test new ideas. We will 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.
It's a very good way to start with. Actually again, a 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. There's absolutely no doubt we should move in that direction.
Thank you, Ludo. Thank you, Pete. We have a question from Wimal Kapadia. Wimal, you're on.
Great. Thank you. Thanks very much. Great. Thanks everyone. Can I just ask about the growth franchise and how easy would it be to transition from Norditropin to semaglutide ?
How should we think about the opportunity in the adult population, just given the majority of your sales come from the pediatric setting?
Now, which indications do you see the most upside potential for a weekly product? Given the adult population treatment weight is so much lower, can we assume this is now a growth franchise with that?
Yeah, Wimal, it was a little bit hard to hear your question. I think your microphone is pointing the wrong way or something like that.
Yeah. Now we can.
If perhaps you could just restate it briefly for the transition from Norditropin to Sogroya, please restate.
Sorry. I think the ease of the transition from Norditropin to semaglutide . Just thinking about the adult opportunity, just given the sales, the majority of your sales in the pediatric setting, you know, which indications do you see the most upside potential for a weekly product? Can we assume growth for the franchise from here?
To you, Ludo.
Yes. You want to talk maybe about the trials we have on that to extend the population, and then I can talk about that.
Moving beyond growth hormone deficiency, we are planning to conduct studies, phase III studies in new indications, such as small for gestational age, idiopathic short stature, Turner syndrome, and maybe even Noonan syndrome. Building beyond and thereby maximizing the potential of Sogroya, if I understood the question.
Yeah. The market today is split into three 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%-42% of the market. The remaining 50% of the market are the other indications, small for gestational age and ISS, plus the micro indications of 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 with somapacitan we'll be able to cover a wide spectrum of indications. That's why we believe that that plus the fact that today, as I mentioned, only more than 22% of the kids patients actually do miss one or two 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 gonna change, well, I don't think it's gonna be one single speed. Because if you listen to physicians, they will, some will tell you, "Listen, we're very well covered with the daily." Others will tell you, "We wanna go to the weekly." It's very likely that the two 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 two short-acting and long-acting coexisting for the next few years. That's why it's so important again to have a portfolio and why our established position with Norditropin will continue to help us also in the growth of somapacitan.
Definitely looking forward for growth in tha t aspect, for sure.
Thank you, Ludo. Thank you, Wimal. This concludes the Q&A session. Now we're moving into breakout sessions. A number of really exciting breakout sessions. 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. For the people in audience, you have it on your name tags, which session you have signed up to. Then there'll be people helping you understanding where to go based on this very simple graphic on the chart. If you have any questions, reach out to Investor Relations.
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. If that is the case, then yeah, there's still opportunity. 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 from Martin. Actually joined by two 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 four 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.
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Thank you.
Congratulations. What we will do, if we get over the forward-looking statement and our aspirations, which you all know by now, is actually do a 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 a bit more insights 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. We'll spend half of the time that we have actually in a Q&A dialogue. Yeah.
Taking off from the broad technology space, which, you know, if you've 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 in disease. I think we hopefully can convince you that this is a very, very broad toolbox. 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. That actually is a challenge sometimes of choice. Where do we start and where do we want to engage? We've for now chosen a few disease areas, Parkinson's disease, heart failure, obviously diabetes. How could we not do this in dry AMD? We're not talking about the latter. 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.
I tried to allude to that earlier this morning when 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 the differentiating factor. 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. 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. We enter the mid to long game, which is actually manufacturing quantity, quality control, distribution, and commercial models.
Really, once again, this end-to-end mindset is where we feel ultimately we will decide which product will be successful, will reach many patients and which not. I want to show you two examples, and don't get hung up too much on the very simplistic trial design here. One is our efforts with Heartseed. Martin already spoke to it. This is actually, and I think there was a small typo. We're actually treating patients with reduced ejection fraction less than 40%. So really, where contractility of the heart matters. Yeah, 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 in this first instance patients that actually undergo heart surgery for other reasons. That also has made recruitment certainly not a simple play, to say the least. 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, improvements in ejection fraction. 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. Yeah, you also will not see healthy volunteers that undergo cardiac surgery. Yeah, I think maybe I'm stating the obvious. 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's, similar opportunity and challenge, direct CNS applications through a specially made device or catheter. In some areas like outside of Japan, for example, there's talk about sham surgery as a control in Japan that is not needed. We're actually also learning here, in which regions do we which clinical trials and what is the particular outcome of those. We have two trials, you know, one is called STEM-PD 1 and STEM-PD 2. The first one you can think about like a run-in trial where we actually figure out which patient population might be most stable, which might benefit the most from such a treatment. That in its own right is not a simple feat.
Cool news is, and this is where I wanna leave you with here, both start actually in the first half of this year, if all goes well, of course. That clearly is our aim. We'll learn by the end of the year, and in next year we will have learned a lot about stem cell therapies. 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 siRNAs, and you also now heard Marcus talk about cell-based therapies. I'll talk about gene editing in a short while. 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? The short answer is yes, and it of course have two 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.
What you see on the left side is two major investments that we're 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 a platform where you can do full recombinant proteins of any type combined with peptide synthesis, chemical modification in one end-to-end setup. It will allow us to do what we call multidimensional screening. We'll screen all the needed biology properties coming from Karen'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 Seattle. Those two investments will allow us to do the new molecules that we need for our protein and peptide strategy that will still be center for Novo Nordisk. This is a substantial and big investments that will cater for those needs going forward. I just wanna 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 wanna 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 like to do with a gene, it actually is translated back to a protein. In many cases, you do reverse engineering. If you want to have good gene, then you need to know your protein and do the engineering. I'll show this in a short while why it matters. Likewise, with mRNA, it codes for a protein. If you wanna do good mRNA design, you need to do good protein engineering.
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. Let me showcase it by going in and talk about what we are doing in gene editing. 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 know one. We have collaborated with them to tailor the enzyme we need to do a cut in a very precise place in our chromosomal DNA.
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 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, and the full-length factor VIII is larger than that vector. For you to be able to deliver that protein, you have to engineer a mini-factor VIII, and that is of course the core of Novo Nordisk. We have engineered the gene that can be delivered in the AAV. Here you see the two-component systems that we're operating with in gene editing.
On the one hand, we have an mRNA encoding for the MegaTAL that is formulated in a lipid nanoparticle. On the other hand, you see the AAV that carries the DNA that we have engineered with the factor VIII gene. Both of these two systems will be administered, and what will happen is that both of them will be taken up by the hepatocytes. The mRNA will be translated in the cytosol into the full-length enzyme that will diffuse into the nuclei of the cell, and the AAV will do its job by delivering the DNA cargo all the way also into the nucleus of the cell.
When you have those two components in the nuclei of the cell, the MegaTAL will 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. If you don't have integration of your DNA into the chromosome, you'll see that your plasmid, if you have a episomal plasmid, will dilute over time, and that will not happen when we go in and do gene editing. With these two slides, I wanna highlight that gene editing is connected to protein engineering, likewise will be with mRNA.
I will show you one 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 to show us that this can be done. What you see on the right-hand side panel is the integration of the factor VIII and the control that is just episomal expression of factor VIII. What you see on the outermost panel is the normalization of bleed time in the tail part of the mouse model. Actually, it's looking very promising. It's 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. Karin, we need some more targets to use all these wonderful technologies within. How do we do that?
Thank you, Lars. As you have seen, we are taking opportunity of leverage of the technologies with very well-known biology in the case of factor VIII. The reality is that the challenge that we have today is much larger. 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. How are we going to be able to deliver the next generation of innovation with these, with the challenges that we have? The trick here is that we have the opportunity and the responsibility to 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 certain level, but the reality is that patients continue to progress. It is defining what is the residual risk in these individuals where we can actually identify ways to help. 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, is 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 diseases.
By utilizing not only circulatory biomarkers, but also looking at the level of the cell, the level of the nuclei, 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 the novel technologies, and then eventually we can offer a cure. Let me take you on a deep dive into how we are doing this in the case of obesity.
We heard a lot about today about the different patients that we have, the responsibility and the opportunity that we have here. 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. If we take the opportunity to grab the patient and walk 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.
When we start to really understand what is the journey from the physician, 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 circulating biomarkers, with the data that we collect from the different wearable devices, with 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're dealing with.
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. 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.
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. With this, I turn to Marcus to let us wrap up.
Thank you, Karin and Lars. This is really just a summary what you've just heard from the three 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 the journey. Everything we do starts with data from our patients, big data and analytics. 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. I hope I've also convinced you that we actually have the toolbox to then, you know, 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. 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. Karin decides who gets the microphone exactly.
Hi. 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? There is a lot more that we can tap into these days with the technology advancing. 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?
Thank you.
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? That's kind of one part of the question. And then separately, perhaps cost and kind of any specifics you can provide us on how much of your R&D budget is kind of towards this exciting stuff. 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, you wanna start with the-
Yes.
The first one, and I might even take a stab at number two, but Karsten, feel free to chip in. Yes.
Yeah. 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 AI-made 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 reacted very promptly when we saw the results coming out of AlphaFold to establish the group in AI. I would say that we are on par regarding use of AI in protein engineering.
What we'll see going forward is that we will be able to generate exclusive Novo Nordisk data to drive our AI. We have an AI flywheel, right, regarding the data we can produce in the LabDroid to guide us into even better protein design using AI. We would like to establish an AI flywheel in the protein design space, and there, I think we'll stand strong. Regarding AI in other fields, we are basically trying to establish all these various paths where we can do it, and we have an approach where we do both 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 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, you know, 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. I think, you know, 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 early or risky or this much on later.
I think we're in total alignment here. If you look back just the last couple of two or three 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. 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, as if I remember correctly, EUR 10 million up front, and then running a phase I study to give us actual data to see whether that antibody would deliver on its promise. It didn't, at least not to what we thought could look like. That's the kind of stuff, you know, how you can actually work through uncertainty and de-risk some novel biology or technology. I would say we're well equipped in this, but Karsten, feel free to chip in or add something.
I think first of all, I'll come back to it later on. A way to think of it in a financial context, then you just saw the technology platforms. We have the table with the therapy areas and technology platforms. When we look at it, then we set aside a given amount of resources for research.
Then we have a discussion around basically on technology platforms. What are the right allocation to proteins, peptides, versus RNA, versus stem cells, versus the oral platform. It's basically a collaboration about all, you know, 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? Now we are maintaining our investments in proteins and peptides, and then we're stepping up in RNA. We did that based on our assessment of maturity of the platform and the three first human doses per year, as Marco showed.
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. As we see it matures, then we double down on it. I would say it's rational investment decisions based on risk reward.
That's actually a beautiful segue into the question I got online, which is diabetes is an active area of investigation externally for stem cell therapy. Any thoughts for the Vertex and ViaCyte 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. 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. 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.
These beta cells need to be of the highest quality. 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. I don't believe that is necessarily the future for a large patient population out there, that they should be on immunosuppression. It actually gives you potentially a nice way into understanding how cells behave in a human body. I applaud and I respect sort of those scientific advancements. To think about a product in the long run, I think will take many more aspects of this. In particular, the game around devices, I think is still a very active area of research and development, I think, where we're all in.
I think we're out of time. Is that correct? We could take one more question. If there's one in the room, then we take the room.
Can I be cheeky and ask two 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.
Yeah.
Dicerna you bought in-house. What was different about Dicerna?
Yeah. Yeah.
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?
Mm-hmm.
Is the nicest thing a cure the only way?
On Dicerna, I tried to elaborate it this morning. We obviously had a very specific strategic collaboration on hepatocyte targets. At some point in time, we could anticipate that we would have exhausted that target space. 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. Our ability to address adipocytes, muscle, cardiomyocytes even, has become really important. 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. I don't know, Karin, do you wanna take a stab at treatment duration and yeah.
Yeah. This is the key question, right? Especially when we're talking about bringing gene therapy. The challenge, and I think it's between the efficacy profile that you will be able to deliver. 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 two years are winding off. I would say, you know, it's probably the easy way to say it is the longer the better, as long as you're able to deliver something safe. But I think that the jury is still out, and if you're delivering value for five years or longer, I think you will have to take it like this.
Maybe at the beginning, it's going to be a period like that we are aspiring while you are able to deliver something for more extended period of time.
Thank you for your great questions, and, thanks for your attention.
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 two fantastic colleagues with me, Karin Conde-Knape and Lars Iversen, and maybe you introduce yourself.
Yes. Good afternoon, and 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 Iversen. I'm heading up global research technologies.
Great. 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 a modern age and in the future, which has a lot to do with digitalization and data. 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, you know, 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 stem cells, which is an interesting area, not only of research, but actually as a novel potential therapeutics. As you can imagine, when we have the ability, which we do today, through either generation or 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.
I think it's also fantastic to see that there's an opportunity space out there in a number of disease area where it's very clear if you were to replace a dysfunctional or destroyed cell type in the human body, you actually make a fundamental difference to those patients. That ultimately gets us very close to what we would call curative. We had a question in the previous session about duration of treatment or duration of effect. That obviously is a very important consideration. 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 actually came up through a long-standing collaboration with Lund University in Sweden, a small company called BioLamina, and we're also working with University of Cambridge on our device. 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. 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 wanna call it a commodity, but something that is actually firmly established in science and medicine in our industry. 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. At the end of the day, I think, Lars, you actually alluded to it, is what kind of commercial model do we send then see? Are there treatment centers?
Are there different ways of how we're actually getting those treatments to patients? I fundamentally believe that this is the 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. I wanna give you two examples and also 2022 will be really exciting year because we are, if all goes well, starting two 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 failure with reduced ejection fraction. 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 wanna call out here is, you know, 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. Yeah. There are no human volunteers that actually undergo cardiac surgery just to receive placebo. That does not happen. Yeah. They're all on trial.
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 where we're gonna 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. I think that is also a learning journey for all of us in the industry to see, you know, 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. Interesting space.
Two new starts of first human trials in the first half of this year, COVID permitting, with patient recruitment and, you know, we're very optimistic about this. Over to you, Lars.
Thank you, Marcus.
You heard Marcus this morning telling about our investments and development in siRNAs. Marcus has told you about our approach in cell therapy, and in a short while, I'll talk about gene editing. I just wanna 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 a two handful of excellent designs of proteins and peptides, and we wanna 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 a few kilometers here in our labs in Måløv. That is an end-to-end system where we can do any type of protein or peptide fully chemically modified and screen it in a multidimensional space, whether it's in vivo or 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. This will strengthen our core business. 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. I will show you that a little bit later. Remember that when you wanna design a gene, it will translate into a protein.
Designing a good gene means that you need to understand the protein that you are 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's coding for. That's why staying really sharp on protein engineering will allow you also to be good at gene design and mRNA design. Let's look at it because we used it in what we are doing in gene editing. We have teamed up with 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 it to fit into the AAV. Hence, without protein engineering capability, you will not be able to engineer the gene going into the virus. These two things have been protein engineered. We'll exemplify them as an mRNA and a piece of DNA. The mRNA will be delivered in a lipid nanoparticle, and the gene will be delivered in the AAV virus. Those two 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 component will 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.
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 a 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 transection model, where we see a total normalization of the bleed time within these bleed mice. 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 bring to man. We have all these wonderful platforms, Karin. What can we put into them?
Yeah. Absolutely, Lars, that's the key question. Right now you have seen how we are leveraging technology with very well-known biology. 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. In cardiovascular and metabolism especially, we have the opportunity to drive, you know, human-centric innovation here. By accessing the datasets that we currently have internally, but also those that we have been able 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 the comorbidities. In the cardiovascular and metabolism space, we have really to understand what is the residual risk.
Therefore, by focusing on this, therefore identify what are the next generation treatments that we can deliver. 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. 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. It's no longer about talking about genetics as a standalone, but really marrying it with what happens at the deep level in the tissue in disease versus health.
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. 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. Also we heard from the patient that this is not necessarily an easy journey. 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 a stage that we can collect so much information, not only on the basis of the regular clinical chemistries that we do, you know, through 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 a patient journey. Is this patient going to continue be 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.
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 that are healthy today, but with their history, their environmental factors, or their societal components, have a higher propensity to develop further into their journey or in the disease. 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. With this, I will turn to Marcus so that he can wrap it up.
Thank you. I'm good at wrapping. If you've paid attention, which you have, obviously there's nothing new on this slide that you haven't heard before today. 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. I think that is the piece, and many people ask me, 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. Then you overlay machine learning, you overlay data analytics to this. I think both of them need to come together.
We're very serious about this human-centric approach, and you see to us 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. 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. Yeah, we're not quite there yet, but we're really much on our way. Then we want to change your mind a little bit to think from an all-comers population to stratified and personalized medicine. Go beyond maybe an initial reaction, or are the patient population smaller? Yes. It actually also means that the value proposition for those patient populations will be, relatively speaking, larger. Yeah.
I think that makes perfect sense, and we can learn a lot from some of our colleagues here and in rare diseases, but also, for example, in the oncology space. Hopefully, we'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. We're building on the strong legacy. I think that is important. We're not doing anything that, you know, we feel is crazy. The new technology platforms are adding to this, and they're filling a void, certainly that we've identified. We're actually driving de novo target discovery much more than we've ever done before. Thank you for your attention, and happy for questions. Yes. Karin.
Thanks very much. 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 25x-30x bigger. Given that there are a number of mutations that lead to hemophilia A, how much can you cover with one
With one gene edit. 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. Firstly, how differentiated is it? Secondly, how applicable is that? Because it strikes me that that gives you a degree of precision on protein discovery that we've not seen before. Thanks so much.
Lars.
Thank you. The construct that we are making for insertion will cover all mutations, because remember that any mutations in the gene is actually halting the expression of a functional factor VIII. The inserts that we are doing is functional, so it will cover all mutations and also spontaneous mutations that you see in that disease. It's one that will be good for all in hemophilia A. Secondly, you're absolutely right, and 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 peptides and protein formats. You have seen it sometimes for antibodies, which is relatively simple, I would say.
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, in brackets, negative trial results underreported. Is that no longer an issue?
It is definitely an issue.
Mm.
I think for any types of AI and machine learning, the amount of 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. For now, the more the merrier in terms of data. Since we don't have a quantum computer yet, we need the data. The day we have to quantum, we'll absolutely go out of needing that much data.
Yeah. Oh, sorry.
Hi. 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. Just around the platform, you know, do you have a bias towards sort of encapsulated versus maybe CRISPR gene edited? Because it would seem that, you know, the devices have been difficult, the ones that have been tried so far, and maybe, you know, a CRISPR gene edited approach might be kind of a more broadly applicable. Just wondering where your mind's at there and whether it's gonna be different for different diseases.
You're absolutely right. I would say if we paint for a moment an ideal picture, then the cell therapy products that we're 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. I wouldn't say it in absolute terms, 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. 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.
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 the 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 you know.
Yeah. 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 I 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. Yeah. 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 ask about choices of cell therapy product.
It's not at this point in time an active decision-making process, whether it's has to be encapsulated or can be directly injected, like in the eye, for example, or in the brain, which sort of is immuno-privileged, as you know. 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 a good shape right now to cover a broad space. Yeah.
Hi, Evan , Guggenheim. Can you expand a little bit more on your target identification efforts in cardiovascular disease? Was that related to your 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?
Yeah. Let me talk generally around the target discovery efforts. As I mentioned, especially in the cardiovascular space, we are very much interested in that residual risk. You know, from the dyslipidemia perspective, you know, LDL cholesterol, it's well served. As you heard also this morning, we have an oral PCSK9. We are working on, and other dyslipidemia, which is high triglycerides. There is still more to be done, right? The plaque at the end of the day is a very complex organ.
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. This is at the same time marrying it up with the genetics, which we know that in cardiovascular disease is actually quite strong. I think it's again, going after the right biology with the right technology then around. 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.
I have an online question here which says: You made it very clear that you are aiming for three 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 three? First, let me clarify. This is not three products, and I'm sorry if that came across. It's three first time in humans, right? That is still a fundamental difference. There's still a journey to be had until we actually see a product out of the siRNA platform, because three products per year, that would be very ambitious, and even I wouldn't be as bold as stating this. 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. I think building on the question and Karin's answer to this, of course, the single monogenic disease drivers, ENPP3, 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. It's also not yet a slam dunk. The interesting part comes when we talk about, you know, multigenic drivers, polygenic risk scores, and so forth. Of course, keep in mind also siRNA has the potential for combination therapy, right? Nobody says we only have to have one siRNA. You could actually have multiple targets in a single preparation.
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. In that, we're also articulating a productivity metric. 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, thank you very much for your attention and great questions. Thank you. Thanks, Karin and Lars.
Thank you, Marcus.
Thank you.
With that, Mike. As you stay there, I think Andrzej can join you.
Yeah.
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.
Hi, 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?
Yeah, 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. The reason being, we don't really have the same level of access right now as Doug has in the U.S. More specific to Europe, maybe
Yeah. A few reflections. I think a positive readout will be positive in terms of enhancing access.
Mm-hmm.
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 will have a positive effect. With that, potentially also for other countries, but NICE and U.K. is often the one that is looked towards.
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 two years or so. Most are coming in. We have a number of other countries where we have submitted application, but I don't wanna speculate as to when and if they will come back.
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. I go to the cyberspace, and this could be for you, Andrzej, and then maybe you wanna add on, Frederik. With more high potent GLP-1 coming to the market, is there a risk that we might see some sort of a tender for the class? I guess they're making reference to our competitor.
Mm-hmm.
They're 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 the normal setup, for sure in Europe. If I think about rest of EMEA market, which is the place where we have a pleasure to cover. GLP-1s, if reimbursed, they are mostly reimbursed on the negotiation price negotiation basis. There are no tenders organized.
It's the same.
Yeah.
Completely.
Yeah.
Okay. I think that the main reason for it is 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 five, six, seven 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 insulin, maybe and none then on the modern insulin segment, but very rarely on the top end and next generation insulins.
Very good. Yes, please.
Carsten Sørensen, BankInvest. Wegovy is approved in Europe, but you haven't launched yet. Could you talk us through the timelines and perhaps also most likely first markets to launch?
Yes. Can I start? Please. 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. Whenever we come to the end of this year, it's probably likely that we'll see launches in Europe of Wegovy.
Yeah, 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. 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 2023 with more.
Yes.
Andersson, ABG Sundal . Since last time we met here 2.5 years ago, you launched this target of 6%-10%. As you showed on one of the first slides, you have been nicely outgrowing. I guess the combination with the fit for market. Can you allude to why you have been able to beat, what has surprised you the most, and what to expect going forward here?
You wanna do the 6-10?
You wanna start?
I can start, and then.
Thank you, John.
I think we've been doing extremely well with Ozempic, much better than expected or really outperforming competition. Ozempic itself is really extremely well-recognized treatment across HCPs, doctors, patients. Highly appreciated, that's one. Secondly, we outperform 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 Soliqua, we can accelerate growth, so we've been doing much better than we thought. In overall market share, we gain more than we expected, so that's good execution.
If I can add, I think one is we just have wonderful products that we're able to launch, and that gives us.
Yeah, they're coming to fruition now in terms of Saxenda really picking up. I think we have improved the way we go to market. We have had a discussion in IO management where we all sit 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.
Mm-hmm.
The last comment I will make is obesity is continuing to surprise us in terms of the potential that we have and the commercial success. We're now getting Europe on board as well, and we had that hope two years ago. We were not sure that was happening. That's one of the things I see are changing the trajectory.
Mm-hmm.
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.
We cannot go.
You cannot sell them in Europe.
Yeah.
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. 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 then 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, they are leading the top ten packs in many ways in international operations on obesity sales, and that is only to come. 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.
Are you starting to see a salary inflation and inflation on other input costs, and what are your options to deal with it?
The answer 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 wanna speak to-
It is selective, and it's part of, let's say, regular
Yeah
business,
When you look at the different markets and different countries, you know, we've been dealing with inflation rates like Turkey for let's say last 10 years. You know, I've been working in previous setup in Latin America. Think about Argentina. This is ongoing business. We know how to handle this. Yeah, it's part of the game.
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 have to manage that and w e do so. 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.
That probably we will have to do as we will see where the rest of the inflation will take us.
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 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.
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. 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-
Mm-hmm.
Is this a product for Europe?
I think, Camilla was speaking to that we haven't set the pricing strategy yet. We do believe that this is innovation that also will benefit European patients. For sure it will be a good product for Europe, regardless of what pricing strategy we're gonna end up with.
That leads me to another question that maybe you could connect it, again for Michael. It says that we didn't really speak about Xultophy today.
Mm-hmm.
In the past, you have referred to this product, Ozempic, in countries like France.
Yeah.
Is that still a driver? Has the market now moved on to Ozempic? Maybe you can speak to, of course, Xultophy in general and maybe France, but Xultophy also, I like to remind people, 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.
Mm-hmm.
Yeah. I think Xultophy, especially for the region that I'm responsible for, is having a large presence in France.
Mm-hmm.
Xultophy together with Ryzodeg actually led us to, for the first time ever, to be a basal leader in the homeland of Sanofi. That was a good moment for us at least to be able to. Xultophy played a key role in ensuring that. France also has 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 a GLP-1 space.
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 increasing of Ozempic in higher dose in a safe manner, like the Ozempic high dose that we will be introducing, will delay insulinization for us and for our competitors. We would probably have to put that in context. There are a number of countries where Xultophy will do well.
Mm-hmm.
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. It should not probably be seen as a general product that we will see in all markets. Yes, we go there.
One more maybe, Mike.
Sorry?
We're about on time, so maybe one more.
One more then. Yeah. You go ahead. We'll try.
That is it.
I've only had one question.
Mind your own business. It's a question about Rybelsus. Looking at efficiency, it should be a no-brainer to switch from DPP-4s to Rybelsus. Could you talk us through the main obstacles on that switch?
Yeah. 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. We are pricing Rybelsus as a GLP-1, and access is according to a GLP-1, which often is a bit later in the process. That's one of the obstacles. When that is being said, we of course are working in terms of, as I said here, replacing DPP4 because we do believe that either if they're in a combination with an SGLT2 or alone, Rybelsus should fit in there. Efficacy is trumping that of a DPP4 any day, but of course, the pricing difference do in some countries play a role.
Yeah. When the access is granted, then we actually see a huge uptake of a DPP-4 switches to GLP-1. The graph I showed earlier on in Japan, that 50% of that uptake is actually coming from DPP-4. If you mix then DPP-4s with SGLT2 combos.
Mm-hmm
Some 70% of that graph is actually being sourced from other modern OADs.
Yeah. A recent launch in Italy.
The recent launch in Italy shows the same.
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, and uptake is simply amazing. It's anecdotal because, you know, we've seen data for the first month, but we reached 5.2% market share in OADs, which is. If we continue like this, that means that Rybelsus, as you say, is no-brainer. Everybody will use it.
With that, I have to say thank you very much. Good luck to the next session. Hopefully it's half as good as this one. See you back on the podium. The best one
Yes. My name is Mike. I'm Managing International Operations. We have a deep dive on region EMEA. Region EMEA is managed by two of my good colleagues, two 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. They will run you through their slides. Hopefully it will take about 10, 15 minutes through the slides, 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 into that, and pass it to you, Andrzej.
Thank you, Mike. Good afternoon. We have two slides which will introduce you to the market, to the market, how EMEA is growing within 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 in obesity. Starting from EMEA, we cover 30% of the population of the world, and we are very diverse region, as you can see. You know, starting from Africa, ending on Russia, and having the whole Europe West run by Frederik. That means different healthcare systems, different political systems, different economies, different purchasing power of patients, different willingness from the payers to pay for innovation.
We have to maneuver, and we have to apply our, let's say, market fit 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 will foresee within the next 25 years. For the time being, it's DKK 100 million market, where you can see 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 market leader. What's...
There are two segments which are growing much faster, where we want to be very much present and have significant importance. First is OAD. It's growing 10%. 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 market leader and our let's say appetite and our investments are growing this segment. 8% t otal growth. How we are doing then as Novo Nordisk? We have accelerated our growth significantly. We've been growing in 2017, 5%.
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. Within GLP-1, majority of growth is coming from GLP-1 injectable. Soon we will see acceleration in GLP-1 oral. 18% of the growth is coming from obesity. It's coming from Saxenda. We've launched Saxenda in 40 markets across EMEA. Last year we have grown our business by 66% within our region, right? All in all, it's. Growth is coming where we expect it to come from because of course, you know, we I think two years ago already when we had the 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 couple of years ago, and now Ozempic represents 80% of share of growth. From the first slide, we remember 30%. This market is growing 30%. On the very dynamic market, we are taking 80% of the growth. I think it's pretty good performance. Majority of patients are coming from failure on oral treatment and add on insulin. That means that explains this graph. Since in last two years, we have grown our market share in GLP-1 injectable segment, with Ozempic growing pretty fast. Victoza of course, you know, 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. GLP-1 injectable I think is good performance. Now I'd like to ask Frederik to share with you how we wanna repeat the same kind of a performance in the GLP-1 oral, and how we wanna build obesity market.
Thank you, Andrzej. Did you click? Oh, I'll do it. Good. Welcome. We are entering for the first time the modern OD segment with Rybelsus. EMEA represent DKK 35 billion, growing by 14%. On your left-hand side, you see the uptake curves within that segment for the countries in which we have market share data. We launched in 2024 at this point in time. The uptake is what Doug said we're 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 every one 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 posed challenges on two fronts. One is that the dynamic in the segment is not as we would like it to be because patients are not going and seeking change in treatment as normally. 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 endos whom we've known for many years, but more specifically, we have added new customers to our target list, especially in the DP segment, to establish a relationship during COVID has proven to be challenging.
All these learnings, both how 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 two 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 anecdotally, 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 spoken to earlier today, huge unmet clinical need. In this region, there 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 two 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, it's 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 required. I'm not gonna 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. Basically people that are only solely focused on obesity, people we have invited into the company who has experience from selling out-of-pocket and have a different profile than our diabetes rep, 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 three pillars, one of payers, one of patients, one 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 of 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 one, two, comorbidities could then be less. Secondly, also in some countries, they are restricting the number of physicians that are actually eligible 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, and 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 Cardior partnership in Germany. Here I brought two U.K. examples. We could have done the same for Middle East. The two I wanna bring is two 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. Majority of those are offering also a weight management service. They do it with in physical stores. Boots do it online. 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. A lot of public campaigns, many of you might have seen them either on buses, in printed media, in TV or whatever. We are doing a lot of public campaigns in order to pursue this opportunity. What we have found, and Doug was speaking a bit to it, and Lisa was in the morning, it's difficult to find a doctor that actually either is knowledgeable or willing to treat obesity. Therefore, maybe I'm belittling the point, but think of the HCP locator as a dating site.
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 wanna search for HCPs, physicians that have shown an interest, are willing to treat obesity." 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 four countries. 17 more are gonna come during this year. 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 physiology 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 one where they will be completely going apart. 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. Ozempic on track to become the most used GLP-1.
With Rybelsus, we are entering a completely new segment, one that will give us a lot of joy for years to come. 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. With that, Mike, you will take charge.
Thank you very much. Yes, I saw Pete first, and then Michael, and then yes.
Thanks. Pete. Thanks, Pete from Citi. Could you just describe generally, like given the growth we're seeing in GLP-1, just the reimbursement environment here, is it sort of blowing hot, getting better, or do you get a concern that restrictions are gonna come in? And then just for Saxenda and Rybelsus, could you just give us a flavor, the top three markets in EMEA for those two products? Just can you give us a flavor what are the biggest three top markets? I know you're not gonna disclose actual sales, but just give us a flavor.
Yeah. You can go one after the other.
I can start with the Western European front, GLP-1 and access. No. We don't see it. We don't feel it either at this point in time that there's a general pressure either on prices or access levels.
It's a similar situation.
Yeah, I would say so.
In my part of the world, especially that reimbursement in, let's say, my region is quite limited. Very often we sell our innovation out of pocket and so patients, they have to pay from. There are few markets where reimbursement is available and no progress.
You saw from my graph, Pete, also that proportionally, GLP-1 is very small.
Yeah
... 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.
Mm-hmm.
Yeah. In terms of Saxenda sales-
Yeah
It would be without being one to ten, the largest one there 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. Those would be some of the large ones.
That was almost one.
No, yeah, but not in that order.
actually add
Add Brazil and Colombia to it, then you have your top 10, yeah.
Yeah, yeah.
At this point of time, it will probably be U.K. in absolute sales. We are seeing some of the newer launches that are coming in and also.
We've just launched in my region.
Yeah.
That's what I have to say.
I think that the biggest potential will be, as I mentioned, Japan to start with.
Yeah.
It will be U.K., Spain, Italy.
Yeah.
Then you will basically have to exclude the two usual ones, that's Germany and France, because we are not launching there. Then outside of these two gentlemen's territory, add again, Brazil, India, Saudi Arabia.
Mm-hmm
... was mentioned-
Yeah
... would be the top ten for that. Yeah.
Good. Yeah, Michael, and then we go there or, yeah. Yeah, Michael is here.
Staying on the reimbursement side, is there any sort of rational reason besides cost why U.K. NICE decided to sort of cap it at two 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 Wegovy?
I can start. I can only speculate on your first one, but I'll give you what I have. For the U.K., we are in a draft situation, and of course, the final one will come end of April to beginning of May. Those are some of the discussions we have with them. We don't have a stopping rule on Saxenda. They are willing or want to have it on Wegovy.
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 gonna tear my budget apart.
Yes, please.
A quick question on oral GLP-1 Rybelsus. Your goal is to replace DPP4. I was just wondering whether you would have a specific marketing campaign ready or when the DPP4 will lose their exclusivity, if there is a specific timeframe or specific strategy that you have already in place to push for Rybelsus prescriptions and marketing campaigns.
Yeah. 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 it due to the LOE. There is no secret that yes, the strategy is to not replace but displace them. The ultimate aim is to eventually become a market leader in the modern OAD segment, which means the DPP-4s and the SGLT2s. The competitor you could say in some way is the SGLT2, as they are also seeing good growth rates.
With regards to timelines, I, you know, unlike our strategic aspirations, where we say by this date we want to be that market share, we don't have a very specific target that we externally communicate. 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 2024, 2025 is when DPP-4s will lose their exclusivity, so we do hopefully see that there will be a bit of a jump at that moment as well.
Yes. 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-$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 MSD's, I guess? And what feedback do you get from the governments and on obesity price? Yeah.
Mid-single.
Mid-single digits, yeah.
Does any of you guys wanna say how 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.
Yeah. I mean, the discussions we have with the authorities are of course based on that they do an evaluation of the cost benefit when we go to reimbursement.
Mm-hmm.
What we are seeing are costs that are in line with what's been stated here. At this point of time, we're gonna 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. 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. Hence they actually had some pretty nice appraisal of Wegovy in the U.K.
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 then I come to Carsten.
Thanks. Just on Saxenda and some of the ways of trying to sustain patients and increase their stay time. How's stay time developed over time? Have some of these you know online tools meant that that has increased? Just thoughts. Thanks.
You wanna start?
We have introduced several patient support programs, which are quite comprehensive because of course, you know, stay time was a big problem for us. In the markets where we have introduced this, we have seen significant improvement, like 20%, 25%, 30% longer stay time than normal. 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'll launch product, we were just hoping that single prescription will be sufficient.
That was not paying off as according to our wish, because of course, patients, they lost a bit and then they were discouraged either by, let's say, price, because of course, majority of the sales are coming from out-of-pocket, or lack of support, because, you know, like after two or three months of treatment, you feel like, "Hmm, 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.
Mm.
Maybe to add to that, and it is logical what I'm gonna say, but the countries where we are having and getting reimbursement, we see a significant increase on the stay time as well.
Yeah. I can actually give you a little bit of a flavor on that. The average stay time is around 3-4 months in international operations, which is substantially lower than if you would ask my colleague, Doug in the U.S. The reason behind it is really the reimbursement. You know, as humans, we feel weight has to go down and down and down to nothingness. So after a while, like glucose, like lipid, it stabilizes, but then we kinda feel like the product's no longer working. If you're paying for the product, then you maybe 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. With weight, kinda there's an education element to that. If you have to pay for it, then of course you kinda 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 better than with daily products. There's some obvious math behind that as well. Carsten.
Thank you. Back to the U.K. NICE decision or recommendation, it was obviously very interesting. But can you try to compare to some of the other times you have discussed with U.K. NICE about Saxenda, liraglutide, Ozempic, whatever. How was this discussion? Was it easier, harder? What did you feel from the discussion? And one more, if I can sneak it in. In Japan, the uptake you're seeing so far with Rybelsus, has it impacted Ozempic in any way?
Mm-hmm. I can start with the U.K. one. It's probably difficult for me to sort of balance whether it was easy or more difficult. What we are seeing is that following COVID and specifically Boris Johnson's plea 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 there was a potential request also from the authority side to have a very efficacious product entering the market. 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.
Yeah. To Japan, the data you see, of course, is from last year, where there's only one or two months of massive uptick post- restriction lift-offs. You know, in Japan, you have the first year restricted, it opens up. We have to wait and see, of course, what happens this year. Having said this, 75% of the patients that we are pulling in from Japan are either on DPP-4s or a combination of a DPP-4 and SGLT2s. You could argue that at one point or the other, you're getting patients that are naive, basically, to a GLP-1 coming into it, and that portion, one could have argued we would have pushed through with Ozempic if it did not have a Rybelsus.
Now, of course, they might favor g oing for an oral medical rather than an injectable and l eave 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 the barrier to injection that's much, much higher than when you get started.
One more question. Yes, please.
I think I'll go without the mic.
I think you have to use the mic because of the hybrid thing.
Okay. Yeah. Just a question on the during the day when you talk obesity, you talk about changing the stigma both with healthcare personnel 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.?
Um-
Is it a different discussion?
No, not compared to U.S. I think compared to how we were all doing it three, four years ago, I see a massive difference. You know, 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 kinda bundled everything together, and we tried 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 realized that if you think about patients first, these two patients are fundamentally different.
Mm.
A patient with diabetes is scared of their life and the 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. Therefore, we actually structured it with different business units. We brought different people in than the ones that were just clever in selling diabetes. That has been a big part of the success, on the back of, you know, 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 through that learning.
Yeah. We have to build HCP pool. Many of them
Correct. They are not skilled.
Yeah.
They were not skilled like four or five years ago.
Yeah.
I do think as we go forward, digital health and telemedicine, online pharmacy will play a massive role in all of this. You'll see that in whatever city you come from, most of the stores that 20 years ago were selling extra large clothing are no longer there. It all has moved to online.
Mm.
The reason is the shame. People prefer to sit in 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. 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 we do.
Mm-hmm.
With that, I'd like to say thank you very much.
Thank you.
See you in the next session. Yeah.
Thank you.
Welcome to this, we hope, very exciting session on two of our other serious chronic diseases. We already covered cardiovascular disease in the previous session, but we felt that we wanted to spend some time in the NASH and in the Alzheimer's space. We have our forward-looking statements. You've seen those. Obviously, again, this speaks into our strategic aspirations. We need to expand, and we like to diversify into what we call adjacent or other serious chronic diseases. Just like with cardiovascular, we are actually a little bit excited, not only by the acquisition of Dicerna, which lends itself to a strong potential for preclinical pipeline, soon to be hopefully a clinical pipeline, but also having a clinical pipeline already now as we speak in the NASH, in the Alzheimer's space.
Now, to be very, very honest, and obviously we have to be that here, NASH was smack in the center of our original R&D strategy. Alzheimer's was actually not so much. It fits, and I'll come back to that and why it fits, but we actually choose to go into Alzheimer's disease in the clinical space because of clinical data that compelled us to do so. Alzheimer's is still very closely related to the cardiometabolic space. Having obesity is associated with at least a doubling, and having diabetes associated with at least a tripling of the risk of developing Alzheimer's disease. Some even call it type 3 diabetes, so it fits into what we wanna do. It was a little bit reactive based on data. Sorry. I am going in the wrong way.
Obviously, with everything else we do, we want to address unmet needs. In NASH, there's a tremendous unmet need. There's such an unmet need that we don't even know how many patients are out there because there's no treatment, and there are no really, really good diagnostics out there to support us in that. In Alzheimer's disease, I'll venture the little bit naughty statement, there's virtually no treatments out there. We do acknowledge that there have been some recent approvals, but they have not really had a major impact on the disease and the patients. Big unmet need. Looking at our clinical pipeline, obviously again, going back to the maximizing semaglutide value, you see semaglutide in monotherapy in what we call F2 and F3, which is sort of the mid- stage of NASH disease.
We believe that semaglutide is superbly fit in that space, but we also look towards the combination therapies moving to the later stage of NASH, namely F3 and F4. In order to do that, we've been looking towards our internal pipeline, FGF21 w hich is currently in phase II. We've also looked towards external collaboration, and we have a really strong collaboration with Gilead Sciences. In the research space, obviously in the development space, we are currently conducting a phase II-B study together with them, combining semaglutide with two of their assets.
Actually also hopefully soon to be in the commercial space, where we combine our knowledge, building synergies between the two companies, because we acknowledge they complement us on stuff that we maybe not have, and we complement stuff that they don't have in the research, in the development, and in the commercial space. We are actually becoming more bullish on NASH. Three years ago, when Mads decided that we had to go into NASH, it was a really good idea. There was more than 100 assets in clinical development for NASH, and we were maybe looking at a potential of being number 10 to market. Today, based on a number of recent failures, we are actually looking at the potential of becoming almost first to market. We are looking into a less crowded space.
That still speaks to the tremendous potential, but also to the tremendous unmet need of NASH. The reason why we are bullish is basically based on our phase II trial. Some of you were asking, "Why did you do almost 400 patients in phase II? And why did you do 72 weeks of treatment?" Most of our competitors have been doing 12 weeks or 24 weeks, and they have been doing it in fairly small studies. The answers here gives us a robust basis for taking some good conclusion based on data. Regulatory requirements in NASH is twofold. Based on liver biopsy, you had to show improvement in hepatic steatosis without worsening of fibrosis, and you actually also had to then prove or demonstrate improvement in fibrosis. We did just that in phase II.
On the steatosis part, we improved steatosis in two-thirds of the patients to be compared with approximately 23% in placebo. This is clinically relevant, highly relevant, and statistically significant. Maybe even more importantly, we are among the only ones who've demonstrated a clinically relevant improvement in fibrosis. Now, in the regulatory required endpoints, it's not statistically significant, but the study was not powered to do so. If we see the same difference in phase III, we are in a really, really good place. It will be significant, and it will be highly clinically relevant. If we look at fibrosis in a slightly different way, namely how many progress to the next level, we see a 75% reduction in the risk of progressing to the next level of fibrosis. You don't have to take my word for it.
The U.S. FDA looked at this data and said two things. First of all, you get breakthrough designation. That's sort of a blue stamp of the validity of the data. Second of all, they also said these are clinically significant and will allow you to use this study as one of the two pivotal trials that we require for a regulatory approval. We don't have to do two phase III studies or one super large phase III study. We can actually do with this one and then the next one. This is the ESSENCE trial. This is ongoing, randomizing patients with NASH F2 and F3 to either semaglutide 2.4 mg or placebo. The study is ongoing. We've recruited actually more than half of the patients already now.
That's ahead of our own timelines, and it's actually also the fastest recruitment that we've seen at this space so far, including Gilead. I had to give credit to Gilead because they've actually helped us a little bit on that. We've actually become reasonably good at doing these clinical trials. The study is also special and I'll take the same sort of approach in the Alzheimer's trial. Just so you understand our thinking, there's a regulatory requirement based on biopsies. There's 72 weeks of treatment. Again, we had to show improvement in steatosis and improvement in fibrosis. For payer purposes, for physician purposes, moving into a new space, maybe we need to go beyond biopsies. We would like to demonstrate hard endpoints, hard outcomes on liver outcomes, but also on cardiovascular outcomes.
That means that we need a little more time to accrue our events. The full study will be 240 weeks, almost five years. The regulatory part and the approval, approvability part is only 72 weeks. This is something that will hit us reasonably soon, which is also why we have to find another focus area for ourselves. I just mentioned that there's no real good diagnostics for NASH out there as we speak. That's a challenge because honestly speaking, I don't know how many of you, I hope none, have tried a liver biopsy. It's not super pleasant. It's actually quite painful, it's invasive, and it's also dangerous, and it costs money.
Therefore, not a lot of physician, certainly not if we want them to go into broader treatment, and not a lot of patients want this. It is currently the regulatory requirement. What we need to do is to look at how can we help the treating physicians who are already out there diagnosing their patients to validate the biomarkers that are not invasive. We have given some examples here. The ELF is one of the non-invasive biomarkers that we are looking towards maybe supporting. What we can do is to establish academic but also commercial collaborations with commercial players who have these biomarkers available and help them validate their biomarkers. What regulators are looking for is to, in the same trial, have a liver biopsy and then this biomarker, and then to see the correlation and the validity of the biomarker.
With our ongoing phase II trial in FDA 301 and obviously also in the ESSENCE trial, we have a unique opportunity to actually help validating biomarkers. This is a new approach to us, but I think, Camilla and I agree that if we are to be commercially successful and also to serve the patients who actually need this, we need to help making the diagnostics more readily available. We won't stop at the diagnostics. We'll also look for treatment monitoring and potentially also for prognosis biomarkers. We'll start with that. With that, I would like to hand over to Camilla.
Yeah. Thanks a lot, Martin. Just a few perspectives on the commercial potential here and how we view NASH. What you see here is that we expect that around 22 million people are living with NASH, F2 to F4. The problem is, of course, that right now not many of them are diagnosed, and for sure, people don't have access to treatment. The potential that we will be looking at, of course, depends a lot on how many can be diagnosed, and of course, the effectiveness of the treatment that we are now testing, as Martin explained. Basically, the reason, or the hurdles between the prevalence of NASH and then the patient getting access to it are made of low disease awareness.
Basically, because as you explained, Martin, for many years, there has been no treatment here, so there has been no point in trying to diagnose and for sure not to do a biopsy with all the risk that it includes when there is no treatment to get at the other end. When we look at what we need to do to maybe be commercially successful, it of course relates to building the presence with the physicians. Those are endos, hepatologists and primary care physicians, but just as much also to focus on increasing the diagnostic rate.
Those are some of the partnerships that Martin just talked to, that if we can do that also in a non-invasive way, then of course this will ease the burden for the patients, but also for the physicians and the healthcare system to get to the actual treatment. Here of course, we are now looking at how can we generate the evidence, proof of the cost-effectiveness of this, and of course, what can we do to show how we can stop clinical progression, so that both physicians and payers understand this. Those are the very basic steps that we need to work with. It might look quite simple to just get this done, but keep in mind that this is a disease area that has not been treated before.
There is a lot of new habits that we need to work with. I would suggest, Martin, we move on to Alzheimer's disease, and then we will get questions on both at the end, if you're okay with that.
Yeah, I'll try to be brief. Just two words on why we're doing this. Again, it fits very nicely into the cardiometabolic space where we have defined for ourselves we need to be. Alzheimer's is high risk. 99% failure rate historically in drug development for Alzheimer's disease. Again, it speaks to the tremendous unmet need. I think most of us know someone who suffers from Alzheimer's or dementia. It's a devastating disease for the person who has it, but certainly also for families and to an extent also to society. Big, big unmet needs. We had a very, very cool statistician who decided that she wanted to look at an external database and see what does GLP-1 do for patients in Alzheimer's. It's a big database. It's a Danish database, and she was able to go 10 years back.
To cut a long story short, she was able to demonstrate one year on GLP-1 treatment was associated with an 11% decrease in risk of having a dementia diagnosis. Two years of treatment, 25% decrease in risk of having an Alzheimer's diagnosis. Again, in an area where there's really nothing out there, this is a tremendous upside. Problem with databases is obviously they are confounded. We had to adjust for confounders. In a Danish database, we could actually do that a little bit. So some will ask, if you are on GLP-1, is it just because you are affluent and you are well educated and stuff like that? The others get the not so good drugs and therefore there is a difference already there.
In the Danish database, we could adjust for educational level, and that meant nothing. We could adjust for a number of different factors. Basically anything we choose to adjust for demonstrated the same reduction in risk of having a dementia diagnosis. It's still a big decision, we took it further. We tested three more databases coming to the same conclusion. Being on a GLP-1 analog is associated with a dramatic decrease in risk of having a dementia diagnosis. We decided, okay, we need to take the step further because again, databases, they do have their confounders. We cannot adjust for everything. We looked at some RCTs. We had the LEADER trial. We had the SUSTAIN and PIONEER trials, outcomes trials not designed to look at dementia, but big numbers and long treatment with GLP-1 analogs.
In that setting, pooling Victoza and semaglutide data, we demonstrated a 53% decrease in risk of having a dementia diagnosis if you were on a GLP-1 versus being on placebo. We looked at other prospective RCTs, all demonstrated either cognitive, metabolic or direct brain morphology improvements in being on a GLP-1 analog for a longer period of time. We've obviously also conducted preclinical studies demonstrating the findings on cognitive impairment, but also looking into a potential motivation. Why should this actually be? It's not intuitive that GLP-1 analog should be really, really good in Alzheimer's disease. In part, it's probably central glycemic control, not having a glycemic overload in the brain. But in part, we also believe it's due to the anti-inflammatory traits that semaglutide have. You know, we reduce CRP with 50% when treating with semaglutide in obesity.
We can see in animal studies reduced central inflammation. It's a key part of the pathophysiology of Alzheimer's development. Combining real world evidence, combining RCTs, and combining preclinical studies, we basically came to the same conclusion. This is a big potential. It's also high risk. 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. We've designed two trials. I show only one 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. Then we follow up because we want to look at hard endpoints for regulatory, but also for pay purposes, demonstrating that we can actually decrease the risk of having a dementia diagnosis. The difference between the two studies is, and this is a good thing, in EVOKE Plus, 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 exciting. Two studies currently ongoing. Two years of treatment.
Once we recruited all patients, and that basically also mean it's gonna hit Camilla pretty soon.
Not Alzheimer's, I hope you mean.
Yeah, talking about potential, what you see here is around 70 million we expect have mild cognitive impairment or mild dementia of the Alzheimer's type. Of course, again, the ability to diagnose and the ability to treat is what will make up the potential in the end. These are some of the numbers that you can relate to. Again, to support the difference between the prevalence and the actual treatment rate, there is little bit like in NASH also, the preparedness of the healthcare system. We expect that this, of course, is a disease that is likely to increase also over the coming decades. This will have a significant impact on the workforce, but also of course on the healthcare system. The understanding of that is what we're preparing for.
The diagnostic rate's very important also, and we can work with that again with non-invasive 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. Those are some of the same physicians that we of course already see as part of our diabetes and obesity business to a large extent. On the evidence generation, what is the impact of delaying the disease progression, the role of neuroinflammation, 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 to better document what are the cost effectiveness of this and the impact of actually making a difference here.
For both NASH and Alzheimer's, these diseases 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. We are focusing on specific patient populations here, being F2, F3 in NASH and mild cognitive impairment and mild dementia in Alzheimer's disease. 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 five-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 produce. The way we're gonna 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'll be hearing about later. 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. That's the way that we are building our presence from headquarters to regions to affiliates over time. 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.
Yes.
if you want.
Yep. Michael-
I'll let you know if there are more.
Yeah. Michael from Nordea. So two questions to Alzheimer's. First of all, why did you go for the 14 mg oral dose of semaglutide? Now we see it sort of being more the 25 mg and 50 mg you're testing, and there could also perhaps be less variability from injectable. That's the one question. The second question, how do you sort of cater for not being in a situation as you've been with Wegovy and the uptake and supply? Because there's no doubt if this hits the mark, then obviously there's gonna be overwhelming demand. Maybe you could just explain how you're trying to safeguard that in four or five years from now. Okay.
On the dose, as with everything else, there's a 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. We know that all of the data that we have have been generated on the diabetes doses. Either with Victoza or with semaglutide, these have proven to be efficacious doses in the Alzheimer's space. In order not to jeopardize any safety considerations, we basically choose the diabetes dose to be the right dose in this space.
Yeah. 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 could be potentially to a large extent also a patient-driven or family-driven demand. 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 the 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. Maybe that's one way to at least think about preparing for the supply situation.
Okay. We have a lot of questions here. If you're just out on the front row here, then maybe you can pass the microphone down the line.
Thanks, Pete. Just two 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. You know, you're asking Alzheimer's patients to take oral medication. You know, it's not gonna be the same as Rybelsus, I hope, in terms of a bit of water, hour fasting. Is that really a fly?
On the recruitment rate, in ESSENCE specifically, we have some metrics to compare up against, and we're actually currently recruiting ESSENCE faster than any other phase III trial in the NASH space. Super nice. On the two 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 recruited approximately 500 patients. On the dosing side, yes, it is gonna be Rybelsus, 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.
Hi. 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, you know, 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, you know, early Alzheimer's? Because that would impact uptake curves. And then the last one, I've actually spoken about, you know, what you've sort of imputed as your sort of magnitude of difference between the treatment arm just to, you know, to help you understand powering and impact of effect it might have.
Absolutely. On the first one, the only data that we have, again, are clinical data. Obviously also a little bit on pre-clinical data. What we could adjust for in the original database study was actually vascular or cardiovascular disease. When adjusting for cardiovascular disease, back to your question on microstrokes, we did see absolutely nothing. It still is appearing to be a very robust finding irrespective of vascular status.
Just for example, in those like, dementia data that you have, you don't. You've no idea what percentage of that is confirmed Alzheimer's versus non?
No, I mean, there we have to look at epidemiology. We know that approximately 60%-70% of all dementia patients are Alzheimer's patients. That sort of helps us a little bit. These are obviously some of the discussions that we've had with the regulatory authorities. Now you have to remind me of the next question.
Yeah. Whether patients had 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 one of the two but with historical data. They don't have to have one new assessment as part of the enrollment into the trial. That obviously ease our sort of trial conduct and recruitment, but it will also ease what happens to the market. Going back to Camilla's point, even here we will be looking towards less invasive, less costly diagnostics, supporting basically the validation of those diagnostics, blood-based measurements of amyloid or tau, so that it will become easier to find those patients.
Sorry, the last one was just what the estimated, you know, efficacy impact would be within your sort of-
For the primary endpoint, we're looking at CDR-SB and a slowing down in reduction in cognitive impairment. It's basically a 0.5 estimate in that. I think in the longer extension part, we will be looking at with power to the tune of something that we've seen in our real world evidence and our historical CTs.
Thanks.
Thank you. Florent Cespedes, Société Générale. Quick question on Alzheimer's. Other class of drugs demonstrated or were supposed to have an impact on inflammation and on Alzheimer's disease, NSAIDs or statins, and they also had at the time some clinical evidence of potential efficacy and unfortunately they all failed. 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 some subgroup analysis? Because Alzheimer's disease is supposed to be a kind of autoimmune disease, so maybe it's not one population but different population, if you have already factored all that in your clinical trial design.
Yes. 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 part, 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. 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.
There's a group analysis even through the year?
Yeah. 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. We know that there are also other dementias, Lewy body dementia and so on. 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.
Very interesting. Thanks.
Thanks, Martin. We are getting signs from investor relations that we are really out of time, but if it's very fast and the answer is also very fast, then I think we can go. Yeah, you. Very fast.
Thanks so much. I will be quick. Just on Alzheimer's again, you said about adding vascular dementia patients to broaden the label. Can I flip it round and ask, 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 for another 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.
There are pre-specified endpoints.
Yes.
On there. Great. Thank you.
Great. Thank you very much. Now I guess you're on to the next session somewhere in this neighborhood. Thank you, Martin.
Now I will start, and hopefully you can hear me. Welcome to this super exciting extension of our other serious chronic disease session, where we'll 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 rundown 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. We define the 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. Just for your information, having obesity is associated with a doubling in risk of having an Alzheimer's diagnosis. Having diabetes is associated with a tripling in risk, and some even call Alzheimer's disease type 3 diabetes. 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.
We are looking towards Marcus and his people towards a very strong pre-clinical 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. 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 a 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 F 2 and F 3. We do believe that if we are to serve patients with the advanced form of the disease, F 4, then we have to look at combination with other modalities. This is why we in our clinical pipeline are looking at combination with our own internal asset, FGF2 1, and this is currently ongoing in phase II. 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. We are doing combination evaluation, so in a phase IIb setting, of two of their assets in combination with semaglutide to see if we can serve patients suffering from the late stage of NASH.
Our big shot on goal, and I'll come back to why that is F2 and F3 with semaglutide in monotherapy. Obviously also I 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 it to that in just a minute. The reason why we think a big shot on goal in NASH, F2 and F3, is semaglutide, is basically our phase II data. We decided a couple of years ago, almost five years ago, to do a big robust phase II trial. Almost 400 patients treated for 72 weeks.
Those of you who know the NASH space, looking at what comes from our competitors, typically 12, 24 weeks of treatment, very small sample sizes. The advantage is then to be in a situation today where we now have the most advanced asset almost in industry based on this phase II data that are robust and reliable, in part because of the sample size, in part because of a longer treatment duration. 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. The secondary endpoint or the primary secondary. The co-primary endpoint it's called was reduction in fibrosis.
With semaglutide we saw both, and we are basically the only company who's managed to do that in the phase II setting. We saw two-thirds 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. These are really, really strong data. The good thing is you don't have to take my word for it. U.S. FDA have looked at these data, and they've done two things. They granted us breakthrough designation because they like the data. That sort of blue stamp of this is good and valid data. They even took it a step further and said, "Normally we require two 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." I don't have to go out and do two phase II studies now, I only have to do one, 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. That's cool, 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 sees them. This obviously has made us very enthusiastic, so we've initiated a phase III trial. This is a reasonably large 1,200 patients trial that will be conducted in two parts, and I'll come back to that in just a minute.
Patients will be randomized to semaglutide 2.4 mg or placebo. Now, what we do is we look at two 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 wanna 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. A full 240 weeks of treatment, five years of treatment, will allow us to accrue data to look at liver outcomes, cardiovascular outcomes, harder outcomes than just the liver biopsies. We'll get the regulatory approval after already 72 weeks.
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's no established non-invasive diagnostic. The regulators, sometimes also the payers, are saying that they require liver biopsy for diagnosis. 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. We are looking for something else. Can't do 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 give us an incredibly strong platform when we get to the market, if we succeed, to have the diagnostics available. That's not gonna be, I think, a commercial sort of win for Novo Nordisk, but it is a prerequisite for us to be commercially viable. Then obviously, having semaglutide on the market.
Thank you, Martin. 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. You know, 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. The diagnostic tools has meant, and the lack of treatment has meant that there is a low awareness of NASH.
That is a clear hurdle from a commercial point of view between the prevalence rate and the actual treatment rate in the end. Of course, that means that the three things we would focus on from a commercial point of view is to build a strong presence, of course. 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'll be in a much better position to actually also give solutions to the market. 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 non-invasive tools becomes extremely important, both for screening and for monitoring.
Finally, we also, of course, need to provide them with insights on is it cost effective to treat NASH? What does it mean? 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. I would propose we move on to Alzheimer's, and following that, we will then take questions on both topics.
Very briefly, oftentimes we get the question, "Why did you go into Alzheimer's disease? We didn't have phase I, we didn't have phase II, why did we go directly into phase III?" Basically did that because we conducted a retrospective database evaluation of what does it mean to be on a GLP-1 analog vis-à-vis having a dementia diagnosis. What we saw was, and there was. This was a very big Danish database that we started out with. 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 one year. Being on a GLP-1 analog for two years was associated with a 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 had to take that kind of data with a bit of a grain of salt. It was a Danish database, so we knew more than we would from normal databases. What we could adjust for, we did, and we found a very robust finding. One year, 11%, two years, 25% risk reduction in having a dementia diagnosis in a tremendous area of unmet need. We followed up by three more database searches because you tend to not trust just one database. Again, there are confounders 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 big data research, we then said, "Okay, we have some RCTs that we can look at." We have our own historical outcomes trials with Victoza, with semaglutide. If we pool those, pooling LEADER, SUSTAIN 6, PIONEER 6, we get a big patient pool treated for several years with a GLP-1 analog. What does that show? It basically demonstrated a 53% decrease in risk of having a dementia diagnosis versus placebo. Quite dramatic. We felt that we had sort of a good base to start on. It appears that being on a GLP-1 analog is associated with a decreased risk of having dementia.
We then followed up, looked at other prospective RCTs, demonstrating that being on a GLP-1 analog is associated with, in some studies, improvement or a slowing decline in cognitive impairment, improved brain morphology, improved brain metabolism. We could then follow up in our preclinical 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 inflammations, which is the other underlying piece in Alzheimer's pathology. 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 base that any in 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's zero risk here. There's actually quite big risk. Historically, Alzheimer's clinical development is associated with a 99% failure rate. Just taking that number into account, there is risk, and we'll never belittle that.
Looking at the potential of reducing the risk of having Alzheimer's disease to the tune of somewhere between 25% and 50%, we felt that we had an obligation to at least assess this in phase III. This is what we're doing. We are conducting two very similar looking trials, 1,800 patients in each trial, being randomized to either semaglutide 14 mg or placebo, with again, a two-tier approach or two-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 endpoints, risk of having a dementia diagnosis, for regulatory purposes, but also for payer purposes. The only difference between the two trials is, and this is a good thing from a regulatory perspective, regulators, U.S. FDA, EMA allowed us to, in one 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. We are currently in the midst of recruiting those two trials, and therefore, again, think about two years of treatment. This is something that is potentially being on the market very soon.
Yeah. Again, if we look at the commercial potential here, we just included patients with mild cognitive impairment or mild dementia of the Alzheimer's types. 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 there are between the prevalence and then the getting the treatment are, of course, the recognition of the symptoms. It's also the testing of the diagnostics and then the simple biomarkers and simple tests. 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, like, that Martin just referred to, we expect that the prevalence of Alzheimer's is likely to increase in the future. This will put a significant strain on the healthcare system, both in primary care, but of course, also in the specialist system. 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. Education around this screening, easy screening tools for primary care that are often the first people who meet the patients, would be important.
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. Of course, all of this we are preparing for while we are waiting for the exciting results of the phase III trial that, of course, none of us know about yet. In summary, NASH and 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. We will be focusing initially on NASH F2, F3, and on mild cognitive impairment and mild dementia due to Alzheimer's disease. With that, we are ready for some questions if you have.
Online, you can also type in questions, and we will get those here on the iPad. Martin, I suggest you handle the questions. Yeah?
Yeah.
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?
I can't go too much into detail on our discussions with regulatory authorities. I think it's 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 database that some sponsors have given to them, very small, very short phase II trials, leading to failure in phase III. They've granted us a breakthrough designation, but they want to see more data before they probably want to discuss accelerated approval timelines or stuff like that. I think that's absolutely fair. We had to raise the bar for what kind of data do we generate in this space.
Just clarification on that. 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 that dialogue when we've seen the data. Obviously, the disease is representing a tremendous unmet need, but also the FDA again wants to see robust data. So we have to take that dialogue when we get there. We're not sort of in a position where we can say we do that now.
Separately, Camilla, as you think about kind of the commercial part for NASH, obviously big, you need the non-interventional diagnosis to get sorted for it to be a really big product.
Mm-hmm.
How do you assess the likelihood that we will get some form of non-interventional diagnosis before kind of the phase III reads out, that is approved by the FDA and kind of across the world?
Yeah, maybe I can start, and then Martin can add on. Right now we are looking at, you know, 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, you know, be able to provide diagnostic tools. From that, there could be a good collaboration, not necessarily just with one partner on this. So, we're working with a short list that we might zoom in a bit on a few on that, but that's sort of where we are. Clearly, this is an important step for us to get solved, not necessarily having to do it ourselves.
Yeah, 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. The FDA has very strict requirements for what they want to see in terms of a diagnostic specificity sensitivity. What we can help is validating those biomarkers. We are taking the liver biopsies, which currently is the gold standard, and then we are also measuring, for example, ELF. We are using FibroScan in our clinical trials, so we can help the manufacturers of those tests to validate their diagnostic tools. If we can do it within the timeframe, that's clearly our aspiration, and it should be doable.
Two quick ones, one here. Just firstly, just going back to the NASH phase III, I just want to be crystal clear. The FDA said you need to hit both of the primary endpoints-
Yes.
For approval. Yeah. Both need to be statistically significant, but that then is acceptable for regulatory filing without the follow-up, yeah?
Correct.
Just with regards to then you talk about partnering collaboration just now for diagnosis, non-invasive tests. Equally on the treatment side of things, you've got a sort of collaboration with Gilead in SELECT. But really that's as far as you've got so far. Do you see it that you're gonna get semi over the line before you then go broader? Or you know, 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 go?
We don't necessarily need to see semaglutide go over the line, but what we do need to see is scientific clinical plausibility that this combination could work. 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 requests for collaboration, some of which we're taking into consideration, some of which are honestly not necessarily meeting our bar.
Sorry, just quickly. You have so far other than Gilead, there's not been any other things you tested?
No.
I'd like to ask about the blood pressure for Alzheimer's. Are you screening for high blood pressure, and are you using that as a secondary endpoint?
The answer is no and no. We do measure blood pressure, and we will have the data. But in order to not, I mean, the more exclusion criteria you have, the more difficult it is to recruit, and therefore we have it as an important assessment. I don't wanna 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 population or the Alzheimer's population in terms of the trial? 'Cause obviously you set off with a, "These are the number of patients that progressed to getting dementia and 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 sema treatment?
I've come to realize over the last 25 years I should never be too confident. 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. 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. Mild 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. Doesn't necessarily mean that we don't want to. 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. I mean, time will tell, but this is, at this point in time, as good as we can do it.
Good. Any final questions? Yeah.
Just on Alzheimer's, obviously we're gonna 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? 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 these sema studies would have had a different standard of care?
From a clinical and from a trial conduct 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, slightly earlier population than what has been investigated by, for example, Biogen and Lilly, but also a safety offering that is very well-established, where we know that the antibody treatment does have some safety issues.
I think from our perspective, we are maybe looking at slightly different populations, and we are 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.
Do you think one of the studies, other studies shows cognition benefits?
I was about to say I hope so. 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.
From this point of view, without making further analogies, it also reminds us a little bit about 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 how what it feels like every day for families. We also expect that this will be more of a patient or family-driven sort of a disease in the sense different from NASH and from diabetes, for example, where it is a specialist-driven sort of approach to it. This might tell us something about also the shape of the uptake curves by the time we get to launch. Clearly, efficacy and safety has always played important parameters when we have to think about access and uptake.
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 this is post-hoc trawling through data and finding out, 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 mechanisms?
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 as a disease, and that will potentially allow us to expand into other modes of 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.
Great.
Thank you, Martin. I think that concludes our session. I get the sign that time is up. I think you will get a small break right before we have to be back in the plenum. Yeah. Thank you.
Thank you so much.
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 colors 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.
Manufacturing do need to be not only in front of sales, we need to be in front of all demands across the organization. How do we do that when we also want to drive operational efficiency as we have already 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? Oops. There's a lag on this. This one. First of all, we have an extremely 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 the pinprick on the map is very small, we have all the capabilities here. They are extremely close to R&D activities. I'll 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 the U.S. We have also, in the recent years, established large API capabilities in the U.S. We have touched upon it a couple of times today. We have also started our cell therapy adventure in the U.S. This structure is, despite geopolitical tensions, COVID-19 pandemic, 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.
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 4 x up the manufacturing volume as we did in 2019. If you just take the brand itself of Ozempic, we are 3 x up in our fill finish area, and that's global numbers here. It's a significant increase compared to the good old Novo Nordisk of the insulin developments.
I'll come back to what we are doing to defend this. Here I've tried to illustrate what we also communicated in the full year, that basically for 2022 we are now at a pace of DKK 12 billion in CapEx. 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-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 pile all the marketed products on the right-hand side here. We have touched upon many of them and what is the potentials of those products. I've 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.
It's not that it's a one-to-one, you know, investment, and then we increase the risk for not utilizing this capacity in the future. How is our manufacturing principles? First of all, we need to ensure that we have sufficient capacity. Secondly, capacity without compliance up against cGMP, you cannot use that. Then finally, driving efficiencies across manufacturing. We will continue expand our highly efficient internal capacity worldwide. We have touched upon it a couple of times today, we will see more devices in 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 around the CMOs of the world.
We will use the top-tier CMOs for ramp up against the high volume demands, but certainly also to have a broader and higher flexibility when we respond to the pipeline. Finally, we are working with backup factories and safety stocks that also together with other companies in this area has been under pressure due to the supply chain disruptions during COVID-19. This is fundamental for us to work with that. 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 two 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. Of course we also have the constant chase of lower unit costs that, where we use tools like lean, et cetera. Let me bring a famous example of how we deal with a 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 two platforms. We are working on a single-dose device that is the famous one with the CMO. 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 assemble and pack both in Europe and in U.S. and other places over time, utilizing this platform to increase the volumes. The same goes for assembly and packaging within the FlexTouch platform. 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 an illustration that the newer products 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 4.5, version 4.5 or something. I think I've only received version 1, maybe soon version 2. 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. 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. You see the older products where you can actually also take human insulin, where we have managed to optimize a very old platform and actually drive those unit costs further down. We work on technology platforms, and we do that constantly over time. I mentioned the obvious things here on the right-hand side, the scaling, technology upgrades and then simpler processes, et cetera. 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.
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 a CFO-friendly type of slide. It's also a very investor-friendly type of slide. This picture that Henrik showed here and explained, kind of the operational tactics in delivering this is super important for investors in Nordisk. First of all, this is the background for why we as a company can have gross margins in excess of 80%. 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 toward 2025, because continuing to do so and drive efficiencies is part of mitigating the price pressures we heard from our commercial colleagues.
Really, really important, and thank you for doing that, Henrik. Talking about resource allocation, now you heard our plans, so it's actually pretty simple to allocate resources. This is more or less like a summary, a financial summary of our plans. 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. This is our where to play. We allocate, of course, our resources according to where to play as a starting point. Secondly, the cornerstone of our resource allocation is driving growth. It's driving growth in the short term, in the medium term, and in the long term. We have the opportunity to do so. We are in a unique position today. Let me just go through it.
You see it on the right-hand side. 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. 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. Further out, we have the rare disease opportunities. You heard about Mim8, you heard about concizumab, you heard about Sogroya. Clearly a growth opportunity in the medium term for our rare disease franchise in the medium and long term.
Within other serious chronic diseases, you heard about ziltivekimab, you heard about NASH, you heard about Alzheimer's in the breakouts. Also fantastic growth opportunities for Novo Nordisk to invest in today, to benefit from in the medium to long term. 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. 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 twenties but into the thirties and forties. That's what especially Marcus and Martin explained early on. Investing in growth today, investing in platforms today, so we're able to drive growth after sema LOE.
That we do through our research technology platforms. 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're 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 a CFO, part of my job is also keeping score. So one thing is about talking about strategies, talking about the future, talking about the thirties, that's also important. I like to kind of understand where we stand today.
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 three years. We pulled out the COVID vaccine manufacturers because kind of their numbers are, you know, significantly impacted the last few years. When I look at our performance over the last three years, look at sales growth, 3 percentage points stronger than the industry at large. Our margin, 42% operating margin. I think right now is also the right point in time to remind you, these are based on clean accounting. These are not adjusted core earnings, kind of whatever kind of metric. This is the real deal, what you see is what you get. This is our pure operating margin, IFRS-based.
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 three years compared to 70% of that of the industry. That's the financial discipline that's very, very important to us. 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, you know, whatever companies you're looking at. I think we're pretty competitive in that prospect if not number one .
Sorry, this might be a little bit too bragging, but I just wanted to bring this two decades, at least I know Ms. Krogsgaard is gonna enjoy this slide. Two decades of capital allocation to shareholders. Look at this, DKK 400 billion of capital allocation to shareholders over the last two decades. More than DKK 200 billion returned to shareholders just over the last six years. Assuming approved by the AGM a few weeks from now, our dividend per share will have increased for now 26 consecutive years. Just another testament to our financial discipline in terms of driving performance, focus on cash, and ensuring that we return cash to our shareholders. Talking about cash conversion, you know our principles take our net profit last year, DKK 48 billion. Our free cash flow last year was DKK 29 billion. Of course, we had an impact from the Dicerna acquisition.
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. Of that, we returned DKK 41 billion to shareholders. Our ability to do so is based on a premise, and that's a slight change compared to when we were here back in 2019. Now we're investing more in our pipeline, also based on business development activities. What we're 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. 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 40th year on the New York Stock Exchange by coincidence. We did so at an all-in interest rate of 0%. Clearly also good from a WACC point of view. 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 EBITDA ratio of around zero. With our current credit ratings of a double A, then that yields substantial capacity for further business development activities without impacting our credit rating by S&P or Moody's.
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. Coming back to our resource allocation, now I'm just gonna go through some of our, main P&L lines in our P&L. First of all, commercial investments, we call it sales and distribution cost in our functional P&L. The very simple story is, as I said before, we have a fantastic growth opportunity ahead of us. What are we allocating our commercial investments against? Guess what? Rybelsus, Ozempic, obesity, including Wegovy toward 2025. That's how we're gonna drive our business. That's how we're gonna capture the commercial opportunity with the assets we have at hand today.
The investments we're gonna do will increase at a slower pace than our top line, given the attractive top-line profile we have. As a consequence, you should expect towards 2025 that our OpEX ratio to sales will be gradually going down towards 2025 compared to the 26-something% level we're at today. In R&D, again, the main financing of our increased R&D investments come from the increased top line. With the top-line growth we're 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 increase our R&D investments even further than our sales growth. We will be adding more into R&D, investing more into R&D incrementally than we've ever done before.
We do so to create assets, to create opportunities and optionality for the long term for Novo Nordisk. As I said before, this is not something we do in a happy-go-lucky manner. We have a very thoughtful approach. 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. Then we're looking at the premise and maturity of those platforms and the return they're able to give.
Put very simply, and Marcus showed it, now is the time to step up on RNA, and the commitment is to have three first human doses on an annual basis from that platform going forward. 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 stage-gates approach. It's not like Martin just gets the 2/3 of our R&D investments and then just run. 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. It's a very rational approach, and it's also a very rational decision from our perspective to be stepping up our R&D investments. As you see here on 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. In research, you heard Marcus talking about speeds from pre-project into first human dose. You heard Marcus talk about reducing the cost per first human dose.
We have similar metrics for the development organization and 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. Efficiency is also very much in fashion in R&D. Talking about efficiencies, I just want to share just a couple of, you know, very concrete examples around how we drive efficiencies across the company. The first one is our global business shared service center in Bangalore, in India. Here we're showing the step up in growth in terms of FTEs in Bangalore, in India. Some of you noted the increase in employees in Novo Nordisk on a global scale. Part of that increase happens in Bangalore.
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 one place, standardize, automate, digitalize, ensuring a very efficient service delivery model across the company. Another way to drive efficiencies is through procurement. What we've done over the past few years is that we've installed a, I would say best-in-breed digital platform called Coupa. This platform now we have of our indirect spend, which is pretty much all spend outside the spend going into products and manufacturing, which is handled in a different setup. All that spend. Of all that spend, 90% is now consolidated on that platform.
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, doing RFPs and securing attractive pricing, and thereby getting gearing for the investments and the budget dollars we have in our budgets across the company. Ultimately, that leads to, of course, attractive financials. 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. 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.
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. All in all, a broadly stable operating margin towards 2025. That concludes the financial section, and now it's over to you, Lars, to moderate the Q&A.
Please come up, those of you who have just presented. No, just yep.
Sorry.
We're on a Q&A session now covering the two operational units, manufacturing and finances. Yep, Michael, do you want to start?
Yeah. Thanks. Michael from Nordea. Two questions. First to the launch of the Wegovy in IO. So is it gonna differ between countries in IO, whether you launch in the single dose or the multi-dose? Because it seems like you are still considering to launch in some countries in the single dose. 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%-2% for some time in the U.S. and then accelerating growth. Now you don't really commit to a new growth target. Maybe you could elaborate a bit on where you see business going.
Is it further, you know, not acceleration from 13% obviously, but how do you sort of envision the growth track for the U.S. business?
Mike, first on Wegovy launch.
I think the quick answer is yes, Michael. We're going to use both platforms. The message has been that the two 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. That would be the case also. Country by country, we'll make that assessment.
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.
Yeah. Michael, what's really important is we wanna complete this transformation of 70%, and we aim to do that this year. We think the sources of the growth are primarily gonna come from that foundational component of semaglutide, which is gonna be in the form of Ozempic, Rybelsus and Wegovy. That is where we're gonna drive our growth. We have strong momentum. We expect the momentum to continue into this year.
Good. Maybe we'll take one virtual, Sachin Jain.
Hi there. Can you hear me?
Yep.
One for Doug on Wegovy inflection in the back half of the year. I think you mentioned in your prior comments a couple hundred thousand co-pay cards in which only half were activated. Do you have good understanding of why they haven't been activated, and 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 co-pay activation could double that. The second one is a real big picture one, I guess, for Lars. I know you don't wanna give top-line guidance, but I wonder if you could just speak to the following.
The top end of 2021 guidance is double-digit despite 340B, VBP, half year of obesity, so why shouldn't we be thinking double-digit growth for 2023 and beyond? Thank you.
Doug, first on what's left of activation card, how long can they be used, and is that something that will play into second half?
Yeah. Thanks, Sachin. That will not. We discontinued that program. The cards that are out there, we'll honor that. 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. 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 wean itself out over the next couple of months.
Just to add on that, the cards we're honoring are the cards which were initiated in 2021. There are no new cards being initiated since January 1 this year. That's not possible.
Yep. You know that we are not into guiding for 2023 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. We are not only concerned about impact from tirzepatide. 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. Of course, that will also carry into 2023. 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, with small disruptions like we see with VBP in China this year. With what goes on in the world right now, it is to be anticipated that there are headwinds from time to time. We're really comfortable with the growth outlook we have over the short to medium term. You'll not get me to comment on double digits or not for 2023.
Can I make a quick addition to what Sachin mentioned? VBP in China, Sachin, was announced last year but was not impacted last year. You made a reference that last year you had VBP and this year you had VBP. Actually, VBP in China is only impacting us this year and not last year.
Yeah. A bit next year.
The first quarter of next year.
Yeah. Good. Richard?
Thanks. Richard Vosser at JP Morgan. Just, you mentioned in reference to geopolitical issues, and they come along from time to time. Any idea of quantification for 2022 from geopolitical issues in IO? And then secondly, on CDMOs, could you give us a flavor beyond Wegovy how much CDMO use you have today? Where would you 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. Thanks.
Mike, first on geopolitical.
Yeah. 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 points. 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. I don't wanna start speculating what can possibly happen.
That was the potential direct impact?
That's the potential direct impact.
Yeah.
Correct.
Henrik, on use of, CMO?
Yeah. The short version of that is compared to the capabilities and capacity of Novo Nordisk, it will be limited. It will be used for flexibility and high growth in certain time, and then we will consolidate over time with both internally and externally. If you look at the totality of what we're able to do internally, it's a limited capacity compared to our power of our internal factories.
Good.
We also use it partly for API, for clinical manufacturing purposes. For some pipeline projects, we do use CDMOs.
Yeah. I think we had a question here. Yeah.
Thank you. Keyur Parekh from Goldman. Two questions and a clarification, please. The two 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 base than diabetes? And if so, kind of how should we think about the timeframe by when you get there? That's one. Secondly, Karsten, you referenced kind of your firepower or kind of M&A capacity.
I'm 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 Novo would benefit from given where you are today, given Dicerna, given kind of the strong growth you have over the next 3-5 years? Just kind of big picture preferences in M&A question. Then lastly, clarification, Henrik. Kind of when we look at that 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.
'Cause 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.
Good. Thank you, Keyur. We're really losing discipline here. Now we're up to three questions at the last second.
They're broad.
We have now guided on obesity that we want to get to more than DKK 25 billion by 2025. I'm not going to model you know over a 10-year period how this can develop. Of course, when you look at the number of patients, it's a significant number of patients compared to those who have diabetes. It's a sustained growth opportunity for us. We have by far the strongest pipeline in the industry. We are building the market. You know, I'm really bold on obesity, but I'll not get into to comment on the relative size of our businesses. Karsten, on M&A capacity and how you look at that?
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. The way we segment it is basically, as I said, initially, we start with our core strategy, our where to play. That's therapeutic categories that we've just been through during the day.
We're filtering based on scientific merits of the projects we see within those categories. We do an evaluation both on scientific merits, financial merits and of course, when they kick in, sales growth wise. With the momentum now, we are not out in the market to buy empty calories, if you will. We're not out buying top line today or tomorrow. We are out buying innovation, I would say, in the more early stages for our pipeline in order to secure growth in the medium- to- longer-term for Novo Nordisk across the categories.
Thank you, Karsten. Henrik, on unit cost development.
Yeah.
Sources.
The short answer is, it depends, but I will say within our core technology of API, process optimization technology upgrade is extremely important for us, and this is a heavy lift within our unit cost in that area. That is a close collaboration between R, 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. In fill finish is more volume based, except for the tablet that goes at the same path as the APIs.
Good. I'd actually like to close down this Q&A session and invite the rest of the executive management up here, because then we can continue and you can ask questions for everybody. While they get up, we play a small video.
Yes.
Good. With a full dream team on stage, we will continue the Q&A session. I think we had a question over here. Yeah.
Thank you. Carsten from SEB. I got the microphone before, so this is still a question for Lars.
You can ask anyone.
Yeah, yeah. I know, I know. It's a question to Karsten and the gross margin outlook. If we look three or four years back, you have had what could be a catastrophic case for gross margin with massive price declines in the U.S. insulin market, bread and butter franchise. That is now gone. It's difficult to get that one more time. On the other hand side, you have a GLP-1 franchise thriving. We can see Henrik, you reduce unit costs, and you'll be highly dependent on GLP-1 by 2025. My question is, how you manage to keep your gross margin down?
Thank you for that question, Carsten. The first part or the last part of your premise is we're not managing to keep our gross margin down. Henrik and I, we get up, you know, every day to drive our gross margin in the best possible way. Henrik nicely shared the perspectives around quality, cost and delivery in terms of how we run manufacturing. Clearly, unit cost is a key premise. Even more important is quality and our ability to deliver. Looking towards 2025, the important part is to understand our starting point is north of 80% in gross margin. We are already among the strongest in the industry of gross margins.
When we look forward, 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, you know, we're shipping products out of that factory. 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. Even though you could say, you know, we had lower exposure in some areas than we do have VBP in China. There will still be pricing pressures in different geographies. As you say, yes, a positive product mix.
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, Karsten. We'll continue virtually with Wimal, and you have your microphone down, I can see, so we should all be good.
Thanks. Wimal Kapadia from Bernstein. You mentioned earlier in the day, generic entry of DPP-4s and SGLT2s would have an impact on the market. Maybe you could just elaborate on that a little bit, please, particularly in the U.S. You know, 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 a step edit is a likely outcome. You know, just given, you know, SGLT2s offer quite a number of benefits beyond blood sugar, and they'll probably cost about $1 a day, just thinking, you know, 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., y ou know, given that it's best to reset the body weight relatively early, what does Novo Nordisk worry about obesity in that setting? I'm just curious, really, because I appreciate your belly scratching and surface-level results. Just curious to hear your thoughts. Thanks.
Wimal, first, Doug, on how do you see kind of pricing impact and potential step edits from DPP-4s and SGLT2 in the U.S. context? Then, Martin, you can perhaps talk to obesity in children.
Yeah. Well, Wimal, it's a good question, and thank you for that. I mean, I don't wanna predict if there'll be a step edit or not. I think we're too far out from that. I guess it could always be a possibility. Anytime there's a generic entry, it's certainly gonna 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.
Yeah. On obesity in children, I think I would like to share this one with Camilla because, I mean, there are two aspects. Obviously one is being treatment with Wegovy in children. We're pursuing that as we speak, conducting a clinical trial. We do believe it to be very, very important. Maybe even more importantly in the long term is to look for prevention of obesity starting specifically in children, and maybe you wanna put a few words on that.
Only that we have actually just started that, and we are working on finding ways. 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 would have a spillover impact on more countries. 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. We continue to pursue obesity in children because that is important for the future.
Good. Thank you. Yeah, Simon.
Thank you. 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? 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. 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. 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 to, with pens what Denmark has done with glass bottles. Thanks so much.
Thanks, Simon. 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.
Yeah. First on how we manage the risk. Basically what we are doing is to try and model what are the investments required also from a commercial point of view the next five years in the new areas that Martin and I spoke to. All of these investments are clearly laid out, depending on trigger points. We are trying to make sure that we invest sufficiently but not overly, depending on when we get clinical trials results.
At the same time, some of us talked about in the workshops 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. 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 you know multiple partners in the Danish environment that all were happy to contribute to this, being a diabetes care association, logistics providers and others. There is already a you know a multi-faceted 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. 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 else, and we want it to be easy for people living with chronic diseases.
Thank you. Yeah.
Thank you. Erik Berrigaud, Stifel. Two questions. First, we ended today 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 three years, and it's maybe difficult to understand how those 15 additional billion in sales in three years are not translating into additional growth for the group or any additional operating margin. Can you help us understand how this is absorbed over the next three years in other lines like R&D or others?
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 2025, for instance? Thank you.
Thank you for those two questions. First, Karsten, the stronger growth in obesity, how does that translate into, say, P&L, and margin?
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. Top line, everything else equal is stronger than 2.5 years ago for sure. Then you say, "So, what about our P&L and our margin?" There I'll 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 we've not seen at that point in time.
We've seen the initial uptake in the U.S. of Wegovy. 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. 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. We're more bullish and thereby also investing harder than we were 2.5 years ago. 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-year 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. How do you 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 ultra-rare specialty care or rare disease sector. 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. 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. Again, it will change one year on the other based on what we launch.
As you can see, we have three products to launch over 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. Yeah. A question over here.
Hi there. Harry Sephton from Credit Suisse. Two questions please. The first is just on your plan to increase R&D as a percentage of sales. 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. From the data that we can track 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? Thank you.
Good. Thank you. Karsten, first on the ability to, you know, flex on R&D spend based on underlying performance.
First of all, it's not a simple mathematical that if you change one parameter then kind of everything else is automatic, then we'll have, you know, also a smaller finance function. Our starting point is of course that what we invest in R&D, both in R& D, we invest in those two areas based on the premise that we believe we're able to generate attractive returns. In reality, of course, it's a function of, you know, our investment capacity as well, but the core starting point is whether we believe we can make an attractive return on the investments we do, both in R& D.
Doug, on the U.S., rebating, both the point that we are already giving, you know, a good level of rebates, and the strong momentum in Ozempic, there's a competing product coming. Do you see, you know, a major change in say access environment, because of that?
Yes, that's a good question, Harry. Thank you. In the end, you know, we, as I mentioned earlier, we have 95% access for Ozempic, and that is enabling us to commercialize our product. It's an 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'd like to compete in that. 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 mid-year, and so I don't know, again, what will happen. I don't wanna predict that at this point.
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 are on the high dose, which will be the medium dose so far. 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. We're quite confident in our ability to compete based on that. Are there any final questions? Yeah.
Hi. I'm Victoria Caman from Verod Capital Partners. Just a quick question on the Wegovy composition and gender. Looks like there are a lot more women than men, to the tune of about 80% women. I'm 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? 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. Just curious.
Yeah. Camilla, would you like to talk to that?
Yeah. When we look at the real-world evidence that we see now, it's right that around 80% are women. 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. Of course, the more we can inform people about that there is help to get, the more without having any gender bias, I get, I guess, we will get to everyone at some point in time. 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. This, of course, in itself is also a way that people inform each other. Not a primary issue or focus for us for now.
We're still a long way from getting to everybody, unfortunately.
Good. Just a final question. Yeah. Okay, you.
Thanks, Lars. Just kind of perhaps a big-picture industry question for you. Kind of you've gone with everything going on, kind of you've almost forgotten COVID. But the industry's 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 five years. Yet from a public perspective, every time we hear about insulin, it's about how bad insulin pricing is. Just wondering if you have thoughts on a 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.
Yeah, 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 all 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, 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. Of course, if you're a policymaker and you are facing a hugely complex healthcare system, and the population expect from politicians that you can actually change the complexity of that in a way that it benefits patients, sometimes you have, you know, a need for articulating the problem as it's seen by the individual patient, if you're in a situation where it's really, really hard for you to change the system.
I think some of the rhetoric that comes out from a political point of view is political, and it's talking to you know the population, where actually when it comes to making policy change, there's actually more say a fact-based approach to it. I believe we will keep having intellectual property rights as an industry. I also have my doubts that there will be major healthcare reform, because basically, when you look at this deteriorating insulin price in the U.S., that comes on the backdrop of significant rebates actually being passed on into the system and is actually funding the delivery of healthcare. If you instead pass that on to patients, there is a funding gap for the healthcare system. It's hugely complex.
Our role is to make sure that we help the most vulnerable patients. I feel really good about the affordability programs we have put in place and the patients we help. 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. 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 then means that the task moves to them in terms of changing the healthcare system. I have to stop here because I can talk about this for ages, and maybe we can do it over drinks later on.
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 on stage for the Q&A. Please take a seat, and we'll try to wrap up the meeting. 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. 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.
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. We've seen a tremendous uptake, so we lift that to more than 25 by 25. Easy to remember. My aim was also that we should share with you the unique opportunity we have for driving short-term, medium-term growth based on our portfolio within diabetes, both with insulin and GLP-1, and how we're unlocking the obesity opportunity based on GLP-1. We've 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.
That's going to fuel our short-term, medium-term growth. While we deliver on that, I hope you also sense that we have one of the, 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 pipeline for the future, and in a thoughtful way, taking a few steps away from the core, also diversifying Novo Nordisk. Thereby, we do not promise for the next hundred years, but at least having a really, really long perspective on how we deliver growth. That is all about living our purpose. That is about driving change and getting to more and more patients. It's all about being a sustainable company.
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. 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. thanks for enduring that. we hope it was worth the time 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, 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 as one.
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. That concludes the formal part of the program. For the people in attendance, it would be our pleasure to invite you to a drink and a snack just outside here. For the people not here, have a great rest of the day, and hope to see you around on the road somewhere. Thank you so much.