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

Welcome to the Novo presentation at the JPMorgan Healthcare Conference. I'm Richard Vosser, European pharma analyst with JPMorgan. It's my great pleasure to welcome from Novo Mads Krogsgaard Thomsen, Chief Scientific Officer; and Marcus Schindler, SVP of Global Drug Development (sic) [ Discovery ], to present to you. Just before I hand over to Mads, after the presentation, the breakout is in the Georgian Room, which is just on the right-hand side. Mads, welcome to the conference.

Thank you, Richard. It's a great pleasure to be back at the JPMorgan. Many years ago, we were here, and now we're back. So Marcus will take the more scientific parts towards the end of the presentation. But what I'll share with you is with a great focus on the R&D elements of the company, what we're all about. So these are the forward-looking statements. As a company for many years, we've been driven by our passion and our purpose, and the purpose is basically to drive change to defeat diabetes and the other serious chronic diseases that we work within the company. The thing that has not changed is the Novo Nordisk way that remains pretty constant year after year after year, the way we do our business. What has changed, however, is the amount of core technology platforms where we believe we have a leading position in terms of creating innovation based upon those platforms. Marcus will speak more to that a little bit later. Now in diabetes care, what we are setting out to do is further strengthen the leadership position. We today command 28% of the global diabetes market. The 2025 ambition is to move to at least 33% of the total global diabetes market and do so by strong innovation and also, of course, strong commercial execution to the benefit of patients. If we look at obesity, it's about building the market by creating data that show that this is a serious, chronic, progressive and treatable disease as we will hope to show in the outcome study that is currently ongoing with our GLP-1 analog, semaglutide, and then create a market and expand it against the benefit of the millions of people suffering from diabetes. If we look at biopharmaceuticals, it is to maintain the leading position by building on what we have within hemophilia and the growth hormone area, expanding beyond that and also finding rare endocrine and rare metabolic disorders or hematologic disorders where we can make a difference based on our core capabilities. And then finally, in other serious chronic diseases, which we define as cardiovascular disease, as NASH, as chronic kidney disease, we basically set out to establish a presence through scientific leadership and building a strong pipeline. Now we, in November at the Capital Markets Day, decided to abandon our long-term financial targets not because we could not deliver in the future. We have actually aspirations for 2025 that we will at least double the obesity market of Novo Nordisk and we will increase the diabetes market share, as I just mentioned. However, today, those strategic aspirations that are manifold within our sustainability approach, innovation, within commercial execution and in with the financial outlook, but today, we're only going to focus relatively narrowly on the innovation of the company. We are 2 R&D folks after all. Now on the next slide, you will basically see that it is not over at all when it comes to even disruptive innovation in the insulin space. We're constantly hearing about the ever-dropping prices of insulin in the United States. However, as we are now migrating towards the top of the first innovation cycle or curve, it has taken us 100 years to create a pharmacokinetically optimized insulin, so-called LAI287, that allows for once-weekly administration and once-weekly blood glucose measurement, something that we expect to deliver, hopefully, really good data very, very soon in the Phase II proof-of-concept studies. But the new innovation cycle is there deliberately in order to show that it's more disruptive innovation. We do believe that after a couple of decades, we have now cracked the nut in terms of understanding how to create an insulin molecule that has a glucose-sensing moiety built into it that allows for turning on and off the switch on the molecule in the physiological range of glucose concentrations, i.e., between 3 and 10 millimolar. So a very strong breakthrough that makes us optimistic on that front on behalf of the patients. And when you then look at the pipeline as it stands today in terms of preserving insulin secretion, not replenishing it but preserving it, we have completed a Phase II type 1 diabetes intervention program with the anti-IL-21 antibody. And we are right now in discussions with the FDA as to how to proceed into a, hopefully, Phase III program on that one as soon as possible. We are delivering the Phase II results on the once-weekly 287 very, very soon. And we've already shown that it is combinable with semaglutide, the constituent in Ozempic, such that you can have a once-weekly combo of GLP-1 and basal insulin. We have a functionally selective insulin that is in Phase I, and then the glucose-sensitive insulin is entering into [ man ] at a very exciting point in time in the second quarter. And then we are, of course, trying to get our stem cell-based type 1 diabetes therapy into the clinic before the centenarian anniversary of the discovery of insulin. Now the whole trick about GLP-1 is to get it earlier into the treatment paradigm. It is so that today, the average GLP-1 application is either third line or fourth line. We want it to be first or second line, and the way to do that is essentially to go from injectable to oral. We have today the first and only biological medicine available in a tablet in the form of oral semaglutide known as Rybelsus and today already being sold in this market. We expect to launch that towards the primary care segment and so on very, very soon and are geared up for this breakthrough medication, hoping that the GLP-1 market, both as injectable and as oral, will expand significantly into the future. There is much room for expansion of this class of agents. Now as we then look a little bit what is it actually we've seen with semaglutide. Semaglutide is the best-in-class GLP-1 agonist. We've seen twice the weight loss and twice the cardioprotective properties for semaglutide as compared to other GLP-1 members of the class. This, combined with stronger glucose lowering than with any other agent on the market, has meant that we are embarking on a huge outcome program where we're looking into 2 cardiovascular outcome trials, 1 in diabetes, 1 in obesity, 1 with oral, 1 with the injectable version. We're looking into renal outcomes in a diabetic nephropathy trial called the FLOW trial. We're even looking into long-term improvement of the eyesight and visual acuity of people with retinopathy in the FOCUS trial. And then, of course, we are investigating NASH, this new and embryonic area of research and development that everybody talks about, but where no medicines are available on the market today. And equally, we are also awaiting Paul Edison's Alzheimer's trial using liraglutide 1.8 that is emerging not from Novo Nordisk, but from the Imperial College and Hammersmith Hospital in the next month or 2. Now that takes me to obesity. And if we look at obesity, today's available medications, they will deliver maybe 5% weight loss, some a bit more, some a bit less. But there's a huge gap towards what we need -- what many patients need. If you have a BMI of 40, you can convince yourself that you need to lose more than 25% of that weight in order to go below the obesity cutoff, which is a BMI of 30. And we are nowhere close to that as we speak today. There's a gap. It's only gastric bypass surgery that is able today to, in a very invasive way, ameliorate that condition with a lot of side effects. Our job is to change that. And the way we're going to do that is today deliver -- hopefully not today but in a few months' time, results from the STEP program with semaglutide 2.4 milligrams, the once-weekly obesity product. The intention is to deliver approximately 15% weight loss with that agent. We will soon follow with the combination partner, the once-weekly amylin compound called AM833, which in co-injection are expected to give somewhere to the tune of 25% weight loss, getting very close to bariatric surgery levels in a simple-to-administer, once-weekly injection. Following that, we will progress up the innovation curve by making all versions of some of these molecules. It is possible to combine not only one but several incretin motifs into the same molecule and even make it orally available to the patient. And ultimately, who would not want to reset the homeostatic set point in the brain such that when we lose weight, we don't start turning down whole body metabolism but rather maintain it and can continue the weight loss. We're working on that. We're not quite there yet, unfortunately. As we move into biopharmaceuticals, well, we've had a very strong heritage of 35 years' innovation within hemophilia products and within growth hormone products. But to the left-hand side, you can see that we have a broad range of hemophilia molecules available. And I'm extremely happy to say that concizumab up there, the cross-segment agent that targets both hemophilia A, hemophilia B and hemophilia with inhibitors, has received a breakthrough status from the FDA. And we are hoping to complete that first element of the Phase III trials kind of around the turn of this year and submit it immediately thereafter. Also, Mim8, our next-generation factor VIII mimetic molecule based on the Duobody technology, has now entered clinical trials, and we will have a fast-track approach towards getting that through development. Ultimately, we are seeking the cure of hemophilia by gene editing. And there, we are working with a company that was here not too long ago, namely, bluebird bio, such that we can integrate a healthy factor VIII gene in the chromosomes of the cells in the liver in even young kids with hemophilia A. That's the dream. So if you look at the pipeline outlook for this year, it relates to getting concizumab patients onboard in all the Phase III activities; getting Mim8 through the Phase I/IIb activities; and having somapacitan, the first once-weekly growth hormone therapy for adults with GHD, approved during the course of the second half of this year, but also recruiting the Phase III trial for the kids with growth hormone deficiency and also those born small for gestational age, so-called SGA. So a lot of excitement also there. That then leads me into the more long-term future, and this is just to say, handing over to you, Marcus, that the increase in our pipeline assets, and we are expecting to approximately triple the amount of clinical assets from slightly below 20 to close to 60 over the next decade both by internal/external innovation but also by external collaborations and of course, also driven to a large extent by the strong prospects and outlook for the semaglutide assets in the pipeline. With that, over to you, Marcus.

Thank you so much, Mads. And small correction to Richard's introduction. I'm leading discovery and not development, which means we know even less about what we do, but we probably have more fun. And sometimes, ignorance is a good thing. So I'll lead you through where we've taken also our organization over the last probably 2 years or so from, as Mads, I think, very nicely alluded to, semaglutide is the anchor drug. And what it gives us is not probably just a really nice product, but it also has uncovered a number of biologies that we actually didn't anticipate that GLP-1s would do. And I think it has, for us, shaped the entire field of antidiabetic medicines into one where, of course, we see glucose lowering. We also see weight, but we see a plethora of other actions, which also help us to understand there's way more we could do both with this mechanism of action, but also in the patients that we're already dealing with which have diabetes, but also a lot of the comorbidities that Mads has outlined. So as a scientist, if we discover a new target, and I would argue we're probably one of the leading companies in the biologies that we're dealing with, if we then find a novel target and we say, "That's great," as long as it's a peptide drug, that isn't really satisfying. And our patients usually don't care what we can or what we can't do. So the imperative for us really is to have a toolbox of high-quality technologies available to us that allows us to target each and every target. And that's what you have seen us do over the last 1.5 years or so, taking peptide therapeutics from injectables to an oral delivery, and that world is just unfolding as we speak. Going to talk about stem cell technologies a bit later. Gene therapy, we had our colleagues from bluebird here, where we're taking first step now in hemophilia A in gene editing, which is a really interesting area for us, but also oligonucleotides and small molecules. And again, it makes no sense whatsoever if we were to reinvent the wheel where others are already advanced, where they own their technology platforms and where they really know what they're doing with their respective technologies. It makes much more sense that we add our understanding of biology and medicine to this and in particular, take some of those platform technologies also to this big, serious, unmet medical need in the chronic diseases we are dealing with, which requires a long time investment. And this is just a sample of some of the partnerships. And I'd like to call them partnerships rather than deals, although in rare cases, money changes hands. It's actually important for us that we start practicing on a number of those. What you see here, in no particular order, is anything from, on the left-hand side, Embark Biotech, a small outfit where we're actually eyeing a deep target discovery space on human brown adipose tissue to, just below, a collaboration with Gilead, not far from here obviously, where we are teamed up to actually do combination studies in the clinic in NASH with their ACC inhibitor, their FXR agonist and semaglutide because we have the firm belief that NASH will only be solved by aggressive combination treatments in many cases. And again, we don't want to do this alone. We wanted to find a partner who is knowledgeable and very well versed in this area. The technologies, obviously, you see across, I mentioned the hemophilia treatment with bluebird; small molecule which we're doing a partnership with Evotec; but also then single assets that we have both acquired or are partnering with like Staten Biotechnology, a Dutch company, where we have an apoC3 sweeping antibody. One of the take-home messages here, and we can't go through all of them, is that we're actually quite open for all sorts of partnerships. There is actually not a single deal construct or collaboration construct that is the same as another one, so I think that it's really important to find what really works for both parties. Really interesting for us was getting access to a technology that can deal with intracellular targets and efficiently block those targets. The vast majority of the targets that we have interrogated through genetics and transcriptomics are in the intracellular space, which makes it a little bit harder for us who have a lot of knowledge around circulating peptides. And Dicerna Therapeutics out of Boston is the partner we have chosen. And by the way, they have also chosen us. It's always a mutual process in any form of partnership. And we announced a strategic partnership, which means we're going to work over a number of years over a significant number of targets. And I think that is really important. It's also something that is long-standing and it's not just a one-off on one target. But we actually really would like to get into this space. It is important for us. In this case, obviously, we talk about hepatocyte targeting. So we can work on a target-by-target case with Dicerna as long as it's based in hepatocytes because this is what their GalNAc-targeting technology is particularly good at. And that brings me to NASH, and I've mentioned that. And it's a hot area, but it's also a really difficult area. But then I probably would remind you that very few new therapeutic areas, which are just emerging, are going to be solved in the first time around, right? And usually, it does take persistence. And it maybe takes also a number of iteration of drug discovery and drug development rounds to actually nail it. And the numbers I've put up here are probably the best guess of anyone, or maybe not even the best guess. They are a guess. Because one of the crucial elements here that we're missing is a good diagnosis tool. Right now, it's basically a histology diagnosis based on liver biopsies, and that's obviously not something you do en masse or do easily. So we're also working very hard actually, both in collaboration with a number of consortia but also with our colleagues from Gilead, to actually get us to a much, much better tool to increase diagnosis rate significantly. Yet, it is a severe, unmet medical need. It's particularly prevalent actually in our patient population that we already know. 70% to 80% of obese -- of people with NASH are obese, and that's obviously also something we're trying to deal with. It's a progressive disorder. It begins very mild, asymptomatic, right? You don't feel anything. It doesn't hurt. It starts with inflamed tissue. And then if you don't do anything against it, it's simply the disease progresses. It progresses faster in some patients. It sometimes stagnates in others. And we haven't fully understood what makes one patient go one way or another patient go the other way. The end, however, is quite significantly bad. It's liver cirrhosis and also at the end, mortality. The good news, in the small, shaded arrows here, is there is an element of reversibility, right, but it's going to be hard. And I think that is something we really need to team up with to find out is it improving the metabolic status of those patients, weight loss, reducing liver fat, reducing insulin resistance. What about if fibrosis is already established, can we actually reverse this? These are all the questions actually we're dealing with and we're quite busy with. The other element, and again, it's already prevalent in our patient population and we've seen profoundly beneficial effects from all the trials we actually have done with our GLP-1s, most recently with semaglutide of course and then now Rybelsus, is cardiovascular disease, right? And at the end of the day, this is what people die from. The vast majority of people still die from cardiovascular disease, in particular, atherosclerotic diseases and heart failure, heart failure being difficult, right, because it's -- again, there are 2 types with reduced and preserved ejection fraction. In particular, the latter one is difficult to diagnose usually just through exclusion. And if there is no powerful medicine out there who can actually deal with it, it's often ignored, right? And that's something, I think, we in the field need to change, and we're very committed in doing this. And last but not least, I want to spend 1 or 2 minutes on our stem cell technology platform. It might sound new to you, but actually we've been engaged in this way before my time for roughly about 20 years. And this is by the way, I think, how long it takes until you get a technology truly to maturation. Over the last 2 or 3 years, we have started to figure out that the protocols that we have in place, that the cells we're manufacturing are stable. They -- we can tune them to the cell type that we actually want to achieve, and that made us feel very confident to call out our stem cell unit and actually significantly invest in this. And unlike our core diseases where we're very much at home, in diabetes and obesity and hemophilia growth hormone, this is actually something that we see more disease-agnostic because we see the stem cell line or stem cell opportunity, which is based on human embryonic stem cells, by the way, coming out of the University of San Francisco, lend itself really to a number of diseases with an extremely high unmet medical need. And I think that's really what we would like to explore. We've opened up a manufacturing site just down the road here in Fremont. That also shows not only our commitment, but we think this competition is not one in the lab. It's not whether you can make a cell type or not. It's actually whether you can produce the cell type to the highest standards, to high quality and fit for the market. And this is where we feel extremely confident that we probably have a lot of knowledge throughout our technology background to deal with this. And that's all from the exciting early science and back to you, Mads.

Thank you, Marcus. I often use the analogy that we've actually been producing FDA-compliant, GMP-grade mammalian cells since the 1980s when we started NovoSeven production. The only difference is now we are using like 30-plus years of experience on mammalian cell cultivation and nursing in a way where we actually don't use the protein secreted from the cells but actually the cells themselves. So it's a wonderful exploitation of numerous technologies developed in the company over decades. Now this year is going to be one with a relatively extreme clinical readout in quantitative terms because if we look into the area of NASH, Marcus has already hinted that we get not only the biopsy-based Phase II proof-of-concept data for semaglutide in more than 300 patients, but also the combo data from the collaboration with our Gilead partner with the FXR and ACC inhibitor. Also, we have a unique PCSK9 peptide that lends itself to a number of strategic options, purely development wise, and we're having Phase I data emerge very, very soon for that one. As we move into the field of biopharmaceuticals, it is a year of both approvals in terms of getting somapacitan approved, but also getting Mim8 and concizumab through their clinical phases that they are now in, so a lot of work ongoing also there. As we then move into the area of obesity, this is also one where there are some critical inflection points. For semaglutide NASH, we hope to be able to move directly into Phase III. For sema in obesity, we actually hope to be able to move very fast towards NDA submission based on, hopefully, data pointing at a 15% or so weight loss. But also, its combination partner and also the stand-alone monotherapy amylin 833 delivers at approximately the same time Phase II proof-of-concept data. And we even have a multiple-dosing study with the 2 combination paths together in such a way that we can fix the ratio between the 2 before we start injecting people in the Phase III combination studies that are planned. If we look at certain other areas of obesity, they are also moving, but these are earlier stage Phase I things: GDF15, triple agonist, co-agonist, so on and so forth. And finally, we actually were able to squeeze in all the diabetes outcomes. And the first one to appear is actually the LAI287, the once-weekly, first-in-class and best-in-class, we hope, insulin. And that is delivering results very, very soon and will also be combined in Phase III that we hope to be able to start around the turn of this year, but in such a way that we do both monotherapy and a combination with sema in the product that we call LAIsema. Before that, we are approaching PDUFA action date. Six days from now, we have action date for the cardiovascular indications for the semaglutide molecule. So a lot of excitement in that area. And then of course, we have the high-dose semaglutide for those patients who need even more bang for the buck than 1 milligram sema can deliver. We have the SUSTAIN 4 reading out later on. So I think actually I will stop there, Richard, so that we can get over to some Q&A, I guess.

Thank you. Yes, we'll be moving to the Georgian Room.

Let's get over there.

Okay. Welcome to the Novo presentation and breakout, in fact, the breakout at the JPMorgan Health Care Conference. We have Mads, Chief Scientific Officer here; and Marcus Schindler, Head of Global...

Drug Discovery.

Drug Discovery. I've got that right this time. So it's Q&A session. We can just go straight into Q&A.

The first question is on your connected insulin pen. Can you tell us when that will be here in the United States? Secondarily, what is your strategy with that? Are you going to have to pay for it or just give it away? And thirdly, do you have any interest in other device companies?

Yes, so the question relates to our connected pens, because we're being webcast, the first connected pen is the NovoPen 6, a durable pen, and that is going to be launched already in the first half of this year in a number of countries, including China and Europe, but not the U.S., which is not a durable pen market. So first connected device in the U.S. is going to be next year. It's going to be a cap that you put on to the FlexTouch pens that many people are using, literally hundreds of millions of pens every year, and that can connect either to Tresiba or to one of the other insulin products because it's color-coded. And of course, it enables the connectivity via your iPhone so that you can start connecting BGM or CGM data together with insulin dosing and so on. Those are the areas that we are first targeting with our digital health solutions. We are also looking into obesity, how digital can help people become more compliant with the therapy. So we are working with companies like Noom that are learning how to nudge patients to behave better, to comply with therapy and to combine good lifestyle with the effective pharmacotherapy. So those are the main areas for the time being.

Are you going to give away the cap cover? Are you going to...

So the idea is we're not going to make profits on it. That's not the intention. But there is, of course, a cost of either a connected pen or the cost of such a cap, and it will be with a battery life and hence a shelf life or a use -- in-use life span for these products of like 3 years. And that means that the annual cost will be miniscule. So it's more to improve the outcomes for the patients. And we've seen already in 1,000 Swedish patients using NovoPen 6 with type 1 diabetes that the health outcomes improved, their time in zone and everything got better by use of this pen in the dialogue with the physician.

Mads, can you share any thoughts on the [indiscernible] by Lilly's and your expectation [indiscernible] Phase III this year?

Well, I think you should have asked in the preceding session [ the GIP ]. Lilly's tirzepatide is in Phase III? It's still very uncertain, and we have big debates because Richard DiMarchi, the inventor of the dual agonist, triple agonist concept, is working in the Novo Nordisk labs and has also created a once-weekly GIP that we're investigating together with semaglutide. It is still relatively uncertain what is the optimal ratio and what is the contribution of GIP on top of the GLP-1. And I think time will tell us once we have done our experiment, where we actually have semaglutide in one arm and then we have different ratios of GIP to sema. And once we have the outcomes of that data, then we'll scientifically be able to understand is there a contribution of GIP? How big is it? What is the right ratio between these 2 incretin molecules when they're together? And also, what is the side effect and tolerability profile surrounding that? It appears that when we do dual-agonist studies or even triple-agonist studies that we do see more on the GI side of things. But also that we'll investigate in our own clinical trial. I think you should ask the Lilly colleagues more to their compound, specifically.

Maybe following up on that and just thinking about the Ozempic 2 milligram trial. Based on the sort of Phase II data originally for semaglutide and increasing efficacy on weight and HbA1c when you double the dose there, how would you frame that opportunity and that profile of that product or that increase in dose?

Yes, so the interesting thing is when we decided for the dosing of 0.5 and 1.0 milligrams of sema in the SUSTAIN program, we actually had the belief that it would create so much efficacy that people would literally be able to stay on it almost into perpetuity and many patients will remain in excellent control for a long time, for instance, on 1 milligram of semaglutide. But having had Victoza now on the market for 10 years, the once-daily, we have come to realize that over time, typically, after 3 to 4 years, we have seen that Victoza patients either go off the product and go on to insulin or they add something. So we have come to conclude that by going through all the way up to 2 milligrams with a direct escalation from 1 to 2 with no intermediate steps, we can probably prolong the life on product for each patient significantly. And the next step after 2 milligrams of semaglutide, which probably will be then years later, would then be to, for instance, either add a once-weekly insulin, LAI287, or simply shift to the LAIsema product where you both get semaglutide plus a squirt of insulin. So the armamentarium that we're having, ranging from early use of the once-daily Rybelsus tablet which people can decide to stay on, in principle, intensifying with injectable products, we also have the option that people can start on injectable Ozempic intensified with higher doses and end up on a similar pen system but where there's the added benefit of a once-weekly insulin. So I think we are bringing a lot of versatility to the armamentarium.

On the oral GLP-1, you have a rather complex dosing regimen. Can you explain how you plan to deal with that? And what are your expectations for that product here in the United States?

It's not as complex as it sounds. First of all, we're starting to get early feedback here from the U.S., that is, in the clinical trials, it's not been an issue in the PIONEER 7. What you do is you take the tablet in the morning and then you don't eat until 30 minutes. That is the dosing condition. Take when you wake up and then don't eat until 30 minutes later because otherwise, your absorption will be somewhat reduced. This is like if you take thyroid hormone. People who are hypothyroid, they also take their thyroxine in the morning and wait 30 minutes. So a multitude of drugs have it like this, and it's not been an issue in the PIONEER 7 trial. People were either on sitagliptin, Januvia, or on oral semaglutide, and they were asked in a patient-reported outcome scheme how complex they found the treatment regimen for them to be on a visual analogue scale and they scored identically. So the perception of having to wait 30 minutes did not even pan out in the self-reported scheme. So the only way to deal with it is to say if there's a patient who has to have his or her food in the very minute they wake up, then maybe they should be on Ozempic instead of Rybelsus.

Isn't there a water requirement in the trial?

Yes, you drink a glass of water.

No, I mean, like too much water...

Yes, but if you take a big class of water, absorption is slightly reduced but nothing spectacular. But we have to guide with the best evidence we have, and that is a small glass of water. Coffee can probably also do the trick, but we haven't tested it.

So on Rybelsus, the real-world efficacy. I'm just curious if you're getting any anecdotal feedback from clinicians who put patients on the drug as to what the real-world experience is in terms of A1c reduction and how does that compare to what you saw in your clinical trials.

That is going to be really interesting. My expectation would be that -- yes, repeat the question. How are the real-world experiences -- you have to, in principle, go to the center microphone or have me repeat the question. So the real-world evidence for oral semaglutide will emerge very soon. The early anecdotal feedback from physicians who are using the product is that they get very happy patients very fast. That's the early anecdotal feedback, only from the U.S. That's the only market. But if I look at the experience we have with Ozempic and Victoza, these injectables, there, the real-world evidence has more or less panned out in a pretty similar fashion to the clinical trials, which is unusual. Very often, you see a deterioration of the body weight outcomes and all the HbA1c outcomes. But both the ABCD trial, let's say, investigations in the U.K., but also database analysis in the U.S. have actually shown that real-world looks pretty much like clinical trials. It's because these GLP-1 molecules, there's not a lot you have to do in a special way. You just inject or you take the tablet. And of course, if there are patients who do not comply with the 30-minute thing, then either they'll have to escalate the dose to the 14 milligrams or take the once-weekly injectable. But what we are not seeing so far, it's early days, we're not seeing that it's at the expense of Ozempic. We're still growing Ozempic in a nice way, while Rybelsus is starting to take off. We're going into launch mode very soon.

[indiscernible] discussion [indiscernible] around some optionality around Alzheimer's and Victoza. Can you share your thoughts, please?

Yes, it's the discussion about Alzheimer and GLP-1 therapy. Basically, it all started anecdotally by some people doing animal studies that showed positive cognitive properties of GLP-1. Also shown in vitro, the GLP-1 is neurotrophic. It's also a neurotransmitter. It's actually also produced in certain parts of the brain. It also can induce neuronal sprouting and protect against apoptosis. All of this is in vitro. But what got us a bit excited is that we have analyzed our own data from the big outcome trials, and we actually do see a statistically significant reduction in the risk, or chance, risk of a dementia diagnosis in those who are on either Victoza or semaglutide in our trials compared to those who are just on standard of care. And that is now being corroborated by registry-based analysis conducted over many years both in Scandinavia and in the U.S. These data will be published, but more importantly is the ELAD study. ELAD stands for efficacy of liraglutide in Alzheimer's disease, and that is a Imperial College and Hammersmith Hospital study driven in around 18 centers in the U.K. by Dr. Paul Edison. That reads out over the next month or 2. It has [ the 9 ] phases completed. I don't have access to any data and it's not my data anyhow. But we are excited to see where the glucose metabolism is restored and stabilized using FDG-PET scanning and so on, but also, a lot of the secondary testing on cognitive performance. The intention for us as a company is actually to meet up with the regulatory agencies, FDA and EMA, and see whether there is a fast and effective path into pivotal studies in dementia, for instance, taking people with mild cognitive impairment and either preventing an Alzheimer diagnosis from occurring and/or showing functional outcomes improvements using the usual scales.

[indiscernible] [ penetration, how much is it? Is it 100% ] penetration or...

Penetration of what? Oh, blood-brain barrier. Yes, so that differs a lot. The really big molecules like dulaglutide, Trulicity, we find it difficult to get into the brain, which is why you see less weight loss. Then there are small molecules that also do not get that much into the brain. So -- and even liraglutide and semaglutide, for a non-chemist, look similar. But in reality, they are very different. Liraglutide gets much less into the critical brain structures of the brain, such as hypothalamus, as compared to semaglutide. And these are things we're still investigating. Is it the permeability and/or the stay time and stability once you are in the brain that differs? These things we will publish, but it also means that our selection of a drug for brain disorders, whether it's dementia or Parkinson's disease, will be driven by semaglutide and not liraglutide because it simply gets more to the target.

Just following up on that. Just thinking about vascular dementia versus the Alzheimer's. Is it more an effect on vascular dementia? And does that change the way you would design a Phase III trial? Does it matter?

So Dr. Edison's trial is not in vascular dementia. These are diagnosed as Alzheimer's, and they've done a lot of scanning and they're all beta-amyloid and tau and whatnot. So -- but in our clinical trials, it's been a mixture of all kinds of vascular dementia, Alzheimer's kinds, Lewy body dementia. It's a mixed bag and not very well characterized. I would say, though, that there's reason to believe that GLP-1, mechanistically speaking, will protect against vascular dementia because we have seen, when we look at the stroke data from SUSTAIN 6 and [ data in ] PIONEER 6, when we meta-analyze that, we have a statistically significant reduction in stroke by 36% across the trials. That's a lot, and that shows that something is going on in the atherogenesis process in the brain. And many small vessels are also involved in dementia, and either they become obstructed or they bleed and both can create vascular dementia. And that, I think, we can do something about. But the idea is actually, Richard, basically to say it's -- if we take mild cognitive impairment, we don't really care whether the MCI is driven by vascular causes or early -- pre-prodromal symptoms ahead of the Alzheimer's diagnosis. I think that GLP-1 might be able to do the job regardless.

Just to [indiscernible], have you made public the data that you [indiscernible]

No. We will make them public very soon. I can give you ballpark numbers. I cannot -- the registry-based studies in Scandinavia and the U.S. I cannot because they're not mine. There are professors behind them. But our own data are mine. And I can say it's ballpark like 50 diagnosis of dementia on standard-of-care treatment and half of that, around 25-ish, on the GLP-1 therapy. And the amount exposed are the same, of course, because it's 1:1 randomization. So it is statistically significant. It's not huge numbers. It's not a prospective, purposeful-designed dementia study, but it corroborates what we have seen in the registry studies. And Marcus, you've also seen something in your animals, right?

I mean, we've looked at that over a number of years actually. And whatever you think of the validity of some of the animal work, it's actually quite consistent with what we see with our GLP-1 agonists, again, across the class where they improve cognitive impairment. And I think that in -- all put together, I think, gives us quite a lot of confidence that we're actually seeing something that could well be real and -- but we'll soon find more, and then we'll obviously need to decide what the next step should be.

Can I just follow up on that, the U.S., Scandinavia registry data? Is that showing a similar reduction?

Yes. So one of them is based on Scandinavia -- yes, so do the data we have show similar things to the registry-based data on dementia diagnosis? And the short version is yes, but it's done in a different way because one of them is looking at a registry in 300,000 to 400,000 people with diabetes in Denmark, how have they developed over a 15-year period. And in that period, semaglutide has not been available, and most Danish people in that period would take Victoza as a GLP-1 agonist. So most data there are on Victoza, and in the U.S., the data are on the GLP-1 therapies that have been used. But we've tried to weed out the glycemic effects by looking into what do other classes do, insulin, sulphonylureas, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors, and they do not change the risk of onset of dementia in -- at least in the Danish registry. So I think this is not hardcore evidence, but it's many lines of empirical evidence that point towards what might well be a whole new action of GLP-1. And there, clearly, you want something that does get into the right brain structures. And there so far, we've not found anything that is more -- better at permeating and staying there than sema.

And I think that was an important finding that is not simply glucose control, right, that drives this, but you have actually a parallel pathway probably ongoing.

You highlighted in the presentation, obviously, we're waiting for the STEP data program from the obesity trials of semaglutide. Just maybe you could level-set for us how we should think about that data and the size of weight loss and the side effects.

Yes, so these are 4 very different trials. The one you need to look at, if you want to see how will my patient, if you're a physician, how will my patient be expected to lose weight on the drug, that will be step 1. That's a classic 3,000 patients approximately, classic trial where you have just standard, i.e., placebo and then sema. And that's the one I'm expecting the 15% weight loss. Then there's step 2. That's the diabetes trial. And as you know, when you have diabetes, you mitigate a little bit the weight loss because as you improve glycemic control, you have less glycosuria, i.e., you pee out less glucose, and that means that you don't get the full effect of the body weight loss. And then there's also one where we actually are inducing weight loss by dietary management. And then we see whether we can maintain that and build even further upon it. And of course, if people have already lost 6% weight on a low-calorie diet, it's unlikely that we can add a further 15%, if you understand what I mean. And the final one is looking at intensified (sic) [ intensive ] behavioral therapy, IBT, together with semaglutide. And I think semaglutide is so efficacious a weight loss agent that it may well be that it's not like IBT gives 7% and then we give a further 15% because some of the behavioral therapy we're already giving pharmacologically because the drug tells the brain to stop eating. That's the same we actually experienced with the behavior. So it may be that the way forward for sema is semaglutide plus exercise and not so much thinking about diet because the drug takes control of that.

Then maybe just thinking about the amylin analog on top and how we should think about that product and maybe the tolerability of that product as well. We sort of know what semaglutide looks like. But does that bring new tolerability concerns?

I'm always really nervous when I take peptides of different classes either from the gastrointestinal system or from the pancreas, like amylin, and you combine them. I'm always nervous that we get big-time tolerability issues. So what we did in the multiple-dosing study with amylin as a stand-alone drug was to test different titration regimens, and we actually found a titration regimen that was highly efficacious and very tolerable. What I do not have, Richard, is the combo data yet, so I really can't tell you. But I would have known if there were a lot of patients dropping out because we can follow that, and the dropouts are low. But as soon as we have the multiple -- I think it's 12 weeks of dosing with 2.4 milligrams of sema and the different levels of amylin. Right now, my expectation is that it is looking to be tolerable. And of course, escalation to your steady-state dose, that is something where if we find a tolerability issue, if you like, Lilly did with tirzepatide, they're trying to go slow and titrate over very prolonged periods, I'm not sure we need that. But if that is needed, then that's also an option.

Considering the oxyntomodulin [ as a modulator, I mean, do you have any specific ] [indiscernible]?

So in my view, oxyntomodulin, that is just a molecule that you have in your own proglucagon processing cells in the gut. So oxyntomodulin, if you attach a fatty acid to oxyntomodulin and make it as potent and brain-permeating as semaglutide, you might be able to achieve something like a dual agonist, in principle. But what we have so far been disappointed with, in my view, if I were to rank order the combinations, then I'm least impressed by what I've seen from GLP-1 and glucagon combinations or hybrids. I'm perhaps more impressed with the GIP/GLP-1, but that is still a little bit uncertain. And I'm actually most impressed by the combination of GLP-1 and amylin based on sheer numbers that I've seen both in animal experiments, but also in the human studies so far. So I'm relatively, no, very excited to see the amylin data as monotherapy, but also the readout of the short-term, multiple-dosing study so we can -- but that's more to define the ratio for Phase III.

We've got time for one more question.

I was just wondering if you can say broadly speaking what's your fondest wish for this year. What do you want to come back here next year saying?

Okay. In -- on our view, [ Kelly ], I would like to come back next year and say, "Yes, our glucose-sensitive insulin is now in Phase II. You don't need to monitor your glucose. You just take it. And when there's no use for it, it will circulate in your body and be ready for the next meal you ingest." That would be one wish.

Brilliant. Thanks very much.