Hello, and welcome to the Novo Nordisk A/S R&D Investor Call. Throughout the call, all participants will be in listen only mode, so there's no need to mute your individual lines, and afterwards there'll be a question and answer session. I'll hand the floor to our speakers. Please begin the meeting. Thank you. Welcome to the Novo Nordisk Investor Call in connection with ADA. My name is Karsten Munk Knudsen, CFO of Novo Nordisk, and with me today, I have Marcus Schindler, Chief Scientific Officer and EVP of Research and Early Development, as well as Martin Lange, EVP of Global Development. At today's call, there may be forward-looking statements and projections around the future, which by their very nature, inherently are uncertain, and their outcomes may turn out differently. As usual, we anchor our communications around our Strategic Aspirations 2025, which are covering our strategy execution as a company. Today's focus is purely on the quadrant denoted innovation and therapeutic focus, where we'll be covering our progress within raising the innovation bar for diabetes treatments, developing a leading portfolio of obesity medications, as well as building a presence in other serious chronic diseases, especially within cardiovascular disease, NASH, and chronic kidney disease. Today, given we do this in conjunction with ADA, we'll not be providing specific updates on our biopharm pipeline. We'll do that at other opportunities later on. The agenda for today starts out with diabetes and obesity care highlights from ADA by Martin Lange, followed by a Q&A session from the audience. From that, we move into research and early development with a special focus on cardiovascular disease led by Marcus Schindler and also with a presentation by Martin Lange. Also there we'll be doing a Q&A session following that. Without further ado, I'll be handing the presentation over to Martin Lange. Thank you very much, Karsten. First of all, just to start off, I just wanted to share with you our current late-stage pipeline. As you'll see across our therapy areas, across diabetes, across obesity, obviously, rare blood disorders, but also in other serious chronic diseases, we see progress of our clinical pipeline. Specifically, we are going to start a phase III program across all therapy areas, including in NASH, NCD, and in Alzheimer's disease. These activities have not been impaired, and we do not expect them to be impaired by COVID-19, and therefore, we are progressing our pipeline as planned. This basically means that we expect to have roughly 2,000 active patients in our clinical development program by the end of 2021, moving towards actually 65,000 patients in just two years' time. Next slide, please. I'm going to take you for a bit of a tour de force together with Marcus, starting up with what we have on display at the ADA. You probably noted, we have quite a number of presentations at the ADA, I think around 37, and we'll try to give you some of the highlights during the call today. Next slide, please. Starting in diabetes space, obviously, you've seen our SUSTAIN FORTE trial is 2.0 mg of semaglutide versus 1.0 mg of semaglutide in approximately 1,000 patients with very high A1c levels between 8 and 10, baseline being around 8.9, and patients being randomized to either 1.0 mg or 2.0 mg of semaglutide for a treatment duration of four weeks. Primary endpoint, I was about to say as usual, was hemoglobin A1c, which was our key focus of the trial. Next slide, please. Obviously gratifying for us to say a statistically significant and a clinically relevant difference between doses of semaglutide. In addition to that, we saw a clear impact on body weight and also in terms of the proportion of patients reaching pre-specified targets. What was really interesting to us was that, and obviously very comforting, was that increase in dose was associated, as we just discussed, in good increase in efficacy, but with no difference in the gastrointestinal and broader adverse event profile. As shown on the lower right-hand side of the slide, discontinuations due to AEs or overall AEs of nausea, diarrhea, and vomiting was approximately equal to the two doses despite the improved efficacy. We take a lot of comfort in that, and as we've also shown at the ADA, doing sub-analysis, dividing patients into subgroups of baseline A1c or baseline BMI, and we see the difference between the two treatment arms throughout. Next slide, please. Staying in the diabetes space and looking at the PIONEER trial, we've been looking into first PIONEER 1, looking at baseline diabetes duration, so patients having less than one year of diabetes in terms of diagnosis versus patients having more than one year of diabetes in the diagnosis. We clearly saw that the proportion of patients achieving hemoglobin A1c below six was, and this is maybe not so surprising, better achieved if intervention started earlier, namely patients with very early diabetes. Similarly in PIONEER 2, comparing glycemic control between oral semaglutide and empagliflozin, we saw that a larger proportion of subjects maintain good glycemic control with semaglutide as compared to empagliflozin. Obviously, very nice data and very nice results for the Rybelsus brand, and coming out from both the PIONEER 1 and PIONEER 2 trials. Next slide, please. Obviously, with the very strong label that we have with Rybelsus, both the 7 mg and the 14 mg, showing a superior and statistically significant reduction in A1c, and a good as compared to both a placebo, sitagliptin, and a SGLT2 inhibitor, and a good body weight reduction. We also have an ambition to maximize the efficacy that we can achieve with also oral semaglutide. We've already discussed what can be done with subcutaneous semaglutide in the hands of SUSTAIN FORTE. We want to do something similar now in the oral space for Rybelsus. We are currently in phase III, testing higher doses of semaglutide in an oral formulation, namely 25 mg and 50 mg. The intention being that the 50 mg will correspond to approximately 2 mg to 2.4 mg of semaglutide in terms of both efficacy and safety. A very nice efficacy safety profile that is already seen from SUSTAIN FORTE, with a very attractive safety profile to accompany that. Next slide, please. Staying within the diabetes space, obviously, and Marcus will be able to talk about that also in the innovation space. We want to take our diabetes innovation to the next level as well. We have also come to realize, as I think most peers in this space, that monotherapy luckily have been maxed out, and therefore, to get to the next level, we need to look at combination therapy. We have or will in very soon future initiate two phase II trials in the diabetes space to that end. First being with the combination of an amylin analog cagrilintide in combination with semaglutide, where we look at the combination versus the monotherapies in a placebo-controlled setting, looking at a fairly short treatment duration. This will allow us to, if successful, to initiate potentially phase III for diabetes at the same time as we intend to initiate the usage trials for the cagrilintide molecule. In the combination space, we also have a combination with our GIP offering, again, a once-weekly molecule looking at the combination of semaglutide and GIP. In this space, we are still looking towards doses and ratio optimization. We will in phase II investigate a number of different ratios up against the monocomponents. This is a slightly longer trial than the cagrilintide trial. Again, very high hopes for obviously what these compounds can do, not only in the diabetes space but also with the potential of very strong weight loss profiles. We had discussed the CagriSema data in non-diabetes subjects where you've seen weight loss to the tune of 17% over a 20-week treatment period. Next slide, please. Switching gears a little bit, you've probably at this ADA seen a lot of presentations and posters around time in range. This is a reasonably new concept acknowledging that just looking at hemoglobin A1c, just looking at spot blood glucoses or even 7 or 9-point profiles is maybe not enough and not giving us the full picture of good control in diabetes. This is an illustrative slide looking at three sort of patients all with the same level of glycemic control of approximately 8.6 in fasting plasma glucose or 154 mg/dL and 7 or 8 in A1c. Underlying this, if we did continuous glucose monitoring for these patients, we now know that some patients, even with the same A1c or even with the same plasma glucose, have very different time in range profiles. Time in range basically depicting how much time does the patient in what we would call glycemic control. I recently heard an indicator saying it's sort of like the speed limit. If you are to stay within, let's say, 50 and 100 mi/hr, that wouldn't do in the U.S., but it works in kilometers per hour, then that's your goal. If you go too high or too low, you have problems. In this example, we clearly have one patient spending way too much time in high glucose levels, leading to increased risk of next stage complications, but also way too much time in low blood glucose levels leading to risk of hypoglycemia, basically. Then we have an example that's sort of in between, and then we have one patient being in exactly the range where we want the patient to be. Without the technology of continuous glucose monitoring, without the digital tools and the technology to help us interpret this, we wouldn't have those insights. Having those insights, it allows us to better target and tailor make treatments for patients. It allows us to better understand the disease, therefore we see this technology advancement as a major advancement also in the treatment of diabetes. Next slide, please. Specifically in the insulin space, obviously introducing new insulins, we want to make sure that we do see an upside not only on A1c, not only on fasting plasma glucose, but also specifically on time in range, because this is where we know that we can also start predicting outcomes for our patients. As you know, we've conducted phase II for insulin icodec, looking at different titration algorithms and comparing to insulin glargine in a 1-to-1-to-1 randomization in phase II, and a 16-week study duration. In that phase and looking at titration B, we see actually that being on icodec is associated not only with a statistically significant but also clinically relevant 10% more time in range. You can probably imagine throughout the day, being 10% more time in range, it's very attractive to the patients, obviously in everyday life, but also in terms of the outcomes. This gives us very high hopes and very high aspirations on behalf of the icodec molecule. Next slide. Obviously, we intend to investigate that in phase III, and I'm going to show that in just a minute. Specifically, also for phase ADA, we've been able to look more into the risk of hypoglycemia with a once-weekly molecule. This is in fact a recurring story when with the introduction of the longer-acting molecules, for example, Tresiba, there were questions around if this work longer, is the risk of prolonged hypoglycemia then also present? We could show with Tresiba that that was not the case. Actually, duration of hypoglycemia with Tresiba was comparable to that seen with, for example, both Levemir and glargine. Based on what we've seen also for icodec, which is now going from once-daily to once-weekly, we are super happy to see that the risk of having prolonged hypoglycemia is not there. Basically, the timing of hypoglycemic event is the same, both obviously in the different icodec titration arms, but more importantly, comparable to that of insulin glargine. That goes for both overall but also long-term. Very comforting for us to see. Another way of looking at it is obviously, and this is based on the CGM data, time spent below 54 mg/dL, which is in fact downright hypoglycemia. Again, here we see no difference between icodec and glargine, suggesting that even in the occasions where we do have hypoglycemia, the risk of staying too long in that hypoglycemia is not there. Very good data for insulin icodec and obviously adding to our aspirations for that molecule. Next slide, please. To me, very exciting. We are in the progress. We've actually finalized the recruitment for ONWARDS 1, which is our pivotal and obviously also longest trial. We are well on track for ONWARDS 2 to 6, none of them being behind, actually all on time in terms of recruitment. Making us reasonably adamant that we will be able to finalize and report on these trials in a timely fashion. We will be able to do regulatory submission either late 2022 or early 2023. For all of these trials, we obviously apply a treat to target, apart from ONWARDS 5, which is a real-world evidence trial where we're basically using digital tools, allow the patients to control their own treatment together with digital support. A connected device, a connected BGM, obviously an app to guide the patients. We have employed CGM in ONWARDS 1, 2, 4, and 6 to support our assessment of also time in range. We are very excited about insulin icodec and will be equally excited when these data start to read out in 2022. Next slide, please. Moving into the obesity space for a brief while. We talked about a couple of weeks ago in connection with the very nice approval of semaglutide 2.4 mg or Wegovy between friends in the U.S. We shared with you the STEP 5 data. STEP 5 is basically a trial dedicated to look at the sustainability of weight loss with semaglutide. As you know, with current treatments, we do tend to see over time, after approximately one year, a waning off of the weight-lowering effects of the treatment. We set out to investigate if that would also hold true for semaglutide. Very comforting for us, almost boring for us to see that even after two years of treatment with semaglutide, we still see the same 17% weight loss that we have reported for 68 weeks of treatment. Very consistent across all the studies that we reported on semaglutide 2.4 mg so far. Obviously, comparing to placebo, this is not only clinically relevant but also highly statistically significant. As almost pedestrian and boring, the same 40% of patients achieved at least a 20% weight loss even after two years of treatment. Obviously, we are very, very happy, and this is also becoming a feature of semaglutide, an attractive safety and tolerability profile. Exciting for obviously Marcus and myself to see is obviously that we see improvements in lipid profile, but also importantly, C-reactive protein as a marker of anti-inflammation effects of semaglutide. We believe this to be important for semaglutide in the NASH space, in the cardiovascular space, but also in the Alzheimer's space as part of the mode of action for semaglutide in these spaces. Also, these findings have been consistent across all the STEP trials. Next slide, please. In STEP 8, which is a trial that has not yet been reported, this is basically the first. We set out to compare liraglutide to semaglutide 2.4 mg in a placebo-controlled setting, both treatment arms were placebo-controlled. For the sake of simplicity, we include placebo in this slide, but both treatment arms were placebo-controlled. In this space, again, we see a 17% weight loss with semaglutide and the expected approximately 7% weight loss with liraglutide 2.0 mg. Basically, you're talking to the expected effects of the two molecules. What is really nice, obviously, and I don't have time to show that here, is we also see effects on glycemic control even in this non-diabetic population. We also see the impact on lipid profile and inflammatory markers as we just discussed for STEP 5. A very attractive trial, also considering that semaglutide comes out with this very attractive clinical offering, including a benign safety profile. Given that semaglutide will be priced to the level of liraglutide, then with a more attractive clinical offering. Next slide, please. In STEP 1, this is obviously a study that has already been reported. We've done sub-analysis showing the impact of glycemic control in a non-diabetic population. As you see in the right-hand side of STEP 1, you probably remember STEP 1 was our pivotal obesity trial, approximately 2,000 patients being randomized to either placebo or semaglutide. In this space, we see that pre-treatment, approximately 45% of patients in the semaglutide arm and 40% in the placebo arm had pre-diabetes. After 68 weeks of treatment, only around 9% of patients in the semaglutide arm still had pre-diabetes. That is to be compared with 26% having pre-diabetes and 1.6% having overt type 2 diabetes. Obviously, very interesting data in and of itself. What we've not reported so far, but what I can say here is that we actually did an extension of STEP 1 where we observed the patients off treatment for another year, so 52 weeks up until 120 weeks. In this space, we actually see that the legacy effect of having been on semaglutide is maintained. More patients stay in the non-diabetes state with semaglutide than what we see for placebo. Not reverting to sort of a diabetes risk baseline despite the fact that they actually start to regain weight. Very attractive and a good outlook also for semaglutide in particular when we start to see similar data coming out of this [audio distortion]. Next slide, please. In STEP 2, we looked at improved glycemic control and other markers in a post hoc analysis for STEP 2. You know STEP 2 was our weight loss trial in diabetics. What we saw was a marked improvement in waist circumference. We saw improvement in lipid profiles. We saw again improvement in inflammation. Importantly, we also saw improvement in health-related quality of life questionnaires as measured by both SF-36 and the IWQOL. Next slide, please. All in all, we were very happy with the efficacy profiles that we've seen coming out of STEP 1 through 5 and STEP 8. We have seen a very robust but also consistent weight loss. We have seen robust and consistent improvements on cardiovascular biomarkers, including inflammation biomarkers. We've seen this with a very attractive safety profile, that we believe is starting to become a hallmark for semaglutide. Just very briefly here, I hope this is not my timer. We're just showing here the discontinuation rates for semaglutide in STEP 1 and 2, as well as for placebo. As you will see, first of all, these discontinuation rates overall due to adverse events, but specifically also due to GI-related adverse events, are very low and reasonably low, close to the discontinuation rates observed for placebo. These discontinuations of treatment has not led to very high withdrawal rates. Generally, we see withdrawal rate from our trials in the tune of less than around 5%, which is in an obesity setting, a testament also to the acceptance of the drug. Next slide, please. Overall, we believe that we have had an interesting presence at ADA with a number of different abstracts and presentations. We continue to raise the bar in the diabetes space with more benefits of semaglutide, as specifically demonstrated by SUSTAIN FORTE. We continue our insulin innovation. We are very excited both with the current data from phase II but also with the outlook for icodec phase III. We are going to initiate two phase II trials to further raise the innovation bar in the diabetes space. One with the combination of cagrilintide and semaglutide, and the other of semaglutide in combination with GIP. Finally, we show in the obesity space a profound weight loss, with a magnitude and duration that will obviously be explored further, also the impact of which in the ongoing additional STEP trials, but also in this next one. Thank you, Martin. That takes us to our first round of Q&A, operator. I would like to ask the audience to restrain yourself to only one question. We have a lot on the line, everybody can get their question in. Let's try and go with one question each. Operator, please move to Q&A. Thank you. Our first question in the queue comes from the line of Wimal Kapadia of Bernstein. Please go ahead. Well, great. Thank you very much for taking my question. Wimal Kapadia from Bernstein. Just to go in, can I just ask about how you think about the fixed-dose combination approach for GLP-1 and GIP that you're taking versus the dual agonist approach? You mentioned the balance, does the fixed dose really provide better safety outcomes or the potential for superior efficacy if you get the ratios finely balanced? Just curious what you see as differentiated given you're several years behind your main competitor. Thank you. Thanks, Wimal, for that question. This goes to you, Martin. Fixed-dose versus dual agonist approach, consideration. It's a super good question, obviously also an approach that, or a question that we had ourselves. We have tested this both in the preclinical space, but also in the clinical space where we have evaluated a number of different ratios. Clearly, we believe that specifically for a combination of cagrilintide and semaglutide, but also soon for the semaglutide GIP, that we've sort of hit a sweet spot where we've optimized efficacy, but we've also managed to do that without compromising on safety. Specifically on the CagriSema combination, you saw this rather dramatic increase in efficacy, 17% weight loss in 20 weeks, which is to be compared with the 17% weight loss we see with semaglutide in monotherapy in 16 weeks. This comes with no increase in tolerability, no increase in adverse events. We basically get the improved efficacy without compromising at all on safety. Obviously, we have to prove this in phase III as well. We do believe that with our approach, we've managed to find a ratio that optimizes the best of two worlds. Great. Thank you very much. Thank you, Wimal. Thank you, Martin. Next question, please. That comes from the line of Simon Baker in Redburn. Please go ahead. Your line is open. Thanks so much for taking my question. Just on that point about the combination, I just wonder, I know you said earlier, but what data you can share so far, even if it's preclinical. If you have any preclinical data against tirzepatide, that would be very helpful. Thanks so much. Martin, what do we know at this point as tirzepatide on our combination? In the clinical space, and I believe in the preclinical space, we don't have head-to-head evaluations that we normally have at this point in time. At this point, we have to rely on modeling. We've decided not to fully share our modeling of specifically the CagriSema combination. However, we do believe, even with our most conservative modeling, that we will at the very least be able to stack up, if not be superior to what is currently out there. Thank you, Martin. Thank you, Simon. Next question, please. Thank you. That's from the line of Michael Leuchten of UBS. Please go ahead. Yeah, thanks so much. I was just wondering on timing on your cagrilintide phase II. Would there have been a possibility to make this straight into phase III? The reason why I'm asking is Lilly seems to be talking about moving a triple agonist into phase II this year, which then if successful, may then mean they're not that far behind your combination. Just want to be more aggressive with the timing, I guess is my question. Thank you. Thank you, Michael. That's a very good question, and sure thing. Martin, can we move faster than what we've seen here? It's a super good question. Obviously, we're taking a lot of comfort in that we've spent the last couple of years not only in decreasing our white space substantially but also thinking harder in terms of how we go about development. That being said, we always have to do an evaluation of the data and the knowledge that we have and what needs to be done in order to increase our knowledge base before we go into phase III. We have good examples, sotagliflozin one, IcoSema being another, where we go directly into phase III from phase I. However, with the CagriSema, we have assessed that we need a little more data to feel able to design phase III. That is not going to impair our timeline substantially because we have shown that we can both recruit and also conduct our advanced bio assay. Thank you, Martin. Thank you, Michael. Next question, please. That's from the line of Michael Novod at Nordea. Please go ahead. Yeah, thanks a lot. Just a question to STEP 2, and also you had some symposium, or the STEP symposium the other day where there was a discussion between the panelists around use of h igher dose, much faster. How do you see the use of semaglutide 2.4 mg, potentially also in diabetes? Because as [audio distortion] said, it was time to move on to much higher doses in diabetes based on the data that's been presented for this dose in diabetics. How do you see that profile interact with Wegovy in obesity versus the use of this high dose in diabetes? Of course, also bearing in mind to have the 2.0 going to the market too. Thank you, Michael. Martin, this is something we traded when we designed the trial. 2.4 obesity dose versus 2.0 dose in diabetes for semaglutide. Yeah. First of all, as with everything else, this is on an assessment of the individual patient. If the key focus is weight loss, I would go with Wegovy 2.4 mg. If the key focus is diabetes control, I would go with Ozempic, either 1 or 2 mg. Again, I think generally speaking, I don't want to contradict what [audio distortion] said. Obviously, it has to be patient assessment. There will be patients who are on optimized glycemic control at 1 mg, and with a very attractive weight loss. There will also be patients who either need a little bit more or need longer sustainability, so the option of adding a higher dose, which makes the obesity also the 2 mg of Ozempic a very attractive offering. I think it's super important to distinguish between the diabetes focus or the glycemic focus and the weight loss focus. Obviously, the 2.0 mg does also provide a very nice loss. If the key focus is glycemic control, 2.0 mg is the way to go. Okay. Thank you. Thank you, Michael. Thank you, Martin. As you know, we're also pursuing high doses in our oral semaglutide offering as well with the 25 mg and 50 mg. We are clearly looking in that direction. First answer is yes, and second answer is these studies are currently ongoing, and when we've seen the readout and assessed them, you'll be almost the first to know. Thank you. Thanks, Peter. Very clear and short answers from Martin and those questions. Thank you for that, please. Next question, please. That's from the line of Emmanuel Papadakis of Deutsche Bank. Please go ahead. Thanks for the question. Maybe once you actually, if you could just give us a quick update on the latest in terms of cost, certainly on a relative basis for 15 mg. Where do you think the gross margin of that is likely to come in relative to the rest of the franchise given some presumed bulk source improvement? Just a quick clarification, if I heard earlier that you said you thought it could be clinically equivalent to the 2 mg-2.4 mg dose of subcutaneous semaglutide. Did I hear that correctly? Thank you. Yeah. Emmanuel, thanks for that question, that's clearly something that we of course evaluated before we did evaluate before we initiated the high dose oral semaglutide trial. What we've been saying previously has been that we expect for Rybelsus, that we get to group average margin by our strategic aspiration period in terms of gross margin for Rybelsus. What we're doing at the same time as we've been talking to before, we continue to invest in our oral platform in terms of oral formulation and our SNAC platform. That is a Novo classic that, as you've seen with our insulin platforms for many years, we do that with our oral platform also. Clearly, without guiding specifically on the gross margin for the 25 mg and 50 mg, we would not have initiated high dose trials either in diabetes or the obesity oral trial without being able to get to a place with an attractive gross margin for those products. Martin, the second question for you. Yeah, I think you are exactly right. In the diabetes space, we expect the 50 mg correspond to the 2 mg subcutaneously. In obesity space, and again, we see this as two different disease entities, we expect to see the 50 mg approximately correspond to the 2.4 mg in terms of weight loss. In that space, acknowledging that the oral formulation has a slightly higher variability, I would suggest that 50 mg in diabetes will correspond to 2 mg and 50 mg in obesity will correspond to 2.4 mg. Thank you, Martin. Thank you, Emmanuel. It's time for the last question before we move on to Marcus and resource and R&D. Last question, please. That's from the line of Richard Vosser at JP Morgan. Please go ahead. Hi, thanks for taking my question. Just on the icodec, it looks as though you titrated slightly more aggressively than the Lilly weekly insulin BIF in their phase II trials and potentially got a few more patients spending or more time with patients in range. Could you maybe contrast the benefits? Is that right, and the benefits of the product as icodec versus BIF as you see it at this point? Thanks so much. I would be super concerned to compare to another investigational drug. What we've seen so far makes us very confident that icodec has a clear edge. Both in terms of time in range, but also in the maintenance period, we actually saw a lower risk of hypoglycemia with icodec than what we saw when we compared to once-daily drugs, specifically glargine. That being said, obviously, with the titration we had, we saw in the titration period that we needed to do some work, and we basically spent the combination of our phase II data, as you also saw. We have one study with a loading dose when switching from another insulin and so on. The combination of all the data that we had allowed us to do what we think is going to be the good but also ambitious titration algorithm, balancing good efficacy, but also good safety in terms of risk of hypoglycemia. Thank you, Richard. Thank you, Martin. This ends the Q&A session and takes us to the session on research and development. Over to you, Marcus. Thanks very much, Karsten. Can I have the next slide, please? My name is Marcus Schindler. Obviously, as we haven't met in person or probably at any time in my role over the last couple of months, I just wanted to allow myself a little bit to introduce you to research and early development, because we are in the midst of transforming the way we do drug discovery on a number of avenues. I think there's a lot of excitement to see I actually want to share with you rather than spending too much time on individual assets, we will be talking about some exciting news on our cardiovascular asset, because that is the next frontier, obviously, that we're tackling. First of all, maybe to the left on your slide, we're moving really from a world where we have based hypotheses largely on observations based on preclinical animal studies to something what we call human-centric drug discovery. With the power of computing today, human genetics really, I think is moving into the centerpiece, and the initial disappointments on some of the GWAS data actually are getting resolved with the granularity we can interrogate some of those data. That's point number one. Second is we have now large databases from clinical trials, biopsy samples, soluble biomarkers that can be interrogated, and all of that to build actually new hypotheses for novel treatment paradigms. Last one, to use one buzzword, obviously big data, interrogating real-world evidence data will also actually help us to come up with novel ideas. All of this, if you then lump it together with human-centric model systems where we're using organoid systems, for example, to actually test our drugs, leads us to a world where human data and human model systems are at the very core of everything that we do. I hope you agree that's actually quite distinct from where we were, and I would fundamentally argue that's a better place to be because we're taking out early attrition very early on in the pipeline rather than pushing observations later on into clinical development to then deal with the outcomes. We have several thousand employees working hard really on innovation, and it's not something to boast about, but simply also to remind all of us on our leadership position. I've worked in a number of pharma companies. Clearly at Novo Nordisk, we are dedicated to the disease areas, and it's a smaller number than some of our competitors. I think that also gives us a very deep insight into the science and a long-term outlook into the biologics we're working with. We're moving from an organization that has been largely centered around Denmark, has been located into Denmark, across the globe. Why is that a good thing? Because we're tapping into the talent pool that is globally available in other epicenters, obviously, of innovation such as Boston. We're present now in the Bay Area. We have a site in Seattle, very active in Oxford and in Beijing. I think that gives us really a fundamentally good base of cutting-edge scientists and people working on various technologies to do the work that we need to do. We are also moving beyond what was maybe a more traditional functionally structured way of working into one where we have a number of ways of working in traditional units. We call transformational research units. You probably have heard about our center unit with a ring-fenced budget and a level of autonomy within our framework that actually allows them to move incredibly fast, test hypotheses early on, but at the same time, also take accountability and be sort of mini CEOs within our company. Maybe one thing you haven't heard so much in the past is a network of partnerships, because largely all the good things that Martin has showed you were and are the product of in-house innovation. We firmly believe that the next wave of innovation will actually come through dedicated, specific work with partners. Those could be academic institutions, could be biotech, and actually peer pharma companies. We believe that is one way and maybe the best way to tackle a particular number of unknowns that we're dealing with. We have a large number of projects in the pipeline. 90+ doesn't actually tell you a lot. I have to say, what actually energizes me more is that a significant portion of those projects deal with first-in-class novel mode of action. I think that really puts us in a position that we have a significant number of proprietary drug targets where we feel we can be in a leading position. The second piece is we see a larger diversification of the molecular entities that we're using. Of course, you know us as a company leading in the biologics space focused on peptides and proteins, but we're going way beyond this. We've touched on the oral biologics leadership, and that is continuing. I can assure you that. Full steam ahead. We're also entering into the field of siRNA therapeutics to address intracellular targets and silence them more or less completely. We're using stem cells to move us into the regenerative space, and we're actually generally broadening out to other tools, but not leaving what we see as our fundamental scientific core. They're also currently modalities that we're not working on. All of this obviously comes together that we're not only staying and continuing to innovate in diabetes and obesity, but moving beyond. Two-thirds or more of people living with diabetes suffer from cardiovascular disease. Significant portion of them will see cardiorenal disease. Branching out into cardiovascular specific and also chronic kidney disease, I think it's actually a very natural journey. Early work also in the stem cell unit, we're moving towards sort of regenerative spaces, which take us a little bit outside of our therapy areas. We're entering into Parkinson's disease, but we've obviously also have semaglutide now in Alzheimer's disease, which I think is a tremendous opportunity to pursue. Then we're not speaking today because this is the ADA call about the cutting piece, obviously, in the rare blood and the endocrine disorders, which I think gives us actually a very nice angle to start experimenting with and engaging in gene therapy and gene editing. Next slide, please. Many of the things actually I talked about have started, I think with GLP-1, semaglutide in particular, which has really paved the way with seemingly a plethora of biological pathways that we're addressing. For those of you who are old enough to witness when these molecules were started, and that's all today, obviously, Jens Juul Holst getting the Banting for incretin biology. I started decades ago, if you imagine today what we know about GLP-1 and where we see the fundamental effects we're seeing in a number of organ systems, it has really opened our eyes to the opportunities. On the right-hand side, however, giving you some evidence that we're not only broadening out in disease areas, but we're actually doing this AI partnership, and we're using specific platform collaborations to actually broaden our ability then to address targets that we want to pursue. Leading the pack maybe here, the Dicerna collaboration, which we signed a strategic collaboration with Dicerna on siRNA technologies progressing very well, very productive collaboration. We're taking first steps in gene editing with colleagues at bluebird bio in the hemophilia space. Most recently, I'll come to that in a minute, we signed a deal with a Japanese biotech company, Heartseed. Maybe the most prominent some three years ago around this time was our acquisition of Ziylo, the company Carbometrics, which gives us access to the glucose sensor part of one of our tracks on glucose-specific insulin. Of course, you're all aware of the acquisition of Emisphere, which really paves the way now to blast sort of oral biologics and generate better and better technologies here. We'll talk a little bit about cardiovascular today, in particular on ziltivekimab coming from the company Corvidia. As one specific example, I think of a pure pharma-to-pharma collaboration, I just wanted to highlight the Gilead collaboration and how together we are tackling NASH. Next slide, please. The cardiovascular space. On the other hand, maybe even more prominent to collaborate on stem cell-based therapies. Heartseed, over probably two decades of [audio distortion] hard work, has actually come up with a rather unique iPSC preparation for cardiomyocytes. They've really optimized the protocol to come up with cardiomyocytes, which already have seen look very benign. They show no abnormalities once they're implanted into the heart. They've actually come up with a way to implant those cells, and they form little spheres, which I don't want to say guarantees, but has probably a better chance to survive in the heart and stay there for a long time than we have seen with previous versions of stem cells. I'm actually very excited that we can move hopefully into a first-time-in-humans trial very soon and are pretty much on track to do this in the near future. Next slide, please. Moving from a field where stem cells will really help patients to not having to go on a transplant or at least prolong their time, to a much more fundamental biology, which is inflammation. Right. Maybe it sits in line here with the triglycerides and the cholesterol. Maybe we should have actually a bar that cuts across because we do believe it is a fundamental principle that is ongoing. We're going to zoom in on a very particular patient population. Next slide, please. Which will be addressed by an IL-6 block. This is, you remember I spoke briefly about this last year at our call when we just acquired Corvidia. This blocks IL-6, the ligand, not the receptor, we believe actually gives us a better profile, a better therapeutic window, and not to be concerned so much with side effects. The news you have seen probably at ACC is that ziltivekimab does exactly what we were hoping for with very high potency. It basically blocks the hs-CRP to a large degree. Maybe as a fun fact thrown in, before we saw the data, we had made an internal checklist to see what would we expect, what would look great, and what would look outstanding. I can share with you this was in the outstanding box because all three doses actually delivered significant reduction. What we're not showing here, but you've probably seen it in the publication, the reduction is sustained, and that, of course, is very important. We've also seen a very benign side effect profile. These are relatively small patient numbers. It's a phase II trial, but it basically ticks all the boxes we could expect to see from a phase II trial. Next slide, please. That actually gives us confidence to move forward with this drug and let Martin speak to the ZEUS trial. Yeah, very briefly. As Marcus rightly said, we've seen some super exciting and interesting phase II data, both from an efficacy but also from a safety perspective. It has allowed us to identify what we believe to be the optimal dose, and we will actually progress that directly to a cardiovascular outcome trial. The ZEUS trial is going to start recruiting this year. It's going to be 6,200 patients being randomized either to ziltivekimab 50 mg on top of standard care versus placebo. This is a fairly advanced cardiovascular population as compared to what we have seen previously in our trials. All of these patients will, I was about to say, as usual, have established cardiovascular disease. On top of that, they will have chronic kidney disease stages 3 and 4, as well as having an underlying level of inflammation, which leads to a reasonably high risk of cardiovascular events. This is also why we've allowed ourselves to have a smaller sample size than what you've seen previously in our hands. Typically, we are around 10,000 patients in our outcomes trials. In this specific space, because of the expected high incidence rate of MACE, we can make it a little bit smaller. We still had to have exposure for a certain period of time to live up to regulatory requirements. We do expect a fairly fast recruitment and a reasonably fast conduct of the trial, 18 months. Obviously, the job isn't done just by dealing with inflammation. I think it will help us, but there's still unmet medical need, in particular high cholesterol. Next slide, please. In the interest of time, I don't think we need to walk you through how PCSK9 works. You're very familiar with it. What you also know is obviously that antibodies can block the PCSK9 function, and you are, of course, aware that antisense or siRNA can actually block PCSK9. What you might have not known so far is that actually our really genius technologist chemist designed a peptide inhibitor of PCSK9. That is a rather unique molecule, and we share some of the details in a peer-reviewed publication when it's ready. Now, we obviously wanted to test would a peptide inhibitor against PCSK9, something that nobody, to our knowledge, has ever done before, actually work. We designed a small phase I trial here. The next slide, please. I can share with you that we actually got very nice data. We saw a dose escalation here between 10 mg, 50 mg, and 250 mg of this inhibitor. The very interesting thing was not only that we actually could reduce LDL-C significantly, both in a healthy cohort, but also in patients with elevated LDL levels significantly. The interesting part is that this reduction was actually very, very long-lasting. It happened at a dose that would actually make us comfortable that we could turn this peptide into an oral formulation. That we feel is the rather unique value proposition going into this market, that we're moving beyond an injectable space and actually provide an oral offering to the patients out there, with a similar, hopefully, efficacy and side effect profile as we have currently seen. We obviously are very keen to test this profile in later-stage clinical trials. Martin. Yes, indeed. Here, obviously, we are trying to be smart because obviously going directly from subcutaneous to oral could potentially have advantages in other phase I trials. We do believe, however, we understand both PK but also PD properties of our molecule very nicely. Therefore, based on modeling, we have estimated... Sorry, I had my microphone off. First of all, I'd like to say it's super nice to get the oral aspect out in the open. I've been talking about our PCSK9 offering for some time now, and some of you have asked what do we have to offer as compared to anyone else. From our perspective, we obviously believe that an oral offering will be very, very attractive in this space. Also, going back to the question I received before, we are actually trying to be a little bit smart here because it would be natural to say going from subcutaneous to oral, we would have to repeat phase I in the oral space. We do, however, believe that we have a good understanding of the PK/PD properties of our molecule, and therefore we modeled the expected therapeutic doses, and we take them directly into phase II. Sorry, a comparator trial, where the active comparator is going to be REPATHA. Based on that, we intend to be very fast into phase III. Also signifying the fact that we have very high aspirations for this compound. Maybe just to really briefly wrap up, I hope you received some interesting data to showcase and just to give you a few examples. We are venturing into the cardiovascular space. Some might argue we're already in cardiovascular because our drugs show fundamental impact on cardiovascular disease and death. We're just moving into this space in a broader way with a larger offering into our pipeline. Clearly, I think the first one out of the block with a phase III trial, but we're obviously also very curious to see how the oral PCSK9 will evolve. Many of those things we didn't talk about, Staten, the APOC3 compound, which is in pipeline, Heartseed. You will see many more of our programs actually coming through a partnership model to push into this disease area for us. Just to thank for your attention for now. Thank you, Marcus. Thank you, Martin. Clearly, we see a lot of activity not only in development but also in research and early development. It was a pleasure sharing that with the audience today. Just very briefly to summarize, we believe that we're clearly raising the innovation bar in diabetes. We've been discussing icodec, CagriSema, and the sema combination with GIP. You see our pipeline in obesity, both with semaglutide 2.4 mg as well as CagriSema. Biopharma will continue to progress, we'll cover another day. Finally, as Marcus and Martin just covered, we have a lot of activities in other serious chronic diseases. Here we covered cardiovascular disease today. Very good progress on the investment therapeutic focus against our strategic aspirations 2025. With this, we move into the final Q&A, 15 minutes, and we'll proceed with one question per person. Operator, we're ready to take the first question. Thank you. That's from the line of Mark Purcell at Morgan Stanley. Please go ahead. Your line is open. Yeah, thank you for taking my question. One for Martin. Martin, in terms of glucagon receptors, I wonder where you are now in terms of that target. It is a target you previously looked at, but turned away. It seems if you get the right ratio, like Altimmune have nailed it in a NASH trial, it appears to be a very attractive target. Just wondering where you are with that. Just a follow-up to about three questions earlier on GIP. You were doing a phase I trial with your GIP plus sema, and you are now going to phase II with ratios between 1:1 and 1: 9. Obviously, that is a pretty broad range, so I just want to understand what you learned from the phase I trials. Great. Thank you, Mark. Martin, the first one on our view on addressing glucagon receptors, and then the last one on what we learned from phase I since we're starting phase II now on GLP-1 GIP. Yeah. Thank you very much for those two. On the glucagon, obviously, as you also mentioned, we both had our own version or previous version of a co-agonist. We also looked at a tri-agonist, at one point that was in a once-daily setting, whereas the other one was in a once-weekly setting. As with everything else, this is a balance between efficacy and safety. In these sort of dual/triple agonist context, finding the right balance can be difficult. At least on our hands, we actually saw reasonably good efficacy also when combining with the glucagon. However, it did not stack up to what we saw with CagriSema. Given that, as we already discussed, we saw a very nice safety profile with CagriSema from a risk-benefit perspective, it really didn't fit our pipeline. We do believe that we can get optimized efficacy with CagriSema and at the same time, have a substantially more attractive safety profile. GLP-1 GIP phase II. Yeah. Let's just say that we saw data that would suggest that it would be reasonable from an efficacy but also from a safety perspective to go into phase II. Thank you. That was clear, Martin. Next question, please. Thank you, Mark. Thank you. That comes from the line of Peter Verdult of [Citi]. Please go ahead. Your line is open. Thank you for taking my question. Relating to your comment about increasing your patients from 40,000 to 65,000, that's a 60% increase year-over-year. Obviously, where despite targets within the strategic aspirations period, should we anticipate a significant increase in R&D costs going forward? If not, could you please explain the sort of efficacy or efficiency processes that is driving your ability to maintain cost despite such a significant increase in patients, and whether it has some look-for's to, say, on some of the new therapeutic areas that you are venturing into in terms of R&D efficiency? If time permits, if not, just an optional curiosity question of whether AlphaFold is a game changer and whether it's something that you can benefit from. Thank you. Peter, thank you for those questions. If we start out with the impact of the number of active patients on clinical trials, clearly that is driving up costs. Yes, we are going to spend significantly more on R&D in the years to come. We are in the fortunate setting that we have a top line which is showing very solid momentum these days also and these years. As a company, I think it's clearly the right thing to do to continue to invest in R&D. As I started communicating already at our latest Capital Markets Day in late 2019, you should expect our R&D ratio to be increasing gradually over time. You should not be surprised if our R&D investments are growing at a faster pace than sales. On your second part of the question on efficiencies, we're looking for efficiencies across our value chain. Of course, part of the equation of a broadly stable operating profit margin is, of course, efficiencies across the value chain. We get a very nice gearing also in R&D on efficiencies, both in research and development from, I would say, automation and digitalization being the, I would say, the most prominent enabler of continued R&D productivity. Perhaps, Martin, if you give a few words on R&D productivity. Yeah, absolutely. Obviously, Marcus should speak to research, but I think it's a fair statement that Marcus has an ambition of approximately decreasing per asset research cost by 50%. Super ambitious, and we've obviously tried to look for the same. Both in terms of the resources that we spent, but also the money that we spent, we've been looking at efficiency gains over the last three years. We continue to do so. Just to give you an example, in 2018, I had 1,200 employees to conduct trials to the tune of 12,000 or 15,000 patients, I think we were in 2018. Today, I still have the same 1,200 people conducting our clinical trials, and we are, as we just discussed, at 40,000. A substantial efficiency gain already there. To Marcus' point, it is about digitalization. It's also around thinking about which countries, how to do procurement, and so on. Some will say pedestrian, but obviously in our heads, we at this point in time could do approximately twice as much today as we did three years ago for the same amount of money. We'll continue that journey. To your other point, obviously, moving into new disease areas, we have to look at the cost. Typically, we talk about cost per patient. I can tell you already now we had a wide range. Cost per diabetes patient is substantially different than cost, for example, for a hemophilia patient. That also goes for other disease areas. For example, a cardiovascular patient is very much, so to speak, cheaper or less costly than a patient in the Alzheimer's space, which is comparable to diabetes obesity. We see NASH patients being substantially more expensive. Again, across what we do, we have to differentiate a little bit more, but we also have to accrue the efficiencies that we see. I do want to do a shout-out to our model of not using CROs because that in and of itself is cost efficient. We have our own people doing our clinical trials. That allows us to plan better, but also gives us better efficiencies, and it also gives us better quality from a regulatory perspective. We are very happy with that model. On the last question, I think I will leave that to Marcus. I think that was around AlphaFold. Basically the machine learning to predict protein structure and protein folding. Of course, we see that as a really important scientific advancement, and I think the field is very excited about this. In a way, it ties very nicely with efficiencies because obviously we're very interested in how we can use AI in drug discovery and drug design, and I think that will play a very crucial role. We see early biosignals coming up which potentially disrupt basically the field. That is something we are not only aware of, but we're actually taking a deliberate position. Thank you. Thanks, Marcus. Martin, next question, please. That's from the line of Simon Mather of BNP Paribas. Please go ahead. Your line's open. Thank you, guys. Just quickly on the oral GLP-1 agonist side using the SNAC technology, anything that you're aware of, again, with respect to taking on an anti-psychotic, just it wouldn't be the same as [audio distortion]. Just a clarification on Mark's question. Is my understanding that you're not going to go down the triple agonist therapy, including glucagon? On your point that semaglutide is super clean, just wondering why that was the case. Thank you. All right. Dosing conditions are oral PCSK9, Martin, triple agonist, and what was the last one? It was on CagriSema. Sorry, why is CagriSema clean? We do expect to see dosing conditions similar to what we've seen with semaglutide. Obviously, that is part of what we were investigating in our phase II trial. Maybe a little too premature to speculate. It is correct that we do not in our current pipeline, nor in our portfolio, have a triple agonist, and we have no plans to do so at this point. Finally, for CagriSema, semaglutide and amylin are acting on two different parts of the brain. What we have seen so far is that amylin or cagrilintide in monotherapy was associated with a very benign side effect profile. That stayed true when combining with semaglutide. We basically saw a side effect profile that was similar to that of semaglutide 2.4 mg in monotherapy. These patients had side effects, but no more than what we saw for semaglutide 2.4 mg in monotherapy. Thank you, Martin. Thank you, Simon. This will take us to our last question. Operator, please. Thank you. That last question comes from the line of Carsten Lønborg of SEB. Please go ahead. Your line is open. Thanks a lot. I just had the question on ziltivekimab because as you say it targets inflammation and you say it's a driver of increased risk of CV disease. How certain are you of this actually? Because we of course have seen a lot of indications from CANTOS, et cetera, that this is the case. Could you try to sort of describe a little bit more in detail on how certain you are that this is actually the case? Because with almost 90% reduction in inflammation in the phase II trial, it seems like a no-brainer that it should work in phase III as well, if there's a link. I just wanted to hear, Martin, when you say reasonably fast conduct of the trial, could you also try to give a little bit more color on that, knowing that, for example, CANTOS was three and a half years in progress. How fast will your trial be compared to that? Thank you. Great. Thank you, Carsten. I like the notion of no-brainers in R&D. I'll remember that for another session. Marcus, I think it goes to you. Now Martin is going to spend significant resources with more than 16,000 patients in phase III. What makes us confident that the CRP reduction will translate into a MACE benefit? What's given to you? I think I'll only start, Martin can chip in. You highlight it rightly, Carsten. I think for us, it is a fundamental source of information. If you look into the categorization of the hsCRP population there, they had a significant benefit on endpoint. Ultimately, I think that is the fundamental data position number one. The other one is, I think we have increasing evidence through Mendelian randomizations that puts IL-6 at the potential center of some of those effects. Right? I would argue it's circumstantial evidence, because the point you're trying to test here is how does reduction of hsCRP ultimately reduce cardiovascular risk? Ultimately, that is the hypothesis we are now testing. Maybe the second part of the hypothesis is, well, if we're blocking IL-6, can that be delivered in a safe way? As you know, obviously, IL-6 and through the IL-6 receptor also plays a role in the immune response, we're really trying to find the sweet spot. We do firmly believe that ziltivekimab is actually the best drug to test this hypothesis, where we see very clear evidence for a reduction in hs-CRP, at least in the phase II trial that we have seen a very benign side effect profile. When you put this together, I think we have a good drug modality now to take it into a larger outcome trial. CANTOS was a rather heterogeneous outcome population. We're now zooming into a much more defined patient population. By the way, I think that is fundamentally probably the way to think about some of those trials in the future, that we're moving from all comers to more specified or more stratified patient populations, just as a general theme. Martin, anything from you? I very much agree. I think we have in a phase II setting everything that we can have. We had to rely on biomarkers. This is a new setting. I sometimes use the analogy of originally when we started to talk about LDL-C lowering, someone had to do the outcomes trials to actually show that this was associated with improved outcomes. This is specifically the situation we have. To Marcus's point, very strong phase II data, both from an efficacy but also a very benign safety profile in the space and given the mode of action. This obviously does call for some risk on our part. It's not the lowest risk phase III trial that we've conducted so far, but we do believe that we have de-risked it to the extent that we can, given, again, the very good safety profile, the right patient population, and a benign, or sorry, a good efficacy profile. From a trial conduct perspective, obviously, in these outcomes-driven trial, it very much depends on the expected event rate. I know Carsten would love me to speculate and give you a very hard date. Obviously, I can't do that because this is also a new population for us. We made some assumptions, and I'll be happy to discuss in a couple of years if we made the right assumptions or not. That being said, even if we see a very high event rate, higher than we expect, we will still be required to expose patients for a certain number of years, probably at least two years for a proper safety assessment on behalf of the regulators. Again, balancing the event rate with a minimum requirement of exposure. Excellent. Thank you, Martin. Thank you, Carsten. Thank you, Marcus. This concludes today's Novo Nordisk R&D Investor event in connection with the ADA. We thank you for listening in and asking a lot of really good and relevant questions. We will be back with our Q2 results release in August 5th. Looking forward to connect at that point. In the interim, I wish you all a beautiful summer until then. Thank you.