Hello, and welcome to the Novo Nordisk AS R and D Investor Call. Throughout the call, all participants will be in listen only mode,
Thank you. Welcome to the Novo Nordisk Investor Call in connection with ADA. My name is Kasper Lund Knudsen, CFO of Novo Nordisk. And with me Today, I have Markus 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 clearly We are uncertain and where 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 Today, given we do this in conjunction with the ADA, we will not be providing specific updates on our biopharm pipeline. We'll do that at other opportunities The agenda for today starts out with Diabetes From that, we move into research and neurodevelopment with a special focus on cardiovascular disease led by Markus Schindler and Also with the presentation by Martin Lange. And also there, we'll be doing a Q and A session following that. So without further ado, I'll be handing the presentation over to Martin Lang.
Thank you very much, Carsten. So first of all, just to start off, 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 We see progress of our clinical pipeline. Specifically, we are going to start a FISH 3 program across all therapy including in NASH in CBD and in Alzheimer's disease. These activities have not been impaired and we We do not expect them to be impaired by COVID-nineteen. And therefore, we are progressing our pipeline plans.
This basically means that we expect to have active patients in our clinical development program by the end of 2021 moving towards actually 65,000 patients in just 2 years' time. Next slide, So I'm going to take you for the bit of a 24th together with Markus starting up with what we have on display at the ADA. As you probably noted, we have quite a number of presentations at the ADA. I think it's Around 37. And we'll try to give you some of the highlights during the call today.
Next slide please. Starting in the diabetes space, obviously, you've Seeing our SUSTAIN FORWARD trial, it's 2.0 milligram of semaglutide versus 1.0 milligram of semaglutide in approximately 1,000 patients With very high AOT levels between 810 baseline being and patients being randomized to either 1.0 or 2.0 milligram of semaglutide for a Treatment duration of 4 weeks. Primary endpoint, I was about to say as usual Hemoglobin A1c, which was our key focus of the trial. Next slide please. Obviously gratifying, far to say, a statistically Significant and a clinically relevant difference between the doses of somatostine.
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, 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. So as shown on the lower right hand side of the slide, Situations due to AEs overall AEs of nausea, diarrhea and vomiting was approximately equal in the 2 doses despite the improved Obviously, we take a lot of comfort in that. And as we've also shown at ADA doing sub analysis, Dividing patients into subgroups of baseline A1C or baseline B1C, we've seen the difference between the two treatment arms Throughout. Next slide please. Staying in the diabetes space, looking at the PIONEER trial, we We've been looking into 1st PIONEER 1, looking at baseline diabetes duration.
So patients having less than 1 year of diabetes In terms of diagnosis versus patients having more than 1 year of diabetes in the diagnosis. We clearly saw that The proportion of patients achieving hemoglobin A1c below 6 was and this Maybe not so surprising, better achieved if intervention started earlier, namely patients with very early diabetes. And similarly, in PIONEER 2 comparing glycemic control between oral semaglutide We saw that a larger proportion of subjects maintain good glycemic control with the mantle time as compared to Obviously, very nice data and very nice results for the Rebelsus brand And coming out from both the PIONEER 1 and PIONEER 2 trials. Next slide please. Obviously, with the very, very strong label that we We have with Rybelsus both the 7 and the 14 milligram showing a superior and statistically significant reduction in A1c and a good As compared to both placebo zetagliptin and SGLT2 inhibitor and 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 Megalotide in the hands of Sustain 40. We want to do something similar now in the oral space For Robeilsis. So we are currently in Phase III testing higher doses of semaglutide in an oral formulation, namely 25 milligrams and 50 milligrams. The intention being that the 50 milligram will correspond to approximately 2 to 2 Formally granted of semaglutide in terms of both efficacy and safety.
So a very nice efficacy and safety profile Already seen from Stifel with a very attractive safety profile to accompany that. Next slide please. Staying within the diabetes 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 I have most players in this space that Monotherapy luckily have been act 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 2 Phase 2 trials in the diabetes space to that end. First thing with the combination of an amylin analogagwinantide in combination with semariclutide where we look at the combination versus The monotherapy is 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 OVIS digital trials for the cakruzema bond Q. In the combination space, we also have a Combination with our DIP offering against a once weekly molecule looking at the combination of semaglutide and In this space, we are still looking towards doses and ratio optimization.
And we will in To investigate a number of different ratios up against the mono components. This is a slightly longer Trial than the Cagruzema trial. But 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 Crecema data in non diabetes subjects where you've seen weight loss to the tune of 17 Send over a 20 week treatment period. Next slide please.
Now switching gears a little bit. You probably At this, ADA seen a lot of presentations and posters around timing range. This is a reasonably new concept acknowledging that just looking at hemoglobin A1c, just looking at Spot blood glucose 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 illustrative slides looking at 3 thought of patients all with the same level of Glycemic control of approximately 8.6 in fasting plasma glucose Or 154 milligram per deciliter and 7 milligram in A1C. Now underlying this, If we did continue glucose monitoring for these patients, we now know that some patients even with the same A1C Even with the same type of plasma glucose have very different time range performance.
Time range basically depicting how much time does the patient in what we would call the plasma control. I recently heard an indicator saying it's sort of like a dispute. If you are to stay within, let's say, 50 100 miles per hour, that wouldn't do in But it works for incumbents' power. 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 Spending way too much time in high glucose levels leading to increased risk of late stage complications, but also way Too much time in low blood glucose levels leading to risk of hypoglycemia basically. We have an example that's sort of in between and We have one patient being in exactly the range where we want the patient to be. But 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.
And therefore, we 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 second plus for glucose, but also specifically a time in range because this is where we know that we can also start predicting So as you know, we've conducted Phase 2 for insulin hypertek looking at different Taturation algorithms and comparing to insulin glargine in a 1:one:one randomization in Phase 2 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. And 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 Separations on behalf of the IPBEG molecule. Next slide. And obviously, we intend to We'll investigate that in Phase 3 and I'm going to show that in just a minute. Specifically also for Phase 888, 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 active molecules for example Tresiba. There were questions If these 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. But based on what we've Also for Icodec, which is now going from once daily to once weekly, we are super, super happy to see that the risk of having prolonged Hypoglycemia is not there.
So basically, the timing of hypoglycemia glint is the same, Both obviously in the different Icodec fluctuation arms, but more importantly comparable to that of insulin enlargement. And that goes for both overall, but also Very, 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 milligrams per deciliter, which is in fact downright Hypoglycemia. And again, here we see no difference between icotec and Glargine suggesting that even in these locations where we do Hypoglycemia, the risk of staying too long in that hypoglycemia is not there. Again, very, very good data for insulin In Icodec and obviously adding to our aspirations for that molecule.
Next slide please. To me very, very exciting. We are in the progress. We've actually finalized Besides the recruitment for ONWARDS 1, which is our pivotal and obviously also longest trial, we are well on Back for onwards 2 to 6 and actually none of them being behind actually all on And report on these trials in a timely fashion. So we would 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 ALMOST 5, which is a real world evidence Well, we're basically using digital tools, allow the patients to control their own treatment together with digital Support basically a connected device, a CG or a connected BGM and then obviously an app to guide The patients. We have employed CGM in almost 1, 2, 4 and 6 to support our assessment of auto time and range. Obviously, we are very, very excited about insulin I would say, and we'll be clearly excited when these data start to read out in 2022. Next slide please. Now 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 zemaglutide 2.4 milligram of 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 As you know with current treatments, we do tend to see over time after approximately 1 year a waning off of the weight lowering effects of the treatment. And we set out to investigate if that would also hold true for smelting line. Very Something for us almost boring for us to see that even after 2 years of treatment with cementite, we still see the same 17% weight loss that we have reported for 68 weeks of treatment.
Very, very consistent across all the studies that we reported on semaglutide 2.4 So far. Obviously, compared to placebo, this is not only clinically relevant, but also highly statistically significant. As almost Pedestrian or boring, the same 40% of patients achieved at least 20% weight loss even 2 years of treatment. And obviously, we are very, very happy and this is also becoming a feature of semaglutide an And attractive safety and tolerability profile. Exciting for obviously, Markus Myself to see is obviously that we see improvements in lipid profile, but also importantly of C reactive protein as a marker of anti Information effects of somaglutide, we believe this to be important for somaglutide in the NASH space, in the cardiovascular space, but also in the Alzheimer's space as part of action for semaglutide in these spaces.
And also these findings have been consistent across all the step Next slide please. In step 8, which is a trial that has not yet been reported, so this is basically the We set out to compare liraglutide to semaglutide 2.4 milligram in a placebo controlled settings, so both treatment arms were placebo controlled. For the sake of simplicity, we'll do placebo in this slide, but both In this space, again, we see a 17% weight loss with semaglutide and the expected Approximately 7% weight loss with liraglutide 3 point 0 milligram, basically talking to the expected effects of the tumor. What What is really, 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.
And we also
see the impact on lipid profiles and inflammatory And we also see the impact on lipid profile and the inflammatory markers as we just discussed for step 5. So a very attractive trial, also Also considering that the semaglutide comes out with this very attractive offering including a benign safety profile And given that somaglutide will be priced to the level of liraglutide then with a more Next slide please. Now in step 1 and this is obviously a study that has already been reported. We've done some analysis showing the impact of glycemic control in As you see in the right hand side of step 1 and you probably remember step 1 was our pivotal obesity trial approximately two Patients being randomized twice the placebo or semagnetized. And in this space, we see that pretreatment approximately 45% of patients in the semagnet arm and 40% in the placebo arm had 3 diabetes.
After 68 weeks of treatment only around 9% of patients in the semaglutide arm still have prediabetes And that is to be compared with 26% having pre diabetes and 1.6% having overt Type 2 diabetes. Obviously, very, 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 of treatment for another year, so It's expected to weeks up until 120 weeks. And in this space, we actually see that the legacy effect of having been on semaglutide is So more patients stay in the prediabetes sorry in the non diabetes states with semaglutide Then what we see for placebo, so not reverting to sort of a diabetes risk baseline despite the fact They actually start to regain weight. So very, very interactive and a good outlook also for semaglutide in particular when we see We start to see similar data coming out of this electron.
Next slide please. In step 2, we looked at In the improved glycemic control and other markers in a post hoc analysis, For STAT 2, you know STAT 2 was our weight loss trial in diabetes. What we saw was a In the conference, we saw improvement in lipid profiles. We saw again improvement in inflammation. And importantly, we also saw improvement in health related quality of 5 questionnaires as measured by both SF-thirty six and the I wq well.
Next slide please. Overall, we were very, very happy with the efficacy profiles that we've Sheen coming out of step 1 through 5 and step 8. We have seen a very, very Robust, but also consistent weight loss. We have seen robust and consistent improvements on cardiovascular biomarkers including inflammation biomarkers. And we've seen this with a very attractive safety profile that we believe is It's starting to become a hallmark for some actual time.
Just very briefly here. I hope this is not my timer. We're just showing here the discontinuation rates for semaglutide in step 12 As well as for placebo. And 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 close to the discontinuations rates observed for This discontinuation of treatment has not led to very high withdrawal rates. Generally, we see withdrawal rate from our trials in the of less than around 5%, which is in an obesity setting a testament also to the acceptance of the drug.
So overall, we believe that we have had an interesting presence at the ADA with a Different abstracts and presentations. We continue to raise the bar in the diabetes space with more benefit also as specifically demonstrated by Sustainforder. We continue our insulin innovation and we are very, very Both with the current data from Phase 2, but also with the outlook for ICOTEC in Phase 3. We're going to initiate 2 Phase 2 trials Further raised innovation bar in the diabetes space, one with the combination of cabrylantide and semaglutide and the other of semaglutide in combination with And finally, we show in the obesity space a profound weight loss and with the magnitude and That will obviously be explored further also the impact of which In the outgoing additional step to us, but also in the Select one.
Thank you, Martin. That takes us So our first round of Q and A operator and I would like to ask the audience to restrain yourself to only one question. We have a lot on the line So everybody can get their question in. So let's try and go with the one question each. So operator, please move to Q and A.
Thank you. Our first question in the queue comes from the line of Wimal Kapadia of Bernstein. Please go ahead. Your line is open. Great.
Thank you very much for taking my question.
From Bernstein.
To be only I have one only. Can I just ask about how you think about the fixed Combination approach for GLP-one and GIP that you're developing versus the dual agonist approach? You mentioned the balance, but does Zixos So it drives better safety outcomes or is there potential for superior efficacy if you get the ratios finally balanced? Just curious what you see as Differentiated given you're several years behind your main competitor. Thank you.
Thanks, Umerald for that question. And This goes through, Martin. So fixed dose versus dual agonist there or to our consideration there?
So it's a super good question. And obviously also an approach that 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. And clearly, we believe that specifically for the combination of calcminatide and cementlutide, but also soon for the cementlutide See that we've sort of hit a sweet spot where we've optimized efficacy, but we've also managed to do There without compromising on 15. So specifically on the Calcimab combination, you saw this rather dramatic increase in efficacy, percent weight loss in 20 week, which is to be compared with the 17% weight loss received with semaglutide in monotherapy in 68 weeks. But this comes With no increase in tolerability and no increase in adverse events.
So we basically get the improved efficacy Without compromising at all on safety, obviously, we had to prove this in Phase III as well. But we do believe that with our approach, we've managed to find a ratio That optimizes the better 2 worlds.
Great. Thank you very much.
Thank you, Wimal. Thank you, Martin. Next
And 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 I've heard it so early, 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 it's sepsite on our combination?
So in the clinical space and I believe in the Clinical space and I believe in the preclinical space, we don't have head to head evaluations neither we nor Lilly has that at this point in time. So at this point, we have to rely on modeling. And I mean, We have decided not to fully share our modeling of specifically the Cancrozema combination. However, we do believe even With our most conservative modeling that we will at the very least be able to score if not be superior to what is currently out
Thank you.
That's from the line of Michael Leuchten of UBS. Please go ahead. Thanks so much. I was just wondering on timing on your caglutide Phase 2. Would there have been a possibility to make this straight into Phase 3?
And the reason why I'm asking is Lillie seems to be talking about moving a triple agonist If they do this year, which then, if successful, they give, may then mean they're not that far behind your combination. So this Why not be more requested for the timing, I guess, is my question. Thank you.
Thank you, Michael. That's a very good question. And the CFO, thanks so much. And can we move faster than what we've seen here?
It's a super good question. And obviously, we're taking a lot of comfort in that we've spent the last couple We are not only in decreasing our white space substantially, but also taking some data 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 On our speakers before we go into Phase 3, we have good examples, soltify Bm1, icosimba being another where we go directly into Phase Free from Phase 1. However, with the kagresema, we have assessed that we need a little more data to We'll be able to design Phase 3. That is not going to impair our timelines substantially because we have Sure.
That we can both recruit and also conduct our plans very, very fast.
Thank you, Martin. Thank you, Michael. Next question, please.
And that's from the line of Michael Novod at Nordea. Please go ahead.
Yes. Thanks a lot.
Just a question to step 2. And also you have Symposium or the step Symposium was the other day at ADA where there was a discussion between the panelists around use of higher dose much faster. So how do you see the use of CEMET 2.4 potentially also in Because it was clear that RosaStar released, it 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. So how do you see that offer interact with Govee in obesity versus use of this high dose in diabetes? Of course, also bear in mind you have 2.0 going to the
Thank you, Michael. So Martin, this is something we debated when we started the trial. So 2.4 obesity Dose versus 2 dose in diabetes for semaglutide? Yes. So first
of all, I mean, as with everything else, this has been on an assessment of the individual patient. If the If the key focus is weight loss, I would go with Wegovy 2.4 milligram. If the key focus is diabetes I would go with Lucetic, the 1 or 2 milligram. And again, I think generally speaking, I don't want to contradict Julio Rosenstahl. Obviously, it has to be based on the data assessment.
There will be patients who are on optimized glycemic control at 1 milligram And with a very attractive weight loss, but 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 also the 2 milligram of OTECI beta. 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 milligram does also provide a very nice loss. But if the key focus is glycemic SimaControl 2.7 milligram is the way to go.
Okay. Thanks a lot. Thank you, Michael. Thank you, Martin. And as you know, then we're also Shunhain, hi, do you want to say all type of side are offering as well with the 25 50 milligrams.
So we are clearly looking in that direction.
So first answer is yes. And second answer is these studies are currently ongoing. And When we've seen the readout and test them, you'll be almost the first to know.
Thank you. Thanks, Pete. Very clear and short answers from Maarten and those questions. So thank you for that, Pete. Next question, please.
That's from the line of Emmanuel Papadakis of Deutsche Bank. Please go ahead. Thanks for taking the question. Maybe, Monty, actually, Carson, you could just give us a quick update on The latest in terms of COGS, at least on a relative basis, 50 microbials. So where do you think the gross margin of that is I mean, to come in relative
to the rest
of the franchise given some presumably process improvements. And then just a quick clarification, if I heard earlier, I think you said you thought It will be clinically equivalent to the 2 to 2.4 milligram dose of subcutaneous somagatolone, if I heard that correctly. Thank you.
Yes. Emmanuel, thanks for that question. And that's clearly something that we, of course, evaluated We did evaluate before we initiated a high dose oral semaglutide trial. And what we've been saying previously has been that we expect For Rybalsis, that would get to group average margin by our strategic aspirations period for in terms of gross margin for So and what we're doing at the same time is, as we've been talking to before, we continue to invest in our oil platform in terms So for all from Leighton and our snack platform. So that is a Novo classic that as you've seen with our insulin syndicates once for many years, we do that with our oral platform also.
So clearly, without guiding specifically on the gross margin for the 25 mg and 50 mg, then we'd not have indicated high dose To trial either in diabetes or the obesity oral trial without being able to get to a place with an attractive gross margin for those And Martin, I'll then ask the second question for you.
Yes. I think you're exactly right. So in the diabetes space, we expect the 50 milligrams to correspond To the 2 milligram substantially. And in the obesity space and again, we see there is 2 different disease entities. We expect to see the 50 milligram corresponded approximately corresponds to the 2.4 milligram in terms of weight loss.
So in that space, Acknowledging that the oral formulation has a slightly higher variability, our model suggests that 50 milligram in diabetes will Correspond to 2 milligram and 50 milligram in obesity mode correspond to 2.4 milligram.
Thank you, Martin. Thank you, Emmanuel. And then it's time for the last question before we move on to Markus and Resource and Early Development. So last question,
And that's from the line of Richard Vassar at JPMorgan. Please go ahead.
Hi. Thanks for taking my questions.
Just on the Iprospect It looks as though you titrated slightly more aggressively than the Lilly weekly insulin BIF in their Phase trials and potentially got a few more patients spending or more time with patients in range. So could you maybe contrast the benefits? Is that right? And is the benefits of the product, the Vicodex versus Bich as you see it at this point? Thanks very much.
So 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. So both in terms of time and range, but also in the maintenance We actually saw a lower risk of hypoglycemia with Ipatent that what we saw when compared to once beta drugs specifically That being said, obviously with the titration we had, we saw in the titration period that we needed to do And we basically spent the combination of our Phase 2 data. As you also saw, we had one failure with a loading dose when Switching from another insulin and so on. And the combination of all the data that we had allowed us to do what we think is It's going to be 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 and A session and takes To the session on Research and Development. So over to you, Markus.
Thanks very much, Carsten. Can you have Next slide, please. My name is Markus Schindler. Obviously, as we haven't met neither in person nor probably at any time in my new role over the last couple of months, I just wanted to allow myself a 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. And I think there's a lot of exciting to see I actually want to share with you rather than spending too much time on individual assets, but we will be talking about some exciting It was on our cardiovascular asset because that is sort of the next frontier obviously that we're tackling.
First of all, maybe to the left on your slides, 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. So with the power of computing today, human genetics really I think It's moving into the centerpiece and the initial disappointments on some of the GWAS data actually are getting resolved with a granularity. We can interrogate some of those data. So that's point number 1. 2nd 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.
And last one of you is to use 1 buzz with obviously big data interrogating real world evidence data will also actually help us to come up with novel ideas. And all of this, if you then lump it together with human centric model systems where we're using organoid systems, for example, 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. And I hope you agree that's actually quite Staying 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 observations later on into clinical development to then deal with the outcomes. With several 1,000 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. And I've worked in a number of Pharmaco companies, clearly in Novo Nordisk, we are dedicated to the disease areas and it's a smaller number than some of our competitors.
And I think that also gives us a very deep insight into the science and a long term outlook into the biologies we're working with. We're moving from an organization that has In largely centered around Denmark and being located into Denmark across the globe. And 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. So I think that gives us really fundamentally Good base of cutting edge scientists and people working on various technologies to do the work that we need to do. We're also moving beyond, I would say, maybe functional research unit, you probably have heard about our stem cell unit with a Formational research unit, you probably have heard about our stem cell unit with a ring fenced budget and a level of autonomy within our framework that actually allows to move incredibly fast test hypotheses early on, but at the same time also take accountability and be sort of mini CEOs within our 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 Sergio, we are and are the product of in house innovation, but 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. And we believe that is one way and Maybe the best way to tackle in particular number of unknowns that we're dealing with.
Now we have a large number Of project in the pipeline now 90 plus doesn't actually tell you a lot. And I have to say what actually energizes Simo is that a significant portion of those projects deal with 1st in class novel mode of And I think that really puts us in a position that we have a significant number of proprietary drug targets where we We feel we can be in the 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 Leading in the biologics space focused on peptides and proteins, but we're going way beyond this. We've touched From the oral biologics leadership and that is continuing, I can assure you that, puts steam ahead, but 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 course. So there are also Currently, modalities that we're not working on. And all of this obviously comes together that we're not only staying and continuing to Innovate in diabetes and obesity, but be moving beyond. 2 thirds or more of people living with diabetes suffer from cardiovascular disease.
Significant portion of them will see cardiorenal disease. So branching out into cardiovascular specific and For chronic kidney disease, I think it's actually a very natural journey. So early work Also in the stem cell unit, we're moving towards sort of the 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 a semaglutide now in Alzheimer disease, which I think is a tremendous And then we're not speaking today because this is the ADA call about the exciting feedback obviously in the rare blood and rare endocrine disorders, which I think gives us actually a very, very nice angle to start experimenting with and engaging in gene therapy and gene editing. Next slide please.
So many of the things actually I talked about have started I think with GLP-one semaglutide in particular, which has really paved Away with seemingly a plethora of biological pathways that we're addressing. And for those of you who are old enough to witness When these molecules were started and I saw today obviously Jens will host according to the Banten Award for in protein biology. I did started decades ago, but you imagine today what we know about GLP-1 and what we see is 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 ASU partnership and we're using specific platform collaborations to actually broaden our ability then to address the targets that we want to pursue.
So we think the pack maybe here the Dicerna collaboration, which we signed a strategic cooperation with Dicerna on siRNA Technologies progressing very, very well, very productive collaboration. We're taking first steps in gene editing with colleagues at Bluebird Bio In the hemophilia space, most recently and I'll come to that in a minute, we signed a deal with the Japanese biotech company, Heartseeds. And Maybe the most prominent some 3 years ago around this time was our acquisition of Zylo, the legacy company Cabometrix, which gives us access to the glucose sensor part of One of our tracks on glucose is of insulin. And of course, you're all aware of the acquisition of Hemisphere, which really paves A way now to blast sort of oral biologics and generate better and better technologies here. We'll talk a little bit about cardiovascular today, So on bilgerechna coming from the company in Korea.
But then as one fantastic example, I think of a peer pharma to pharma collaboration, I just wanted to highlight the Gilead collaboration Even more prominent to collaborate on stem cell based therapies. So HeartSeed over probably 2 decades of Nopalanxenda's Hard work has actually come up with a rather unique iPSC preparation for cardiomyocytes and they've really optimized the protocol to come up with cardiomyocytes, which all we have seen look very benign. They show no Myocytes, which all we have seen look very benign. They show no abnormalities in once they are implanted into the heart. And 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 We have a chance to survive in the heart and stay there for a long time than we have seen with previous versions of stem cells.
And we're actually very Guided 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 Next slide, please. So 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. And maybe it sits in line here with the triglycerides in the cholesterol. Maybe we should have actually a bar that cuts across because we do believe it is a fundamental principle that is I'll be going to zoom in on a very particular patient population, next slide please, which will be addressed by an IL-six Okay. And this is you remember I spoke briefly about this last year at our call and we just acquired Covidya.
It's floccyll6, the ligand, Not the receptor we believe that actually gives us a better profile, a better therapeutic window and not to be concerned so much And the news you have seen probably at ACC is that siltyvacumab does exactly what we were hoping for with very high By potency, it basically blocks the HSIS CRP to a large degree. And maybe as a fun fact thrown in, All three doses actually delivered significant reduction. And what we're not showing here, but you've probably seen it in the publication, the reduction is sustained and that of course It's very, very important. We've also seen a very benign side effect profile. Now these are small relatively small patient It's a Phase II trial, but it basically ticked all the boxes we could expect to see from a Phase II trial.
Next slide please. And that She gives us confidence to move forward with this drug and I'll let Martin speak to the ZEUS trial.
Yes, very briefly. So as Markus rightly said, we've seen some Super exciting and interesting Phase 2 data both from an efficacy, but also from a safety perspective. It is allowed us to identify what we believe And we will actually progress that directly to a cardiovascular outcomes trial. So the SUS trial is going to start recruitment in Q2 Here, it's going to be 6,200 patients being randomized to either ceilvekumab 15 milligram on top of standard of care versus This is a fairly advanced cardiovascular population as compared to what we have seen previously in our trials. So all of these patients will I was about to say as usual have established cardiovascular disease.
But on top of that, they will have chronic kidney 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 ADCOM 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 labor to Regulatory requirements, but we do expect a fairly fast recruitment and a reasonably fast conduct of the file.
Back to
And 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 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 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, and that is a rather unique molecule, and we share some of the details in 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. And we designed a small Phase I trial here. And on the next slide please. I can share with you that We actually got very nice data.
We saw a dose escalation here between 10.50 and 2.50 milligrams of this inhibitor. And 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, but the interesting part is that this Reduction was actually very, very long lasting. And it happened at a dose that would actually make us comfortable That we could turn this peptide into an oral formulation and 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 With a similar hopefully efficacy and side effect profile as we have currently And we obviously are very keen to test this profile in later stage clinical trial. Martin?
Yes indeed. And here, obviously, we are trying to demand because obviously going directly from some changes to 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 We believe that an oral offering will be very, very attractive in this space. Also going back to the question I received before, we Yes. I'm trying to be a little bit smart here because it would be natural to say going from terpinistol, we would have to repeat Phase 1 in the oral space. We, however, believe that we have a good understanding of the PKPD properties of our module. And therefore, we modeled the expected therapeutic doses and We take them directly into Phase 2 in a combination sorry, a comparator trial where the Comparator is going to be repair.
Based on that, we intend to be very fast Into Phase III, also significant the fact that we have very high aspirations for this compound.
And maybe just to really briefly wrap up, I hope you received some interesting data Sing data that 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 Our drug show fundamental impact on cardiovascular disease and death. So we're just moving into this space in a broader way with a larger offering Into our pipeline. Silky, I think the first one out of the block in with a Phase III trial, but we're obviously also very curious to see How the oral PCSK9 will evolve. And many of those things, we didn't talk about statin, the APOCC compound, which is in Pipeline, hard seat.
So you will see many more of our programs actually coming through a partnership model to push into this disease area for us. And just to thanks for your attention for now.
Thank you, Markus. Thank you, Martin. Clearly, we see a lot of activity not only in development, but also in research and early development. So it was a pleasure Just sharing that with the audience today. So just very briefly to summarize, We believe that we're clearly raising the innovation behind in diabetes.
We've been discussing icodate, kakrosyma and the With the GIP, you see our pipeline innovative both with the semaglutide 2.4 as well as cakri sema. Biopharm We'll continue to progress and we'll cover another day. And then finally, as Markus and Martin just covered, we have a lot of activities in other serious chronic Here we covered cardiovascular disease today. So very good progress on the innovation and therapeutic focus Against our strategic aspirations 2025. So with this, we move into the final Q and A in 15 minutes and we'll proceed with one question per person.
So operator, we're ready to take the first question.
Thank you. And that's from the line of Mark Purcell at Morgan Stanley. Please go ahead. Your line is open.
Yes. Thank you for taking my question. One for Martin. Martin, in terms of glycerin receptors, I wonder where you are now in terms of that target. It's a target you previously looked at, but Turned away.
It seems if you get the right ratio, like Altimmune have nailed it in the NASH trial, it appears to be a very attractive target. So just wondering where you are with that. And it's just a follow-up to about 3 questions earlier on GIP. You were doing a Phase I trial with your GIP plus sema And you're now going to Phase 2 with the ratios of between 1:1 and 1:9. Also, that's a pretty broad range.
So just trying to understand what you learned from the Phase 1 trials.
Thank you, Marc. So Martin, first one on our view on addressing glucagon And then the last one on what we learned from Phase 1 since we're starting Phase 2 now on GLP-1, GIP?
Yes. So thank you very much for those 2. On the glucagon, obviously, as you also mentioned, we both had our own In our previous version of a co agonist, we also looked at a trial agonist. At one point that was in Once daily setting, whereas the other one was in a once weekly setting. As with everything else, this is a balance between efficacy And in these sort of dual triple agonist context, finding the right balance It can be difficult.
And at least in 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 cabozema. And given that as we already discussed, we saw a very nice safety profile with Tagrissema from a risk benefit perspective, it really didn't fit our pipeline. We do believe that we can get optimize The efficacy will take care of SYMPA and at the same time have a substantially more attractive safety profile.
And then Tif one, give
Yes. 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 2.
Thank you. That was clear, Martin. Next Thank you, Mark.
Thank you. That comes from the line of Joseph Fessert of Neilsbanken. Please go ahead. Your line is open.
Thank you for taking my question. Relating to your comment about increasing number of patients from 40,000 to 65,000, that's a Percent increase of course, get the obvious question despite factors within the SG and A period. Should we anticipate
a significant increase in R and
D costs going forward? If not, Could you please explain the sort of efficacy or efficiency processes that is driving your ability to maintain the cost despite significantly increasing patients and whether it has some look process to say some of the new therapeutic areas that we're entering into in terms of And if time permits, it's not just an optional curiosity question on whether AlphaFold is a game changer and whether it's something that you can benefit from? Thank you.
So Peter, thank you for those questions. So If we start out with the impact of the number of active patients on clinical trials, then clearly that It's driving up costs. So yes, we are going to spend significantly more on R and D in the years to come. We are in the fortunate Setting that we have a top line, which is showing very, very solid momentum these days also in these years. So as a company, I think it's clearly the right thing to do to continue to invest in R and D.
And as I Without communicating already at our latest Capital Markets Day in late 2019, You should expect our R and D ratio to be increasing gradually over time. So you should not be surprised if our R and D investments Are growing at a faster pace than our than sales. Of course, we're looking for and on your 2nd part of the question on efficiencies. We're looking for efficiencies across our value chain. So, of course, follow-up the equation of a broadly stable operating Margin is, of course, efficiencies across the value chain, and we get a very nice gearing also in R and Since it's both in research and development from, I'd say, automation and digitalization being, I'd say, the most prominent of continued R and D productivity.
Perhaps Maarten, if you give a few words on R and D productivity?
Absolutely. Obviously, Markus will speak to research, but I think it's a fair statement that Markus has an ambition of approximately decreasing Per asset research cost by 50%. So super As ambitious and we've obviously tried to look for the same. So both in terms of the That we spent, but also the money that we spent. We have been looking at efficiency gains over the last 3 years.
We continue to do so. Just to give you an example, in In 2018, I had 1200 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 1200 people conducting our clinical trials. And we are, as We just discussed at 40,000. So a substantial efficiency gain already there.
2000 point is about Digitalization. But it's also around thinking about which countries how to do procurement And so on. So some will say pedestrian, but obviously in our heads we at this point in time do approximately Twice as much today as we did 3 years ago for the same amount of money. We'll continue that journey. To your other point, Obviously, moving into new disease areas, we had to look at the cost.
And typically, we talk about cost per I cannot tell you already now, we had a wide range. Cost per diabetes patient is substantially Different than cost for example for hemophilia patient and that also goes for our new disease area. So for example, a cardiovascular It's very much, so to speak, cheaper or less costly than a patient in the Alzheimer's space, Which is comparable to diabetes obesity, but then we see NASH patients being substantially more expensive. So 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 Start up 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, so we are very, very happy with that model. On the last question, I think I will leave that to Markus.
And I think that was around AlphaFold. So basically the machine In learning to predict protein structure and protein folding. And of course, we see that as a really important scientific advancement and I think it's the field is very excited about this. And in a way, it ties very nicely in with efficiencies because obviously we're very interested in how we can use AI in drug discovery in drug Discovery in drug line and I think that will be a very crucial role. We see early biotechs coming up, which potentially disrupts basically That is something we are not only aware of, but where we're actually active today, we're making our position.
Thank you, Peter. Thank you, Markus Martin. Next question,
And that's from the line of Simon Mather of BNP Paribas. Please go ahead. Your line is open. Thank you, guys. And just quickly on the oral And I can't say using the Slack technology.
I think we can get a letter again with respect to taking on an empty stack, just it wouldn't be the same as And just a clarification on Mark's question. Is my right to think that you're not going to go down the triple combination therapy including glucagon? And on your comment The summary is super clean. Just wondering why that works.
All right. So, adoption conditions are oral PCSK9 Maxime triple agonist and what was the last one? It was on CapriSema. I'm sorry, why is
So we expect to see dosing conditions similar to what we've With semaglutide, obviously, that is part of what we will investigate in our Phase 2 trial. So maybe a little too premature to 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. And finally for cagrozema, semaglutide and Amylin are acting on 2 Parts of the brain. And what we have seen so far is that amylin or cadrelinide in monotherapy was Associated with a very benign side effect profile and that stayed true when combining with somaglutide. So we basically Saw a side effect profile that was similar to that of semaglutide 2.4 in monotherapy.
So these patients Had side effects, but no more than what we saw for semaglutide 2.4 into monotherapy.
Thank you, Martin. Thank you, Simon. So this will take us to our last question, operator, please.
Thank you. And that last question comes from the line of Carsten Lombard of SCB, please go ahead. Your line is open.
Thanks a lot. I just had a question on Cintiqve came up because As you say, target inflammation and you say it's a driver of increased risk of CV disease, but how certain are you of this actually? Because we, of course, have seen A lot of indications from cancers, etcetera, that this is the case. But could you try to sort of describe a little bit more in detail on how certain you are that this is actually Because with almost 90% reduction in inflammation in the Phase 2 trial, it seems like a no brainer that it should work in Phase 3 as well, if there's a link. And then also I just wanted to hear, Martin, when you say reasonably fast conduct of trial.
Could you also try to give a little bit more color on that knowing that, for example, cancer was 3.5 years in progress of what how fast will your trial be compared to that? Thank you. Great. Thank you, Carsten. I like the notion of no brainers in R and D.
I'll remember that for another So, Markus, I think it goes to you. So now Martin is going to spend significant resources with more than 6,000 patients in Phase 3. So what makes us confident that the CRP reduction will translate into a MACE benefit? What's the difference you have?
I think I'll make it to Martin can chip in. But you highlighted rightly That's right. And I think for us, it is a fundamental source of information. And if you look into the categorization Of the high acid CRP population there, I mean they had a significant benefit on endpoints. And ultimately, I think that That is the fundamental idea proposition number 1.
The other one is, I think we have increasing evidence, so genetics, Mendelian randomization that puts IL6 6 at the potential center of some of those effects, right? So I would argue it's circumstantial evidence because the point Trying to test here is how does reduction of HSCRP ultimately reduce cardiovascular risk? And ultimately, that is the Hypothesis we are now testing. And maybe the second part of the hypothesis is, well, if we are blocking IL-six, can that be delivered in a Safe way, right, because as you know, obviously, IL-six and through the IL-six receptor also plays a role in sort of the immune response. And we're really trying to find a sweet We do firmly believe that cilimumab is actually the best drug to test this hypothesis, but we see very clear evidence for a reduction in HCRP, but at In the Phase II trial that we have seen a very benign side effect profile.
So when you put this together, I think we have a good drug modality now to take it into An after outcome trial. Now CANTOS was a rather heterogeneous all comers population. We're now zooming in A much more defined patient population. And by the way, I think that is fundamentally probably to think about some of those trials in Future that we are moving from all comers to more specified to more stratified patient populations just as a general theme. Martin, anything you want to add?
No. I very much agree. I think we have in a Phase 2 setting everything that we can have. We We had to rely on biomarkers. This is a new setting.
I sometimes use the analogy of originally when we started to talk about LDA lowering, Someone had to do the outcomes, but to actually show that this was associated with improved outcomes. And this is specifically the situation We have to Marcus' point very strong Phase 2 data both from an efficacy, but also a very benign safety profile in this space and given the mode of This obviously does call for some risk on our So 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 give Again, the very good safety profile, the right patient population and a benign sorry, efficacy profile. From a trial conduct perspective, obviously, in these outcomes driven trials, it very much depends on the expected event I know, Gaston, you would love me to speculate and give you a very hard date. And obviously, Yes. 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 rates higher than we Expect we will still be required to expose patients for a certain number of years, probably at least 2 years For a proper safety event sorry, safety assessment on behalf of the regulators. So again, balancing the event rate With a requirement minimum requirement of exposure.
Excellent. Thank you, Markus. This concludes today's Novo Nordisk R and D Investor event in connection with AGA. We thank you for listening And asking a lot of really good and relevant questions. We will be back with our Q2 results release in August 5.
So looking forward to connect at that point in the interim. I wish you all a beautiful summer. Until then. Thank you.