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

Welcome back to the Novo Nordisk virtual R&D investor presentation. Now we're on to the Q&A session. [Operator Instructions] And then I will orchestrate the meeting from here.

[Operator Instructions] So we're ready to take the first question. And the first question goes to Martin Parkhøi from Danske Bank.

As Karsten said, it's Martin Parkhøi from Danske Bank. Firstly, I think is focused on the obesity mass. I guess, the Phase I trial that was in a loose combination. Could you talk a bit about the device for later-stage trials? We know it needs to be a dual-chamber device, but how will you inject it to avoid the compounds being mixed? Are there any risk for any reduced efficacy in this method versus the loose combination? And then secondly, does it make any kind of sense also to investigate the combination in diabetes in order to get a type 2 diabetes drug made with a more attractive weight loss than one you see on Ozempic alone?

Great. Thank you, Martin. So the first device question go to you, Mads. And then perhaps Martin could cover the diabetes question.

Yes. So -- and I think we would expect that these question is also included in NASH and other things where we think it's up and official. But, Martin, on the dual-chamber or whatever you call it, it is true that these molecules ideally should be administered together, and they were in a loose combination here. So we will disclose at the right point in time, the exact device solution that is included in the program. But what I can say is that there should not be an efficacy-related risk with that device solution i.e., you should not expect to see that suddenly the drug doesn't work anymore. But we'll get back to you on that. As I said, we are starting this pharmacokinetic study during the course of the second half, and that will get much more data. So I'm not worried about that, but we are having a device that we can disclose for competitive reasons at a later stage. And Martin, what's your comment on the diabetes thing?

Thank you very much. Well, first of all, shorter-acting amylin is already approved for treatment in combination with insulin. So obviously, the question makes a lot of sense we're not ruling that out. We are still evaluating. In particular, I mean, we haven't seen data from patients suffering from type 2 diabetes. So currently, we have been looking at only obese patients. But this is something that we will pursue. And we also believe that the substantial weight loss in and of itself would also benefit the placebo controller of type 2 diabetes.

And you could consider, of course, the NASH disease as well, Martin. Now that you've added.

Okay. Thanks for that question, Martin. Then we'll move to Kerry Holford from Berenberg.

So a couple of questions on obesity, please. So, Mads, I imagine you highlighted the nice weight loss curves and you discussed a strong and sustained effect of the durability of that effect. I wonder if you can discuss that in the context of the Saxenda curve. Did they look similar? Or did you see some weight loss in the Saxenda that slows after a period of time? Because I mean, the key here is, I guess, it's the durability is superior. Could that be the angle that encourages patients to stay on drug on sema for longer than the average 5 to 6 months that you see on Saxenda today. And then on AM833, the combo data looks very encouraging. So I'm wondering does this combo have a future in the monotherapy setting when you take it into Phase III and mono-only? And if so, why would you choose an amylin analog over GLP-1, the way looks broadly similar. Could it be a side effect profile, superiority annual there? Or is there something else?

Great. Thank you, Kerry. So a question on durability of the weight loss versus Saxenda. As the first question, and I think that will go to you Mads. And then Phase III trial design on AM833. Martin, that's one for you.

I think, Kerry, that when patients and physicians in particular patients end up discontinuing a product. It is that you absolutely correctly state, it's about the durability of the weight they achieve on the pharmacotherapy. It's actually also about the degree of weight loss. And also by the convenience of the product and the quality they feel. And there's no doubt that Saxenda is a once daily product. They have to inject every day. They lose weight for anywhere between 26 and 40 weeks, but then it actually [ packs ] to lose, and in some cases, goes up a bit again. And you're totally correct in saying that for more than a year on semaglutide 2.4, you are seeing week-by-week an actively ongoing weight loss. So they can measure themselves just by getting on the weight scale back in their homes. They also have to inject once a week. And we now know from the health-related quality of life questionnaires that were extensively used in these trials that they actually have a better physical and mental health state when using semaglutide 2.4. So I would argue both the degree of weight loss being 17%, 18%, the duration and durability of weight loss and the convenience with it is achieved and the quality of life that subsequently is derived all speak in favor of semag becoming a drug that can be used on a much more chronic basis than we have seen [ up ] or other anti-obesity medicines so far. And then Martin, what would you do in Phase III for AM833?

Yes. I think the question was whether we would take the monotherapy into Phase III. It's important to state that our key focus is on the combination therapy, both given the very, very attractive efficacy profile, but also the -- as Mads alluded to impressive safety profile. That being said, we're currently evaluating the monotherapy. There are a few patients who may benefit from an amylin treatment that either for, efficacy, safety and preference reasons would not be optimally treated with semaglutide. And that evaluation is ongoing. So for now, our key focus is to initiate the Phase III trials for the combination therapy.

Great. Thank you, Martin. And Thank you, Kerry. So then we'll move on to Carsten Lonborg from SEB.

Yes. I have a couple of questions on icodec where you now aim to demonstrate superiority on HbA1c in the Phase III trial. I was hoping that you could give us a little bit more details on how you'll do this because traditionally, it has, of course, been all about non-inferiority when it comes to HbA1c, and then looking at hypoglycemia. But this is kind of the other way around. And even if you had a numerical increase in hypoglycemia in Phase II, you must feel very certain that this is not something that will have an effect on you in Phase III once you get past the titration phase. So first one is, how do you aim to control this? Should be first for any insulin, I guess? And then on -- maybe a question to Mads because I think you previously said that icodec would come with increased convenience to the patients at no extra cost. And now that you are going for superiority in Phase III, do you still rely on that notion?

Great. Thank you, Carsten. So first question, Martin, on how to get superiority in Phase III on icodec while controlling hypos. And then Mads, the affordability question and how to take it to both patients and price.

Thank you very much. So this all hinges around the very flat stable and with our description profile that I showed in the beginning. That profile allows us to titrate the patients to a reasonable and good placebo control without increasing the risk of hypoglycemia. The more excursions you have, the higher the risk of either getting too high or too low. In that treat-to-target setting, we've now conducted [indiscernible] in the Phase II, all of which in type 2 diabetes, we've sort of seen the same picture. And it's very, very clear that we do have this aspiration that we did -- a flat profile can titrate. Even though we titrate treat-to-target to a level where we will see throughout the day better placebo control for icodec versus in comparison thereby panning out superiority when looking at A1c. You're absolutely right, we have to be very confident in the maintenance phase, as I alluded to, when doing the sub-analysis for the maintenance phase, we actually saw a 50% reduction in the study. I just went through in Level 2 hypoglycemia. So obviously, when moving into Phase III, more variability, more uncertainty comes in. So not to be [indiscernible] we will be aiming at, at least on par with hypoglycemia, but hopefully, also seeing the benefit of the flat profile even on the hypoglycemia.

Mads?

Yes. And I think Carsten, it is true. Before we realize the systematic degree across the 3 trials, where there's a flat profile where you don't have peaks in values every day as you do, for instance, for glargine as elegantly described by Martin. At that point in time, we thought this was a convenience-driven product. Where you save a number of needles, you save a number of BTN strips, you save a number of hassles throughout the week. But as you just heard, we actually believe we can tease out what drives a health care utility cost, namely glycemic improvements. So of course, the -- in particular, in the U.S., the entry market is not the easiest to achieve premium prices in. But if you were ever to have a premium-based product nowadays, then is, of course, has to be driven on showing added value. And that's typically done, here you want to see improvement, plus, of course, reduced costs associated with things such as BTN strips, needles and so on.

Great. Thank you, Mads. So then the next question comes from Peter Verdult from Citi.

Peter Verdult, Citi. Two questions. Can we start on zilti. Just given the patient population you're going after, how quickly -- I mean I'm assuming the event rate will be quite high. So if you're starting Phase III next year. I mean how quickly could you complete this study given -- I'm assuming a higher-than-normal event rate in this severely ill patient population. And then Mads, slightly unfair because I'm asking you we've only just seen Phase I/II data, and you haven't even filed semaglutide 2.4 yet. But from a commercial perspective, we know that Saxenda has done fine, but reimbursement has been terrible. The prescriber base has been terrible, and you've been hamstrung by a pretty high list price because of linear pricing. Would you be willing at all at this point to talk about commercial considerations regarding these new assets in terms of really sort of driving the market and potentially exceeding your doubling of obesity sales target?

Great. Thanks, Pete. So first question on the zilti timelines and the Phase III approach. Martin, if you cover the one, then I will cover the second piece in terms of commercial potential in our obesity franchise?

Yes, absolutely. So in addition, as you allude to the timelines, it will very much depend on the accrual of events, and 2 ways of doing that. Obviously, the rate of the events and then the sample size of the study population. We can try to balance those 2, fully-agreed that the event rate will likely be higher than what we've seen before, and therefore, we have the potential to do this faster. However, from a regulatory perspective, we also don't want to do it too fast. There has to be a level of exposure to the doc in order to establish both the benefit, but certainly also the safety of the drug. So that balance we are evaluating. But you would be looking at somewhere between 2 and [indiscernible].

Thanks, Martin. And in terms of our commercial outlook for our obesity franchise, then as we presented at our Capital Markets Day, and that our obesity business is clearly a growth focus for the company and an area where we are investing significantly in future growth opportunity, both in terms of pipeline assets and in terms of commercial investments into the marketplace currently. So what we have laid out is more than doubling compared to 2019, where we had sales to the tune of DKK 5.5 billion. And with the compelling results that we've not seen in the STEP program and also in the combo amylin program that, of course, increases our confidence that we will be able to deliver on what we laid out in terms of more than doubling our obesity business. So rest assured that this is a growth focus for the company, and we're pushing and investing accordingly. Thanks, Peter. Then we'll move on to Michael Novod from Nordea.

Yes. It's Michael from Nordea. Also 2 questions, perhaps also a bit unfair, but maybe you could just give an update on when you expect the ELAD data to come out? And then secondly, in that same ballpark resulted data in the Lancet neurology on dulaglutide from the REWARD trial showing a benefit in terms of cognition. So looking at the data you have, would you just be considering to move forward in type 2 diabetes as we saw it in the Lancet paper yesterday? Or does it need to be sort of full-blown dementia, Alzheimer's program? And then secondly, based on the PK/PD data we saw at ADA on icodec. I think you also showed it in comparison to insulin 338, which was your old oral insulin. Are you sort of thinking about reviving those plans at some point in time? Or is a once-weekly insulin good enough?

Great. Thank you, Michael. So Mads, if you will cover status on ELAD and the recent Lancet paper and our approach vis-à-vis diabetic population and nondiabetic and what we think in the NGI arena? And then Martin, if you cover the ADA approach and the PK/PD rebounce.

I think the question was about whether we revitalize our oral insulin...

Yes, yes. Sorry. Okay. Thanks.

Okay. So I'll kick-off. And clearly, the ELAD study family has also been delayed because everything has been delayed by COVID-19. And we are not insightful into the timelines for that particular study, Michael. But you are absolutely correct in stating that Lancet yesterday had actually some interesting commission data from the REWARD trial that I also enjoyed last night, and they corroborate some of the notions that we've had across our cardiovascular outcomes trials for these GLP-1 receptor agonist. And I might alert your attention to another paper that came out 2 months ago in International Journal of Obesity, where they had weight max people to either lose 7% body weight by lifestyle intervention or by liraglutide treatment, and these patients actually were nondiabetic mostly. So they were kind of glycemic-independent and weight-independent. And I think when we discuss this around this table, once we make up our minds, it is in the event that we see to -- decide to progress, it is more likely than not that we will be looking into the realm of earlier stages of dementia, including the mild cognitive impairment that's specifically targeting diabetes per se because we actually think the role of GLP-1 as a neurotransmitter, as a neuroprotection, as an anti-inflammatory agent that might reduce microglial and other compartment or cellular activations in the brain, its tendency justifies that it could be something that delays the onset of the clinical dementia, not only people with diabetes but on a broader background. I think I might just on the oral insulin concern because that's a tough one. We would not like an oral insulin. But I have to say, Michael, that today, we have oral GLP-1, like Rybelsus. We -- on the other hand, we also have approaches where we can maybe deliver higher [indiscernible]. Insulin is a lower [ comorbidity ] hormone in the GLP-1. So the amount of insulin you need to deliver orally is quite a bit higher than GLP-1. So to make the mathematics works in terms of full manufacturing costs and so on, then it would be more likely to go down that alley with another approach than just the stack approach that we have for Rybelsus. So we're not ruling out anything. And if any company should make oral insulin available. Of course, it should be Novo Nordisk. And we have a big oral biologics group working on different targets. And of course, on an ongoing basis, they're also evaluating this one.

Great. Thanks, Mads. Then we move to Peter Sehested from Handelsbanken.

Yes. Peter from Handelsbanken. I have 2, and I think I will start off with one of those unfair questions for Mads. And that relates to something that has gotten a bit of attention lately and that is the Pfizer data at the ADA. In the -- in the public domain, there was actually some patented Pfizer data on oral GLP-1s. Have you looked into that in order to potentially synthesize the product and see if there are unfortunate receptor interaction that makes you, let's say, more or less concerned about what they might show in terms of safety in Phase II or other comments in general regarding that type of compound? And secondly, just noticing the [ curve pattern ] of the AM sema data, it's basically more concave than convex, which is sort of what we have been used to look at in terms of obesity curves. Could you sort of indicate what this pattern means for the efficacy, let's say, out to the 68 weeks that we are now being accustomed to look at now.

Great. Thanks, Peter. Two to Mads, one on Pfizer oral GLP1 safety and other comments. And then our combo amylin sema and the shape of the curve that drove relevancy.

Yes. I think it would be unfair for me to comment specifically on the Pfizer compound. My colleague, Michael, [ does seem ] at Pfizer, so should rather do that. What I will say, though, is generically speaking, Peter, the Pfizer compound is clearly having a half-life of like 5 hours. So it is twice stage compound. And I know the company is probably looking into 1 stage as well. But a twice stage compound, it's not the easy so it's not convenient nowadays. And of course, you also have to qualify small molecules all the way through drug-drug interaction studies and the full monitoring of metabolite profiling and safety documentation, both preclinically and in humans. So I won't comment any further on that. You just have to bear in mind that now Ryhelsus is on the market, but Novo Nordisk has been in research making further enhanced versions of oral biologics for diabetes and other indications for a long time now, and we'll keep you updated as data from those efforts emerge in the months and quarters to come. And then on the other one. Yes, there I would more refer to 2 things. The way the titrate in these studies differs. So in fact, whether it's convex or concave or whatnot, you called it, it's actually a bit difficult to make too many estimations on the shape of the curve. Because in some studies, we are titrating once a month in other studies we are titrating twice a month, et cetera. So I don't think you should make 2 deductions other than the fact that in the amylin sema, I would like to notice that there was only 1 dose of the full efficacious dose of 2.4 milligram. And that was given at week 16. So you've only seen 1 week of studies there. So we are pretty comfortable or -- encouraged both by the safety and efficacy because we didn't see any added safety concerns [indiscernible] by giving sema alone. What I'm trying to say is that in terms of efficacy, we will, of course, in Phase III, make sure that just like in the STEP program, we have at least a full year on steady state dose and not just 1 month. And safety-wise, we are seeing surprisingly a profile that more mimics sema 2.4 standalone than sema plus something in GI side effect profile. So additivity, more or less, in terms of efficacy, but no real added tolerability concerns based on the datasets we have so far. So we're encouraged.

Great. Thank you, Peter. Then we move to Simon Baker from Redburn.

Two questions. Continuing with the obesity combo. From what you said, Mads, from the slides about tolerability. It's not entirely clear that you've reached the maximum tolerated dose. So is that the case? And if so, why did you stop at 2.4 milligrams? Or could you indeed go higher? And then moving on to zilti. You mentioned on the slide that your IL-6 doesn't have the impact on lipids that the others do. So I wonder if you could just give us a little bit more color on that, also the impact on liver enzymes.

Great. Thanks, Simon. So Mads, one question on the sema amylin combo. And potentially also a comment related to that on the sixth cohort that you showed on the slide without any results. And then Marcus on zilti.

Yes. Simon, that was very well picked up. And the original protocol estimated that there would be kind of like a max tolerated dose rather than 2.4 milligram level, which clearly turned out not to be the case. So in as much as we have the full data as per protocol, and one does continue to the [indiscernible] level of the 4.5 milligram dose, and we'll report data on that later. So this is almost complete disclosure. But because of the good tolerability, there was this 4.5 dose also together with Sema. And those data will come in later, actually, by the way. And we will, of course, report on them. And then Marcus on zilti.

Yes. It's a great question. Obviously, we have both the IL-6 receptor antibodies and some other IL-6 antibodies already out there, some of them in rheumatoid arthritis. And as you say, rightly so, I mean, they just signal on liver enzymes. And we also see, with those compounds, a significant elevation of cholesterol. Now I can only speak to the data that we have seen so far, and you should keep in mind these are early clinical data. And the larger scale trial will obviously be run in a cardiovascular outcome trial where, as Martin alluded to, we'll see a solid basis for an assessment of safety. What I can say at this point in time, from all the data we have seen from Corvidia, those particular safety signals seem to be absent and/or low. So -- and that was actually what we also based our assumption on that. We might have a key differentiator here in not only having a very powerful drug on IL-6 reduction and CRP reduction. But also, obviously, having found a very attractive therapeutic window to the known side effects of this class. So that has given us a lot of confidence. But do keep in mind, it's early and relatively short-term data so far.

Thanks, Marcus. Then let's move to Richard Vosser from JP Morgan.

All right. First question, just on sema 2.4 milligrams. And just the final strategy seems a little bit vague, and I'm just wondering about the priority review voucher that you have on hand, and how that might be used for this product and, therefore, might accelerate the filing timelines? And then second question, just on the amylin analog. Obviously, very, very strong weight loss and you've alluded to some Phase III programs. But what about cardiovascular benefits for the combination as well, would you think about doing a cardiovascular outcomes trial to try and nail down even greater weight loss and the potential there? Or is that unrequired? I better stop there, I'd like to carry on.

Thanks, Richard. So Mads, a final strategy for sema 2.4. And then amylin combo in cardiovascular.

Yes. And on the final strategy, I did say that we expected to submit the new graphic application in Europe, U.S. around the tune of the year, and that's a fair statement. The use of the voucher is something that Karsten and the company only discloses if and when such decisions have been made, obviously that is an option, but I think that's something whether that is to be used a lot, we will revert to later when such a decision were to be made. Then on -- so Richard, funny thing, the way I look at amylin is that it is unlike many other [ calciotropic ] hormones, so let's say, GLP-1 being 1 example, but there are also others where there is expression of receptors all over the place in the body, GIP has receptors in the gastrointestinal tract and so on and so forth. Amylin actually has a more restricted receptor distribution in the body. And on the one hand, that means they can get an awful lot of nice weight loss, healthy weight loss without side effects. On the other hand, you should not expect that there are very pronounced cardiovascular effects that are unrelated to the weight loss. On the other hand, if you have 25-or-so percent weight loss, then that in its own right price, a reduction in lipids and blockage and things that are beneficial. There is no guidance on obesity drugs that is unequivocally telling us to do a cardiovascular outcome trial. But I think Martin and I and others, together with the management team at the right point in time, will discuss whether or not to do a CVOT. We've come in the habit of doing a lot of CVOTs over the last few years. And mostly, they have come out in a good way. And now we're starting one with zilti next year. And do bear in mind, of course, that we have this huge thing ongoing with the SELECT trial, 17,000 patients, of which the majority are recruited pre-COVID. And we are really also looking extreme -- that couldn't be a true inflection point, also in terms of reimbursement and market access, just like before we started it for the statins to open up the market with reimbursement and mortality improvement, that's one of the main reasons why we did the SELECT trial, of course. So we are busy.

Thank you, Mads. Then let's move to Keyur Parekh from Goldman Sachs.

Two, please, if I may. One, Mads, I think you just alluded to this, but you guys are now running multiple kind of CVOTs. Just kind of -- is there anything that you can do on a platform basis that allows you to run these studies kind of a lot more efficiently, especially as you think about kind of this potential study for the Corvidia compound. Are there kind of patient data sets that you can access of people who have kind of progressed to CKD and stuff like that? That would be one. And then secondly, kind of as you think longer-term about moving into adjacencies kind of beyond the bread and butter kind of diabetes and obesity at this point of time, you clearly got the PCSK9, now you've got an IL-6. As we think -- are those 2 kind of enough from your perspective? Do you think you need to add to that if you were to think of this as a kind of longer-term objective to move away -- to add to diabetes and obesity?

Thank you, Keyur. In terms of cardiovascular outcome trials and efficiency, right now, we're starting to get a lot of experience in this field, and this is Martin Lange's home turf. So, Martin, I'll give that to you. And then our approach in terms of number of assets in cardiovascular. Marcus, if you could cover that one?

Thank you, Karsten. Well, as Karsten alluded to and you also yourself alluded to, we're currently running for our controllers, and we finalized, depending on how you count on it on fall already. So we are becoming briefly good at this in order to fully leverage the pipeline and the portfolio that we have obviously, we need to build on those capabilities. We do believe that we have a very cost-efficient way of broadening these trials but in order to identify more patients faster in order to recruit more patients faster and in order to be cost-effective. We start looking at new platforms, digital tools across the trial value chain from identifying, recruiting and also treating patients in order to support us. This goes specifically for our outcomes trial, but also beyond the outcomes trial into our normal clinical trials in all therapy areas.

Yes. And maybe to add to the question on cardiovascular, we're obviously very much at the beginning of our journey in cardiovascular disease as a stand-alone disease area. As you rightly say, with PCSK9, we have our own dyslipidemia agent in clinical development. However, there are other very interesting genetically validated targets in dyslipidemia we're particularly interested in. I might also point you to our collaboration with Dicerna Therapeutics, which we announced last year. It's a big platform on RNAi technology. There are a large number of potential cardiovascular drugs, and that really work through this particular platform. Inflammation-driven cardiovascular disease. Now with zilti, I think we have a strong presence. And probably one of the leading molecules you can think of. So I think that's fine, and we'll complement that, and we do with our internal pipeline that we're actually accelerating. But then the last leg that I mentioned is heart failure. In particular, heart failure with preserved ejection fraction, where we have an early internal pipeline, but we're also particularly see which assets in the clinical space are out there and available potentially through external partnership to accelerate our journey in this space. So I would say they're certainly more, both from an internal pipeline point of view, but also through external partnerships. So thank you, Marcus. Then let's move on to Sachin Jain from Bank of America Merrill Lynch.

Two, please. Firstly, I wondered if you could just, Mads, dig into sema 2.4 safety a little bit more. Thanks for the headline comments, but could you confirm the discontinuations due to DIE in the mid-single digits consistent with existing? And any specific comments on diarrhea rates? The reason for that question is, I think, that Saxenda label has it roughly 20%. I'm just wondering if it's materially higher than that. And can I extrapolate the 2.4 safety data to SUSTAIN FORTE coming at the end of the year? And as we think about comparison versus tirzepatide. And then just a second quick question on a AM833. You've referenced potential progression to Phase III in NASH. Just to check, you've been used to Phase II there. And if you're going straight to Phase III, do you have an idea already of what NASH resolution of fibrosis improvements the weight loss you're seeing can potentially drive?

Great. Thanks, Sachin. I think there was 2 very elaborate questions with some sub questions in it. So Mads safety profile on sema 2.4 in terms of grade asset on diarrhea and who does it compare with the Saxenda and relate also to Sema FORTE, and then finally, the combo sema amylin in NASH and Phase II/III trial approach.

Right. So Sachin, I'm happy to notice that GI time line were totally as expected. And when I look, for instance, at diarrhea, I'm looking right now as a STEP 1 trend. There was not a week where more than -- below 5% would report diarrhea. In totality throughout the trial, it could be high single-digit reported. We are not in the same league as other companies that have dual agonists that are in the 30-plus percent range. This is actually a low level of diarrhea reporting and lower than for liraglutide. It is true that lira is in the genes, whether that is due to the fact that you have a constant exposure or what, I'm not sure. So a very safe and well tolerated profile throughout this very big STEP program, absolutely. And you could also see that from the fact that the computer rates were extremely high, I mean, kudos to Martin Lange's organization. I mean they're very good at doing their job. But people actually stay on this product. They said -- I showed you the discontinuation STEP 1, there were clearly more actually that ended up discontinuing on placebo than on 2.4. So -- and even in the beginning, there was no real difference. So I think, Sachin, we're really happy to say to you that the safety and tolerability profile of sema is completely as we've seen also for the lower doses of sema and for that matter liraglutide. In terms of FORTE, that will be exciting to see the data in Q4 this year. And we are really looking forward to that. But my statements that I've made so far about our expectation of having a similar efficacy profile to other products such as tirzepatide. But in our view, in all likelihood, with a more benign safety tolerability profile remains undisturbed. In terms of moving into NASH. In the [ quick, you much ] NASH with amylin plus sema, that would be a real strong combination of weight driven value proposition together with a strong inflammatory and other elements that we know from the GLP-1 actions on the NASH liver in the data that Martin showed. We show all data, but could assume data on inflammation and ballooning and stellate cells was just that all point to that direction. So I think we'll get back to that. It's a bit early days. We only just got the data. And I think management needs to discuss the way forward. But it's suffice to say that this combination could hold potential within different opportunities, ranging from obesity over type 2 diabetes into NASH.

Great. Thank you, Mads. Then let's move to Wimal Kapadia from Bernstein.

Great. So can I just start with [Audio Gap] versus Tresiba [indiscernible] superior. So why would you not run the big trial versus Tresiba? And then your drug has been...

Sorry. Wimal, so you just fell out in our end. So could you repeat your first question?

Okay. Sorry. So just on icodec. Why are you -- why is the big Phase III trial being run against glargine? We know that the high [indiscernible] versus Tresiba are significantly superior. So should you not run the big trial versus Tresiba? And then on icodec, your drug has been developed to harness to albumin binding to extend the half life. I just wanted to get, Mads, your thoughts on how that's structurally different to Lilly's weekly that's currently in development? And then my second question is just on discussions with governments on the reimbursement, both in the U.S. and OUS. What is really needed to gain significant reimbursement? Is it the SELECT trial? Is it a mid-teens weight loss? Is it 25% weight loss? Or is it Treat & Reduce Obesity Act? What are they really looking for? Because it seems kind of obvious to me that they should reimburse these products from a cost effectiveness basis.

Great. Thank you, Wimal. So Martin, if you could -- I was counting 3 questions in reality. So on the Phase III trial design, icodec versus glargine versus Tresiba. Can you cover that one?

Yes.

And as the structural design of icodec versus the Lilly weekly. And then I can cover the reimbursement in the obesity space.

So thank you very much, really good question. Whether we like it or not glargine is still the most used basal insulin out there. Obviously, we're aiming to change that. But the regulatory requirements basically calls for going against the gold standard. However, we do agree to your point, so at least one of the other Phase III trials will be in a comparison with Tresiba in order to generate those data and guide both ourselves but also the treating physicians.

Yes. And without giving you a half hour lecture on the molecular design, I would like to highlight a few things. Insulin icodec is using the Vytorin's classic, you can say, sight mutation technology where we have changed 1 amino acid chain and 2 in the [indiscernible] chain to reduce enzymatic degradation. It also has a hydrophilic linker, to which is attached a 320 type fatty acid side chain that enables more than 10x increased binding to albumin, which is the underlying principle behind the 1-week profile. We've also tweaked it into reduced receptor binding to the extent that we actually get the long graded and dynamic half-life. But when you then target the receptor, there's full potency like the human insulin. And when we look at phosphorylation, it's neither longer nor shorter than shown for human insulin. And when we look at Item 1 receptor binding is actually reduced compared to human insulin. And microgenesity in self-conscious is also reduced compared to human insulin. So it looks to be an insulin with a very, very safe profile. But I think your question was actually related to also Eli Lilly's. Eli Lilly is apparently an Fc domain-based single chain insulin and that's as much as I know about that. But we know for sure that our product, once it is internalized, it is like solely degraded. So it's hit-and-run. So when it works, it works. It only works once, and that gives this beautiful smooth profile described by Martin.

Great. Thanks, Mads. And then to the final question around reimbursement for anti-obesity medication in different geographies. And I would say it varies by geography. If we take the U.S. in the public market for seniors in Medicare Part D, you're referring to the Toujeo Act, whereby today, it's not legal to reimburse and to be simulations for our -- for seniors. Of course, we very much think so that, that should be allowed. But ultimately, that's up to the legislators. And with the encouraging data and weight loss data and an increased understanding of the value and benefits of anti-obesity medication, hopefully, we can assist in moving that agenda forward and for the benefit of patients and hence, also through reimbursements. In the private market, you have different mechanisms. But of course, ultimately, for the private payers to see the value of anti-obesity medication become stronger, the stronger benefits we are showing, be that on weight loss, but also from select -- on hard end points. And that would also go for geographies outside of North America, where the health economic benefits for society, of course, will go into the reimbursement discussions with the local authorities. And there, it will be a collective body of evidence, which is different by geography. But clearly, SELECT will improve our position there. Then we go to Steve Scala from Cowen.

A couple of questions. First, on the PCSK9, given that the Phase I trial ended in April, I'm wondering if the data is already in-house. And is that supporting your early enthusiasm? What will be the dosing schedule on follow-on studies? And what are the possibilities for differentiation versus inclisiran? So that's the first question. Second question is I'm just curious, what's the difference between the 2 base [indiscernible] [ 14 36], and [ 9 65 ].

Good. So first question on our Phase I PCSK9 and differentiation versus inclisiran. So if you take that one, Marcus. And then the second question is for the 2 different insulins, early-stage insulins, Mads.

So thanks for the question. I think as we already alluded to, we feel we have an attractive novel principle here with our sort of peptide approach to block PCSK9. And of course, time will tell how this will unfold in terms of a value proposition and what the dosing regimen will be. We think we will be very competitive on cost of goods. And I think the overall clinical profile should be obviously very, very compelling. Do keep in mind, though, that I think when we talked about it last time at the Capital Markets Day, we also highlighted this molecule as a potential backbone for combination therapies with other treatment modalities in our pipeline. And I think this is also a key angle we should take on this rather than just seeing as a monotherapy versus what is already out in the market, but rather seeing it as 1 molecule we have to build on our pipeline.

Good. And then to Rethink Obesity, Mads?

Yes. So they are working in principally very different ways. The way they've been designed, both of them are designed to be cardioprotective. So, i.e., work as full base in insulins with the safe profile and have cardio protection added on top. We have actually not disclosed much other than saying that one of them works through a principle of targeting only insulin resistant tissues by being actually, you can say, promptly selective so that if you are an insulin sensitive tissue, you will also enhance insulin signaling. There are people who think that, that can promote atherogenesis and other kinds of problems. So -- but we -- for competitive reasons, we have not disclosed some related details of these very exciting insulins. But it is true that Martin's team will come out with the data. And as already disclosed, the first promising PK/PD data from one of them, as I think we disclosed at the last quarterly announcement. But we'll give you more detail on it. The tradition of our company is to give you full form uptakes once a Phase I program is completed. That's also why you certainly heard the amylin Phase Ib trial complete. We've had several other AM833 trials that we've not talked about. So as a principle, when the program Phase I is competed, we give you a lot of disclosure, and we'll do that also on these 2 exciting molecules.

Yes. Thanks, Mads, to comment on that. Then we move to Peter Welford from Jefferies.

Yes. I've got 2. Firstly, just coming back to Kerry's question on the amylin. I guess curious, given your comments on the tolerability profile and what it looks like continuous weight loss up to week 20, reaching levels that actually exceed sema 2.4 milligrams. I guess curious, what is it that drivers the decision not to pursue that as monotherapy? Perhaps, I guess, the different profile or shorter-term regimen or, I guess, some other angle in the obesity marketplace, given, as I said, your comments on tolerability. And then just secondly, quickly, just going back to the NASH data on sema. Curious though if you could just give us some insight, I guess, into what we should read into the patient population based on the improvement of fibrosis without worsening of NASH. Looks like roughly over 1/3 of patients in the placebo arm did that. And just to point your clarity, is that chart the F1 to F3? Or is that again just in F2, F3 patients?

Great. Thanks, Peter. So Mads, if you cover the amylin combo [indiscernible], and the discussion around mono versus combo in Phase III. And then Martin the sema NASH patient population.

Well, of course, it is an excellent question, but we are discussing a lot, also around the table together with our commercial colleagues. And we actually believe that sema 2.4, with all the benefits of the molecule, including, hopefully, reductions in cardiovascular mortality in liver fat problems, even in real problems that surprisingly often -- are also present in people with obesity, then sema 2.4 is more poised to become the anchor therapy. The therapy that we start on with obesity, at least, if you BMI is about 35. If you have a BMI of 31, you might do well with Saxenda. But then we see the combination of the 2 molecules A1CV [indiscernible] sema 2.4 as a wonderful combination that will enable even people who are severely obese to become more as normal way. I mean going from 30 takeup, 25% and you're down below 30 and hence your no longer obese. So we are actually setting out to -- on a journey to also define how should the future obesity treatment guidelines and market, as such, develop over time. We think we have all the tools that are needed to do that. But as Martin also said a bit earlier, we cannot rule out that amylin monotherapy is also value in some patients, for instance, because they were not responders to GLP-1-based therapy for one reason or the other. And in near of the benign side effect profile that has been surprisingly benign, we're not ruling out anything, but we are happy to say that we will make a competitive strong Phase III program. Ultimately, that will enable the physician to make his or her treatment decision from among a variety of portfolio options that we are to have in the market or are getting closer.

And Martin, the next base of cooperation?

Yes. And so starting a little bit at the end of your question, the analysis I showed you called about the full spectrum from F1 to F3. We did also do the analysis of F2 to F3, basically showing the same response in the placebo group. Now while this was overall and well randomized study, it's still a tiny small study. And we did see good randomization on parameters such as a diabetes body weight, but also BMI. Where we did not see good randomization was actually in the level of fibrosis as assessed by FibroScan. The patients of placebo came in with a baseline of 8.5, which is borderlining being not fibrotic, while the patients on the free exit treatment arms came in on a baseline of 10.23-ish, which is clearly levels of fibrosis. Now we're looking at a binary endpoint in a fairly small population, basically, also using the selectivity of different biopsy areas, different readings and so on. There's a risk that this is what we'll see. And again, we take some comfort in showing substantial dose-dependent reduction in the progression of fibrosis and also in the more continuous endpoints, like ELF and the FibroScan, seeing a reduction in actual fibrosis burden of these patients.

And that actually means exactly what Martin is saying is that you may well have had a number of very mild F3s in the placebo group that could easily turn over into F 2 based on their baseline fibrosis being lower. That could actually be exciting from a Phase III perspective where the numbers will be much larger, and you will not have any bias vis-à-vis high placebo response because of what Martin discussed. So a very interesting discussion.

Great. Thanks, Martin and Mads. Then let's move to Naresh Chouhan from Intron.

Just 1 actually. On STEP 1 and the discontinuation rate, it seems that around 20%, 25% of patients discontinued pretty soon after they stopped losing weight or they try to cut in terms of weight loss. And that would be reduce treatment duration from about 68 weeks to closer to 40 weeks for those patients. And then in the real world, you'll probably have a less motivated user base potentially, and so discontinuations may be higher at around the 40-week time frame. Is that something you're worried about? And how can you potentially mitigate that?

Mads, you want to go?

Yes. Well, first of all, the amount of patients who discontinue in STEP 1, the trial product being sema 2.4 because of adverse effect was exactly 7.0%. And considering the duration of this trial 6 to 8 weeks, I think a 7.0% discontinuation because of adverse effects is actually low and extremely promising compared to almost all other obesity programs that I've witnessed in my time, which is quite a few. And when I then look more specifically at the curve and compare it to placebo, you can actually see that they are more or less super imposable in the first 24 weeks. You might have -- or 20 weeks. You might have thought that there would be more discontinuations on the sema 2.4 than placebo. They are more discontinuations possible. There might be a few extra, probably that because of nausea. But then over the rest of the period from week-20 and onwards, you actually see that there's a plateauing of discontinuation on sema 2.4 whereas placebo continues. So it is highly unusual that you actually have this degree of trial completers, 83% completing at week 68 in an obese population where in the old days, only 50% would complete in the other programs for Tresiba, and CONTRAVE and so on, is a very high number and actually also quite a bit higher than it was for Saxenda. So when you look at the discontinuation curve that I showed you early on, we're happy about that because you actually don't see any discrimination from placebo. And if there is one, it's in favor of sema 2.4 actually.

Thanks. That takes us to the last round of questions, which goes to Martin Parkhøi from Danske Bank.

Two questions. Firstly, Mads, in the SCALE program on Saxenda, we saw that there was difference in the weight loss depending on the baseline, BMI. As I recall it, there was actually a reduced effect BMI above 40. Have we seen a similar trend in the STEP program? And then secondly, you have talked a lot about the SELECT trial, I can recall, if you have actually commented on that you have predefined the interim look into data on SELECT trials. We maybe look at an earlier look into the CV profile of type 2 and obesity.

Yes. Thanks, Martin. So we're back in the history books with a scaling program and baseline BMI and we've seen something similar for -- in the STEP program, its first question. And then if we have a predefined interim readout in the SELECT trial. Mads?

Yes. I think, Martin, your memory served you well, but you've also been around for a long time. So same experience. We did those analysis and Martin's team will do those analysis where you divide by quartiles, the lowest BMI quarter, the third, the second and the top. And Martin, I don't think you've done those yet, but they will be done. This is a very recent data, and they will be announced at conferences, and they will also be published. So I think you don't know, Martin. But let me tell you one thing. If we are disappointed at BMI 42 with the sema that they don't go close to mild obesity, then we have something else for them because then they need amylin plus sema 2.4, and then they will go down. That has the short answer to that one. And yes, I must confess that Martin and his team had a protocol prespecified interim analysis for termination because of difficult concerns and others at a prespecified point in time that we won't go into more detail with right now.

Perfect. Thank you, Mads. And thank you, Martin. So this concludes the R&D Investor Event from Novo Nordisk. We thank you all for dialing in and for the interest in the company. Should you have any follow-up questions that have not been answered in today's session, please do not hesitate to reach out to Investor Relations, and then we'll be back to you. So wishing you all a great weekend and a nice summer, and see you, if not before then at the Q2 roadshow. Thank you.