AstraZeneca PLC (AZN) Earnings Call Transcript & Summary

Good afternoon, everybody. Thank you so much for joining us for this very exciting discussion today on a very, very important set of data that we have just presented at the ESC. So if we move to the Slide 3, this shows you the agenda for today. I will give you a short introduction, and then you will hear Professor Hiddo Heerspink present the data, and then we'll move to a Q&A. So if we move to Slide 4, just want to say that the presenters for today will be Hiddo, of course; David Wheeler from University College London; Ruud Dobber, our EVP for our BioPharmaceuticals Business Unit; Mene Pangalos, the EVP for BioPharma R&D; and Elisabeth Björk, who is with the SVP for CVRM. They are available for the Q&A, and we may also call on other team members who are with us today in case we have additional questions. We move to Slide 5. This slide actually shows you the, I would think, the incredible journey that Farxiga has been on from the early days when basically everybody saw this molecule as a simple diabetes drug, essentially reducing glucose with, of course, a positive effect on blood pressure and weight loss, but not much more than this. And we actually always believed in this medicine and embarked on the very large program exploring its benefits in cardiovascular disease, but also the potential effect in -- that it could have in heart failure and chronic kidney disease. And this really resulted in a series of really groundbreaking results. It started with the DECLARE study that was presented in 2018 in the type-2 diabetes. But last year, at this very ESC, actually, we presented the groundbreaking results in heart failure in HFrEF patients. But what is really important is these results were -- these positive results were as seen in diabetic patients but also in nondiabetic patients. And today, we are actually presenting results in chronic kidney disease that are truly outstanding. And again, I'll repeat it, in diabetics and nondiabetics. So clearly, this medicine has been -- has gone from being a what I might call a traditional antidiabetic medicine to what is today a medicine with potential benefit in heart failure and kidney disease, and therefore, a broader product across a whole variety of conditions. And we have further data coming up in 2021. Next year, we have another heart failure data set, the DELIVER study in HFpEF. And finally, we're also working on combination products, in particular, combining dapagliflozin with our MCR antagonist. So if you move to the next slide, this actually shows you the importance of the data that are presented today. Kidney disease is actually quite underestimated. People don't realize, but 1 person out of 10, 10% of people in the world are living with CKD. And of course, CKD are of different seriousness, but -- and it's really quite under diagnosed, actually. But the need for these patients to be treated is absolutely enormous, and the costs are gigantic. Medicare costs in the U.S. are $84 billion per year, and those are 2017 numbers, and I'm sure they have gone up. And if you look at the number of patients around the world who suffer from some form of kidney disease, more or less advanced in there are heart disease, of course, the benefit that this medicine can bring to patients is just enormous. And the benefit that this medicine can bring to healthcare system is also very large because those patients, of course, if they have heart failure, they end being hospitalized and they cost a lot of money. And if they progress in their kidney disease and end up on dialysis, their life is miserable, but they also cost a lot of money. So a tremendous medicine that's for a very low cost, actually, can actually bring tremendous benefit to patients and healthcare systems. Probably one of the best examples of cost effectiveness medicines, I think, that the industry can bring to patients and healthcare systems. So if I move to the last and the next one and that would my last slide, it is showing you that, as you know, we are very committed to what we call CVRM, which is, in fact, cardiovascular, metabolism and the organ disease, kidney and the heart. Because we've always believed on the beginning, and now data are supporting our belief that there's a lot of cross talk between the metabolism and the organs and between the organs themselves. So as you can see here, we've been building over the last few years a portfolio of products in this area, and there's more to come in our pipeline. Today, I won't go through this because the results that you're going to -- you're just about to hear are too important, and we want to spend most of the time on this. So with this quick introduction, I will hand over to Hiddo. He's going to take us through the study itself. Over to you.

Thank you, Pascal, for the introduction. Ladies and gentlemen, it's my privilege to present on behalf of my Co-Chair, David Wheeler; and on behalf of the DAPA-CKD investigators, the results of the DAPA-CKD trial. Next slide, Page #9. And these are the slides with my disclosures. And we move to Slide #10, next slide. Chronic kidney disease, as you have just heard, is an important contributor to cardiovascular morbidity all-cause mortality and associated with the diminished quality of life. Until recently, the only classes of medication that has specifically been proving to slow progression of chronic kidney disease were ACE inhibitors or angiotensin receptor blockers. SGLT2 inhibitors, including dapagliflozin, have shown favorable effects on cardiovascular and kidney outcomes in large clinical trials in patients with type-2 diabetes, specifically the DECLARE trial, which was presented 2 years ago. Last year at the European Society of Cardiology Conference, the DAPA-HF trial demonstrated that dapagliflozin reduce the risk of worsening heart failure or death from cardiovascular causes by 26%, and this effect was present in patients with and without type-2 diabetes. We hypothesized that dapagliflozin could also preserve kidney function and improve outcomes in people with chronic kidney disease, again, independently of the presence of diabetes. Next slide, 11. So the objectives of the DAPA-CKD trial were to assess whether treatment with dapagliflozin compared to placebo reduce the risk of renal, cardiovascular events in people with chronic kidney disease with or without type-2 diabetes. And these patients are receiving standard of care, which include a maximum tolerated dose of an ACE inhibitor or ARB. So we were testing the effects of dapagliflozin on top of maximum standard of care. The primary outcome of the trial was a composite outcome of sustained eGFR decline of at least 50%, which is equivalent to an halving of kidney function; end-stage kidney disease, which is defined as chronic dialysis kidney transplantation or kidney function less than 15 ml per minute; or renal or cardiovascular death. The secondary outcomes, which are listed here in hierarchical order, where a composite outcome of sustained 50% eGFR decline, end-stage kidney disease or renal death. So the kidney specific endpoint. The second endpoint was a cardiovascular death or hospitalization for heart failure. And then as a third secondary outcome, we listed -- or we defined all-cause mortality. Next slide, Slide #12. Adult participants with an eGFR kidney function between 25 and 75 ml per minute. These patients had elevated albuminuria, urinary albumin creatinine ratios, between 200 and 5000 milligram per gram. And you can see the key inclusion and exclusion criteria on top of the slide. These participants were randomly assigned to dapagliflozin 10 milligram per day or matched placebo and were followed for 2.4 years, with in-person visits occurring approximately every 4 months. The trial was originally designed to capture 681 events, which provided 90% statistical power to detect 22% relative risk reduction for the primary outcome. Next slide, #13. The DAPA-CKD trial was an international, randomized placebo-controlled clinical trial conducted at 386 clinical sites in 21 countries, which are listed here on the slide in blue. In every country, we enrolled a number of patients, and these numbers of patients are listed between brackets on the slide. In total, we randomized 4,304 participants. Next slide, Slide #14. The first participant in the trial was randomized on the 2nd of February 2017. On the 26th of March this year, the Independent Data Monitoring Committee recommended after a regular review meeting that the trial be stopped early due to overwhelming efficacy. The Executive Committee accepted this recommendation, and the trial closeout procedure started. On 12th of June this year, the last patient's last visit occurred, at which time, the median follow-up was 2.4 years. Next slide, Slide #15. As I already mentioned, we randomized 4,304 participants. These participants were randomized in a 1:1 ratio to dapagliflozin or placebo. In the dapagliflozin group, as you can see on the slide, there were 10 patients who discontinued to study. 8 of them withdrew their consent, and 2 were lost to follow-up. In the placebo arm, there were 5 participants who discontinued the study, 3 withdrew consent and 2 were lost to follow-up. So that means, overall, that 99.7% of the cohort completed the study. At the end of the trial, there were only 5 patients in whom vital status could not be ascertained. So in other words, vital status was known in 99.9% of the cohort, which speaks to the quality of the trial we conducted. Next slide. The baseline characteristics are shown here on the slide, and you'll appreciate that these baseline characteristics were well balanced between the dapagliflozin and placebo group. The mean DAPA-CKD, the average DAPA-CKD participant had an age of 62 years. 1/3 are female, but half of all participants were white, and 1/3 was Asian. 2/3 of the cohort had a diagnosis of type-2 diabetes. The mean eGFR was 43 ml per minute, and the albuminuria level was close to 1,000 milligram per gram. Per protocol, all patients had to be on an ACE inhibitor or angiotensin receptor blocker unless there was a proven intolerance to these drugs. 97% of the cohort used an ACE inhibitor or angiotensin receptor blocker. Next slide, we move to Slide #17, the main results of the trial. During follow-up, the primary endpoint occurred in 312 participants in the placebo group. This number are significantly and clinically meaningful, reduced to 197% in the dapagliflozin group, which led to a 39% relative risk reduction for the primary endpoint hazard ratio of 0.61 and a p-value that indicated a highly statistically significant treatment effect. Next slide. When we then look at the kidney-specific endpoint, so this is the same as the primary outcome, but now we are removing cardiovascular death, we observed that dapagliflozin reduced the number of these events by 101. 243 patients in the placebo group experienced a kidney-specific key secondary endpoint and 142 in the dapagliflozin arm, resulting in a 44% relative risk reduction and a p-value, again, indicating a highly statistically significant treatment effect. Now when we further drill down into this endpoint, next slide, we are now at Slide #19, and we look at a clinically meaningful patient-oriented endpoint of chronic dialysis, kidney transplantation or renal death, dapagliflozin also significantly reduced this prespecified end point by 34%, a hazard ratio of 0.66 and a p-value of 0.0072. Next slide. We're moving to Slide #20. So to summarize these findings, I'm presenting you this slide with -- in the top row, the effect of dapagliflozin on the primary composite end point. Dapagliflozin -- the effect of dapagliflozin on each individual component of the primary composite endpoint is shown below. And you'll appreciate that every individual component contributed to this effect on the composite endpoint because for every individual component, the point estimate was favorite dapagliflozin treatment. In fact, they were all significant, every individual component, except cardiovascular death. Now an important question in the DAPA-CKD trial, just like the DAPA-HF trial from last year, was whether these effects on kidney endpoints were consistent in patients with type-2 diabetes and patients without diabetes. We move to the next slide, Slide #21, where the answer will be given. Again, a forest plot with the effect in all patients in the top row. When we then look at the effect of dapagliflozin in patients with type 2-diabetes, we noticed that dapagliflozin reduced the primary endpoint by 36%, a hazard ratio of 0.64. In patients without type-2 diabetes, there was a 50% relative risk reduction, a hazard ratio of 0.50, which was also statistically significant. So dapagliflozin reduced the primary endpoint, both in patients with type-2 diabetes as well as in patients without type-2 diabetes. Now from a nephrology perspective, it's also important to understand whether these effects are consistent in people with a lower albuminuria level or higher albuminuria level and in people with a reduced or relatively impaired or preserved kidney function in eGFR above or below 45 per ml per minute (sic) [ 45 ml per minute ]. And what you can see here is that, again, just like the analysis by type-2 diabetes, these effects were consistent. Dapagliflozin reduced the primary endpoint regardless of the baseline albuminuria level and regardless of the baseline eGFR level with statistical significant treatment effects in each subgroup. Next slide, Slide #22. The DAPA-CKD trial prespecified in total 8 key subgroups, and these subgroups are listed on this slide. And the aim of this slide is not to illustrate the effect of dapagliflozin in each specific subgroup. But if you look overall at this slide, you will appreciate that dapagliflozin consistently reduced the effect on the primary endpoint in each and every subgroup. And importantly, in each and every subgroup, the effect of dapagliflozin was statistically significant. Next slide, Slide #23. The secondary outcome was a composite endpoint of cardiovascular death or heart failure hospitalization. And this endpoint was reduced by 29% with dapagliflozin. 138 patients in the placebo arm experienced this endpoint and 100 patients in the dapagliflozin arm, which led to a p-value of 0.0089. So to put this in perspective, last year, the DAPA-HF trial demonstrated that dapagliflozin reduced the endpoint of cardiovascular death or heart failure hospitalization or 26% in people with heart failure with reduced ejection fraction. We now demonstrate that dapagliflozin also reduced its endpoint by a similar magnitude, but in patients with chronic kidney disease. And then finally, all-cause mortality, a very important endpoint because all patients with chronic kidney disease often prematurely die. We move to Slide #24. In the placebo arm, there were 146 participants who died during follow-up. This number was reduced to 101 participants in the dapagliflozin arm, which led to a notable 31% relative risk reduction, a hazard ratio of 0.69, with a confidence in the fold that did not cost unity and a p-value of 0.0035, a statistical significant treatment effect. And this is the first drug in chronic kidney disease that demonstrates reductions in all-cause mortality and prolongation of survival or life. Next slide, Slide #25. What about the safety of dapagliflozin in this cohort of patients with chronic kidney disease? The number and proportion of patients who discontinued study drug due to an adverse event or discontinued due to adverse event or had a serious adverse event was similar between the dapagliflozin and placebo group. In this trial, just like the DAPA-HF trial, we also prespecified a number of adverse events of interest. And again, just like the other adverse events, these events were generally comparable between the dapagliflozin and placebo group. And I highlight here 2 adverse events. There were no diabetic ketoacidosis events in the dapagliflozin group and over 2 in the placebo group. Major hypoglycemia occurred less frequently in the dapagliflozin group, 14 participants versus 28 in the placebo group. Importantly, there were no hypoglycemic events reported in patients without type-2 diabetes. And that brings me to my conclusions, next slide, Slide #26. In patients with chronic kidney disease, both with and without type-2 diabetes, dapagliflozin compared to placebo reduced the risk of kidney failure. It reduced the risk of death from cardiovascular cause or hospitalization for heart failure and a prolonged survival. As I showed you, dapagliflozin was well tolerated in keeping with the established safety profile of dapagliflozin. Next slide. It's my pleasure to present these data, but definitely, I did not do the study alone. First and foremost, I would like to thank all the participating investigators, and most importantly, patients and their families who have contributed to this trial. I would also like to thank the members of the Independent Data Monitoring Committee, the Event Adjudication Committee and my colleagues from the DAPA-CKD Executive Committee, whose names are listed on the slide. And finally, I would like to thank AstraZeneca for initiating this trial, for believing in the hypothesis that dapagliflozin would also be effective in patients without type-2 diabetes and chronic kidney disease and for bringing this drug in the near future to patients. Thank you.

Thank you, Hiddo, and thank you for a great presentation. And thank you to you and all those involved in this trial for the conduct of a very, very well conducted clinical trial that delivers outstanding results today. So we will now move to the Q&A.

And so we have questions online. And the first question is from Jo Walton with Credit Suisse. Jo, over to you.

Just a couple of questions. I wonder if you could contrast and compare this data with the canagliflozin data because there is 1 SGLT2 with some data here, whether you feel that this is significantly different, whether this just adds to the overall view that SGLT2s are important or if it differentiates? And just thinking of treatment, in your view, do the majority of patients who have kidney disease, who already are known to be diabetic, are they already taking an SGLT2? And how would you see -- as a clinician, how would you see this being dealt with? If you were looking at the kidney side of a patient and you had a different doctor looking at the diabetes side of the patient, would this be problematic? Or do you think that it can be treated holistically?

Thank you, Jo, for this question. Pascal, I assume I can take this first question on the comparison, on the comparison between CREDENCE and DAPA-CKD. There's, of course, one big difference between CREDENCE and DAPA-CKD. CREDENCE enrolled patients with type-2 diabetes and chronic kidney disease, and DAPA-CKD enrolled patients with and without type-2 diabetes and CKD. So we can compare the effects of dapagliflozin in the type-2 diabetic CKD population with CREDENCE. And I believe that the results between CREDENCE and DAPA-CKD are similar on the primary end point. In CREDENCE, there was a 30% relative risk reduction. In our trial, there was a 36% relative risk reduction, slightly larger effect in our trial, but the confidence in the force -- there's a confidence in the follow-on of these effects. So generally, I believe that these effects are similar. However, the important finding in our trial was, of course, the fact that also in patients without type-2 diabetes, dapagliflozin reduced the primary endpoint by 50%. And thus, this is an important clinical finding because if you look at all patients with chronic kidney disease, 50% have type-2 diabetes, 40% to 50%. But what about the other 50%? Often clinical trials are done in patients with type-2 diabetes and chronic kidney disease, but we now also demonstrate that we have an effective drug in patients without type-2 diabetes and chronic kidney disease. And thus, I believe we add to the literature and to the common understanding that SGLT2 inhibitors are effective and dapagliflozin, not only in type-2 diabetes and chronic kidney disease, but also in patients without type-2 diabetes and chronic kidney disease. Now to your clinical question, I would like to hand over to my Co-Chair, David Wheeler, who is a nephrologist and treat many patients with chronic kidney disease. And David, maybe you can take this question.

Yes. Thank you, Jo. So my experience -- I work in North London, and my experience is that the majority of patients who have diabetes and chronic kidney disease are not on SGLT2 inhibitors. In fact, because these drugs are less good at lowering HbA1c in more advanced kidney disease, the nephrologists and diabetologists have tended not to use them in patients with chronic kidney disease. We should remember this was a drug designed to lower HbA1c. It works via the kidney. And when the kidneys don't work so well, that the drug in terms of lowering blood sugar doesn't work so well. So for that reason, I think that we haven't been using them, and there will need to be a change in practice. The question is who's doing this? These patients often see the diabetic doctor and the kidney doctor and possibly the heart doctor. But I think now there's a great opportunity for us all to work together to make sure that these patients with diabetes and kidney disease and with kidney disease and no diabetes and with kidney disease and heart failure gets on to these drugs. So I think we'll find specialists working together to ensure that these patients are treated appropriately in the future.

Pascal, it might be worth mentioning -- Pascal, it's Mene here. I can ask Hiddo, but I don't believe that CREDENCE demonstrated all-cause mortality reduction. Now whether he did comment on that.

[Operator Instructions] Mene, do you want to go ahead?

I'm just going to say, Pascal, that in CREDENCE. I'm not sure whether Hiddo did comment that they get all-cause mortality because I'm not sure they did.

You're right. You're right. There was no statistical significant treatment effect on all-cause mortality. And so as I mentioned during my presentation, dapagliflozin is the first drug in chronic kidney disease that has shown a significant reduction in all-cause mortality and a clinically meaningful reduction of 31%, which is an important milestone for patients with chronic kidney disease.

[Operator Instructions] Maybe one point was -- we wait for further questions -- one point that I think is important to remember is that the population of patients who have CKD and no diabetes is very large. And the canagliflozin study didn't cover those patients without diabetes, which is more than half, about 60% or so, I believe. So Marietta Miemietz, do you want to go ahead, Marietta, you have a question.

I'm just thinking very generally about treatment paradigms. I mean I think there was a lot of commentary at ESC that the SGLTs really should be used much earlier in disease. So hopefully, over time, the question that Jo just asked about the collaborations between diabetologists and nephrologists will get addressed. But just at the moment, what do you expect to happen to diabetic patients who either have heart failure or chronic kidney disease and who are actually quite happy on an anti-diabetic regimen that does not include an SGLT2? Because can you just actually add the SGLT2 without any risk of inducing sort of hypoglycemias or whatever? I mean maybe it's possible in chronic kidney disease that'd be -- based on what you just said, but I'd be surprised if it was possible in heart failure. And if you actually need to replace some of the other antidiabetics that the patient is on. I mean how much clinical inertia do you think there's going to be? I mean are people actually willing to come off of GLP-1? Or what sort of drugs do you think they would actually take out? Do you think that they might actually take out metformin or more likely to take out one of the drugs that is typically added later on? I'm just really wondering how patients are going to deal with the whole subject of managing the glycemia and if their glycemia is well controlled, what do they do when they add on an SGLT2? And maybe their blood pressure -- blood glucose is actually too low.

So Hiddo and David, it's for you again, I think.

Yes. Thanks for that question. Great question. So look, if I was a patient and you gave me a choice between a drug that lowered my HbA1c and controlled my diabetes and a drug that lowered my HbA1c, perhaps controlled my diabetes but also had benefits in terms of protecting my organs, my heart and my kidneys, I would, of course, as a patient, choose the latter. So I think we've got to change the paradigm. We've got to move the paradigm away from controlling blood sugar to controlling blood sugar with drugs that protect organs in the longer term. And we've now got drugs that do that, and I'm certainly very happy to recommend stopping a glucose lowering drug that perhaps doesn't protect organs. And I'm going to say DPP-4 inhibitors because they are commonly used in my part of the world and substituting an SGLT2 if there is a worry about blood sugars going too low. So I think we need to be proactive, and I think the paradigm is shifting. So I'm hoping that there won't be clinical inertia because docs will pick up the importance of actually treating diabetes with drugs that protect organs. And I think that will drive an increasing amount of SGLT2 prescribing.

And David, I think we should add that in our trial, the diabetics were treated according current standard of care, which included a range of antidiabetic treatments, and we added on top of that, dapagliflozin. And yet, we did not see more hypoglycemia. So the hypoglycemia is absolutely not a concern with these drugs.

Thank you. And as a reminder, DAPA can be combined with all other antidiabetics drug, including GLP-1. So you can definitely combine. The next question is from Peter Welford of Jefferies. Peter, go ahead.

Two questions. The first one actually is very similar to the last one, but I'm just curious if you did monitor in any other extent the sort of diabetes within the type-2 diabetics population. I appreciate you talk about hypos. But I mean was there any other, I guess, measurement or event monitoring related to diabetes? Just curious whether or not, I guess, a similar vein basically whether or not there was any effect on adding the SGLT2 in that population versus not? And then secondly, and I appreciate it's a very small proportion, but it looks as though the effect in black patients was particularly profound. As I said, it's very small subpopulation. But I guess, I think I'm right in saying, in black, typically, ACE inhibitors are not effective and there are issues. So just curious, I guess, first of all, whether or not you can comment at all on this and it is just a small number? And secondly, whether or not was there any potential to perhaps consider follow-up studies in this population, given what maybe, I guess, perhaps an unmet need.

Hiddo, I think this is for you again, this one.

Yes. Great questions. We, of course, measured HbA1c during the trial in the diabetics, and there was a modest reduction in HbA1c, consistent with the Phase IIIb studies that were done previously in patients with impaired kidney function. We know that the effects on HbA1c attenuate when kidney function decline, so we also saw a modest reduction in HbA1c. As to the question around blacks, I think we should be careful with the interpretation of this data because the number of black patients was very small. Overall, there was no evidence to suggest that the effects were different in blacks compared to the other races because the p-value for interactions do not indicate that they are significant. And perhaps we need a larger future trials specifically in blacks to assess the effect because your question is clinically relevant, ACE inhibitors, angiotensin receptor blocker appear to be less effective in that population. So SGLT2 inhibitors could play an important role for these patients, but that requires future studies.

Thank you, Hiddo. David, anything you want to add to this from a clinical perspective?

No, I won't add anything to that. Thank you.

The next question is Tim Anderson at Wolfe Research. Tim, go ahead.

Yes. I have a question. It's not on the data, but it's just on the [Technical Difficulty] that and then also talk about Europe and Japan. And is there any way to extend the franchise, either through other patents you may have beyond composition of matter or through some sort of life cycle management initiatives?

So Tim, I'm really so sorry, but you were breaking up, and we couldn't hear you very well. The last part we heard, but the first part, not so much. Do you mind repeating?

Yes. It's trying to understand when generics come in by geography? So U.S., Europe, Japan? And is there anything that can be done to extend the franchise?

Okay. Sorry. Good. Thank you. Ruud, do you want to take these questions?

Of course, and thank you so much, Tim. So first of all, it's true that we have a variety of patents and patent expiries across the world. For the 2 major geographies, the U.S. and Europe, it's still beyond 2025, 2026 and 2027. We're also applying for the pediatric extension. The big one in the Far East, clearly, is China, where we have our patents until 2023. And we are looking into opportunities in order to combine the flows and with a couple of other attractive molecules and thereby at least, we can aim for data exclusivity. So that's what we are trying to do. But first of all, let's first materialize. I think the very substantial opportunity we have with dapagliflozin in both CKD and heart failure because we are working very hard. And Mene can tell you more about that.

Yes. Ruud, I was going to say not just David, sorry, Pascal, I'd just add a little bit more to what Rudd was saying.

Sure, go ahead. Sure.

I think, Tim, we've got quite a few interesting combinations across kidney disease, heart failure, in particular, where we think combining novel molecules with an SGLT2, given the benefits we've seen, we think will make a very interesting combination. And of course, there's a fixed-dose combination. You'll get the patent life through the novel molecule, so SGLT2 will become a bolt-on onto that. And that we hope will enable us to continue the franchise. And obviously, we're working hard to try and get those moving through mid- and late-stage development as fast as possible.

Thank you, Mene. Our next question is from Damien Conover at Morningstar. Morningstar, sorry. Damien, go ahead.

I just had 2 bigger picture questions. One, when we looked at the SGLT2 class, there's been a lot of pricing pressure. And I guess my question coming out of this data is it looks like there's more differentiation that can be further added to Farxiga with this. And I just want to get a sense of, do you think that with this data, in the U.S. primarily, do you think the pricing power, Farxiga would hold up as well as potentially the class because of increasing differentiation? That's the first question. And then the second question was just in the recent past, when we've seen secondary indications go into cardiometabolic drugs, the launch trajectories don't seem to hit significant inflection points. But I'm wondering if it might be a little bit different here because of the uniqueness of the data. And I was just wondering if you could comment on kind of the outlook of sort of the inflection point with the incrementally [Technical Difficulty] the Farxiga label?

Thank you, Damien. Ruud, it's another question for you. In term of the ramp up, you could also talk about how we're doing so far with heart failure in the U.S. in cardiology in particular.

Absolutely. And thank you so much, Damien, for the question again. So first of all, regarding the pricing pressures. It's fair to say that we have seen substantial pricing pressure in the SGLT2 class in the last few years. But I think you are spot on that. That's with the current data set, we will do everything in order to ease that somewhat and are good reasons for payers, as we know, hospitalization for heart failure as well as kidney disease patients are very expensive patients. So I think we have very good arguments in our hands in order to ease the ongoing pricing pressure. Now more than that, and I think it was David mentioning that, there are several very substantial opportunity to really penetrate in the DPP-4 class that those products have had the utility. But clearly, with the outselling data now in heart failure and CKD, there are no good reasons anymore in order to start patients on a DPP-4. So the volume clearly will play a role there. Then the launch trajectory, we have launched DECLARE as well as DAPA-HF in the United States. And despite all the complexity because it's a virtual launch, at least for DAPA-HF, we're very pleased to see that the volume growth of Farxiga has really accelerated and we expect to continue to see that moving forward, clearly, with this data set as well. It's fair to say that there is a level of inertia as always, and especially among cardiologists. And therefore, we are working very hard together with executive committees around the world in order to get the data sooner than later in guidelines, local guidelines, but also in a couple of the very large guidelines. And we are very bullish about the success of that. So all in all, a very exciting moment for the product.

Thank you, Ruud. The next question is Emily Field at Barclays.

I just had a question on market sizing just because to your point, that with CKD, you can get to very large numbers very easily. Just sort of what would be the ideal stage to initiate treatment? And I would imagine that this is likely going to be specific to the pre-dialysis population? And then any sense in the clinical setting of what could be an average duration of treatment would be helpful.

Thank you, Emily. So Hiddo and David, single trial clinical questions for you.

David, you're first?

Yes. You want me to go first. So when to initiate treatment, I think we know from the DECLARE study that we had about 2 years ago that this drug also prevents the -- or also is protected in the early stages of kidney disease. That was a trial of diabetic patients. It prevented those patients developing the earlier signs of kidney disease and prevented those early signs of kidney disease progressing. I think if you treat too late, you're not going to fix the disease because the damage is done. So my own view is that the earlier we can treat the better, and of course, if you can hold patients off dialysis for longer, then you have a longer period during which patients are on treatment. So the general principle in managing chronic kidney disease is pick it up early, treat with drugs that show progression. The earlier you treat with those drugs, the more likely you are to prevent that patient needing dialysis in years to come.

I have nothing to add to this.

Okay. Very good. So the next question is Jo Walton at Credit Suisse. Jo go ahead.

Two quick questions then, please. The doctor on the ESC Q&A was asked about the mechanism of action for this in terms of all-cause mortality. And I believe you said that you thought 2/3 of the improvement in the mortality came from the CV side rather than the renal side. And I wonder if you could expand a bit on your comments that you made before, perhaps being an issue of infection? And secondly, I just wanted to ask a bit about European pricing. In the past, when you have drugs and you add them and you add new indications in Europe, you can get countries saying more patients, a lower price. Do you think there is a risk of a lower price for Farxiga in Europe, given the potential broadening of the indication?

Thank you, Jo. So the first question maybe should go to Hiddo and the second question to Ruud?

Yes, I can take the first question. There were -- patients in our population with type-2 diabetes and without type-2 diabetes often die because of cardiovascular cause. And in particular, patients with type 2-diabetes die because of cardiovascular cause. And infectious death is also frequently occurring in patients with chronic kidney disease. And we have to better understand the reasons and the effects on the different causes of death in our population, specifically in the nondiabetic population. And as we are doing future research in our dataset to first delineate the different causes of death in the diabetics and nondiabetics, who participated in the DAPA-CKD trial, and then we will assess the effect of dapagliflozin on these different causes of death. It's too early to answer in detail your question. Remember that we only finished the study and closed the database 4 weeks ago, and we have been extremely busy preparing the top line results. But this is a very important issue, which we will address in the months ahead of us.

Okay. And let me try to answer your second point, Jo, regarding the pricing in Europe. And in fact, we are aiming for the opposite. I think Farxiga, both in heart failure and now also in CKD, is an incredibly cost-efficient medicine, reducing the total cost of care quite substantially. Of course, we are not dreaming, but we firmly believe that as a minimum, we will maintain our price. But in some cases, we believe that at least there's a very good case in order to increase our price somewhat. If you compare our price with, for example, another important molecule in heart failure, ENTRESTO, our price is only a fraction of the ENTRESTO price in most of the countries. So I think our case and our market access teams are well equipped in order -- once again, as a minimum, to defend the price and where possible, to further increase the price somewhat.

Thank you, Ruud. So we have no more questions. We'll wait a minute or 2. [Operator Instructions] Otherwise, we will close this call if there is no more question in the next minute or 2. No, very good. Well, thank you so much, everybody. It was really good to have this Q&A in this discussion. I hope you appreciate the importance of this data that were presented to you today. They really will transform, we believe, the care of those patients with kidney disease, just like it will transform the care of heart disease as well. So thank you for David, and thank you to -- for David and Hiddo for joining us, and I wish you a good rest of the day.