Good evening, and welcome to AstraZeneca's Meet the Management webinar, ESC 2025, for investors and analysts. Before I hand over to AstraZeneca, I'd like to read the Safe Harbor Statement. The company intends to utilize the Safe Harbor provisions of the United States Private Securities Litigation Reform Act of 1995. Participants on this call may make forward-looking statements with respect to the operations and financial performance of AstraZeneca. Although we believe our expectations are based on reasonable assumptions, by their very nature, forward-looking statements involve risks and uncertainties, and may be influenced by factors that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. Any forward-looking statements made on this call reflect the knowledge and information available at the time of this call. The company undertakes no obligation to update forward-looking statements. Please also carefully review the forward-looking statements disclaimer in the slide deck that accompanies this presentation and webcast. There will be an opportunity to ask questions after today's presentations. Please use the raise-a-hand feature to indicate you wish to ask a question at any time during the call. And with that, I'd now like to hand the conference over to EVP BioPharmaceuticals Business Unit, Ruud Dobber. Thank you so much, Operator, and good morning, afternoon, and evening, everyone. My name is Ruud Dobber. I'm the Executive Vice President of the BioPharmaceuticals business at AstraZeneca, and I would like to welcome you and thank you for joining us today to hear about our exciting advancements with baxdrostat at the 2025 European Society of Cardiology meeting here in Madrid, following yesterday's presentation of the Phase III BaxHTN trial. As always, the materials presented today will be published on the AstraZeneca Investor Relations website following this presentation. Next slide, please. Here are our usual forward-looking statements, which I encourage you to read. Next slide, please. Today, we will begin with prepared remarks regarding our broader ambitions and cardiovascular, renal, and metabolic strategy. Dr. Bryan Williams, Chair of Medicine at University College London and Principal Investigator for the BaxHTN trial, will then walk us through the exciting baxdrostat Phase III BaxHTN data in patients with uncontrolled or resistant hypertension, and finally, we will discuss the commercial potential of baxdrostat, as well as the potential opportunities with baxdrostat beyond hypertension. Following prepared remarks, we will then open the line for questions and answers. Next slide, please. Let's start with our ambition. Next slide, please. As many of you may recall, we presented our $80 billion risk-adjusted total revenue ambition at our Investor Day in May of last year. Since then, we have made significant progress towards this ambition with a high number of positive Phase III readouts, including baxdrostat, and we remain confident in our growth trajectory to 2030 and beyond. Looking ahead, we have several exciting readouts over the next six to 12 months across oncology, rare disease, and of course, BioPharmaceuticals, and we look forward to providing further updates as we continue to advance our pipeline. Next slide, please. Now, let me hand over to Sharon to discuss how AstraZeneca is well-positioned to address the vast unmet need across a range of cardiorenal and cardiometabolic diseases. Next slide, please, and over to you, Sharon. Thanks, Ruud. At AstraZeneca, we are uniquely positioned to address several of the key risk factors associated with cardiorenal and cardiometabolic diseases that contribute to leading causes of death globally. In these populations, a majority of patients often experience overlapping risk factors in multi-organ conditions, where a disease of one organ system often negatively amplifies another. This complexity and interconnection between risk factors and disease, as well as the growing burden of these conditions, highlights the need for innovative, novel, and combination therapies designed to target multiple risk factors and associated comorbidities. Next slide, please. Our ambition is to transform care across cardiorenal and cardiometabolic diseases that impact huge numbers of patients where large unmet need exists today and continues to grow, particularly in an aging population. To do this, we are pursuing landmark approaches and advancing a robust pipeline of novel mechanisms and combinations to drive the next wave of CVRM medicines and to deliver long-term growth. Next slide, please. Across our pipeline, we have seen positive Phase II data for larioprostat, our oral PCSK9 inhibitor, and have recently initiated three Phase III trials in dyslipidemia. We also see potential to combine this agent with other lipid-lowering therapies to more completely address dyslipidemia. In hypertension and beyond, a positive Phase III data from baxdrostat sets the foundation for baxdrostat as a monotherapy, but also gives us confidence in our combination approach with dapagliflozin, one of the three Phase III dapagliflozin combinations currently underway. In amyloidosis, we've already launched Wainua in ATTR polyneuropathy and have the potential to expand into the much larger ATTR cardiomyopathy population with both Wainua and our novel TTR depleter. Lastly, in weight management and diabetes, we are uniquely positioned to address both the causes and associated risk factors for those living with overweight or obesity and related comorbidities with novel mechanisms and combinations like our oral GLP-1 receptor agonist, AZD5004, to deliver sustainable weight loss and robust organ protection. Next slide, please. Moving now to baxdrostat. In an area where there has been very limited innovation for over two decades, despite the 1.3 billion patients impacted, hypertension remains one of the biggest drivers of morbidity and mortality globally, and approximately half of the patients with hypertension remain uncontrolled despite receiving multiple antihypertensive medicines. It's well known that excess levels of aldosterone are associated with hypertension and several cardiorenal diseases. Baxdrostat, a once-daily, highly selective, and potent aldosterone synthase inhibitor, blocks the aldosterone pathway and has demonstrated robust safety and efficacy in hard-to-control hypertension with no off-target hormonal effects and no clinically relevant drug-drug interactions. Given its efficacy at low doses, baxdrostat also allows the ability to be combined with other agents while maintaining efficacy against high blood pressure. Additionally, early morning hypertension is well documented to cause an increase in cardiac events, meaning that 24-hour control of blood pressure is especially important clinically. The long half-life of baxdrostat has the potential to deliver sustained systolic blood pressure control for a full 24 hours, which we aim to confirm with the Phase III Bax24 trial due to readout in the second half of 2025. With that, I'll turn over to Dr. Bryan Williams, the Chair of Medicine at University College London and Principal Investigator of the BaxHTN trial. Next slide. Thanks, Sharon. It's my pleasure to present these results, which I did yesterday at the Hot Line session at the ESC. So just by way of background, as we've heard, patients with uncontrolled and resistant hypertension are at very high risk of cardiovascular morbidity and mortality and adverse renal outcomes. And we've been doing work for years to try and demonstrate that aldosterone is a key driver of uncontrolled and resistant hypertension and hypertension-mediated organ damage. Now, mineralocorticoid receptor antagonists that block receptor-mediated effects of aldosterone are available, but their clinical utility has been limited by dose-dependent adverse effects. And it's always been an ambition to develop a drug that will selectively inhibit aldosterone synthase and therefore limit the production of aldosterone, and that is what baxdrostat is designed to do. It's a highly selective aldosterone synthase inhibitor. This Phase III trial assessed the efficacy and safety of baxdrostat in patients with uncontrolled and resistant hypertension. Now, the trial had multiple parts, the last of which is still ongoing, to address really multiple key questions. After screening, the patients underwent a run-in for two weeks while staying on their background therapy, and then were randomized to placebo, baxdrostat one milligram or baxdrostat two milligrams for 12 weeks. This is the first double-blind period, and this forms the basis of the primary outcome. Thereafter, we re-randomized the patients, with the majority going on to baxdrostat two milligrams a day. This was to treat patients for a further 12 weeks in preparation for a randomized withdrawal period, which included all patients. The important thing about the randomized withdrawal period is this is a regulatory requirement for the approval of a drug by the FDA and other agencies. So this is when the patients underwent a second double-blind period with randomization, where they were either randomized to baxdrostat two milligrams or withdrawal of therapy and delivery of placebo. What I presented yesterday and will do today are the two randomized control periods of the trial, Parts one, the primary outcome, and Part three, the randomized withdrawal. Now, we included patients who are adults over the age of 18 with uncontrolled or resistant hypertension. They had to have a seated systolic blood pressure above 140 and less than 170 at screening, and they had to be treated with a maximum of maximally tolerated doses of two drugs to be defined as uncontrolled hypertension or three or more drugs to be defined as resistant hypertension, and these treatments must include a diuretic, and they were on those drugs for at least four weeks prior to screening. The eGFR was above 45, and the potassium was in the normal range. The key exclusion criteria was they couldn't be using mineralocorticoid receptor antagonists during the double-blind periods that I'll present, and at randomization, to ensure these patients were hypertensive, they had to have a seated systolic blood pressure greater than 135. The primary endpoint was the change in seated office systolic blood pressure from baseline to week 12, and we had 98% power, abundant power, to detect a difference, which we anticipated, of 6 millimeters of mercury from baseline. We had a series of secondary endpoints, including the randomized withdrawal. These were examined in hierarchical order, and all of the details of these are in the paper in the New England Journal of Medicine. We were also interested in looking at the effect on aldosterone itself, the circulating levels of aldosterone, and we also report a sub-study within the main study, the 24-hour and nighttime ambulatory blood pressures. Of course, we focused on safety endpoints, and we collected a lot of safety data in this trial. This is the first 12-week double-blind period. We screened just over 2,500 patients. We had 1,100 of these patients go into the run-in, and then at the end of the run-in, we randomized 796. Two of those patients never received drug, and therefore 794 comprised the full analysis set for this study. Of those patients, 27% had uncontrolled hypertension and 73% had resistant hypertension. 62% were male, 63% were white, 26% Asian, and 7% Black across the world. However, in the North American cohort, 36% were Black. The mean age was 61, and as you can see, we had really good representation across the worldwide sites. The clinical characteristics of all of these patients were similar at baseline. The baseline average blood pressure was 149 over 87, and the median number of drugs they were receiving was 3. Almost all, apart from just five patients, were actually on a background diuretic, 99.6%, and the rest of the treatments they were receiving were all guideline-directed therapies. 52% had obesity, 38% diabetes, and the baseline potassium and eGFR were shown there. So here's the primary outcome from baseline to week 12. I was really pleased as an investigator to see that the placebo effect was really quite modest, and this really indicates a very robust trial in which we've got very little or any turbulence in background therapy, and that enables us to isolate the true effect of the drug. And we can see we had a very substantial reduction in systolic blood pressure with baxdrostat one milligram and a bigger response, 15.7, with baxdrostat two milligrams. So when we placebo-correct the responses, it was 8.7 reduction for one milligram and 9.8 for two milligrams. These were highly significant and are clearly clinically meaningful reductions in blood pressure. We then went to look at the various subgroups, and we were really pleased to see that there was no evidence of any heterogeneity in response. This is consistent with our hypothesis that aldosterone is driving quite a lot of hypertension in both the uncontrolled and the resistant groups. As you can see here, there's really a good response in every single patient population. Now we turn to the randomized withdrawal. These patients had now been out to 24 weeks. Some of these patients had been on baxdrostat. At time zero at 24 weeks, the patients on two milligrams of baxdrostat now had a baseline systolic blood pressure of 133. That's 16 millimeters of mercury below where we started. Withdrawal of the drug over eight weeks on placebo led to only a very modest increase in blood pressure of 1.4 millimeters of mercury. Continuation of the drug, very interestingly, for another eight weeks, we saw a continuing further reduction in blood pressure of 3.7 millimeters of mercury. So there was, again, a highly statistical difference between these two groups. We are interested in the slow offset of effect of baxdrostat, which could have real clinical utility, and we're also interested in the fact that even out to 32 weeks, we may be seeing continuing blood pressure lowering. Baxdrostat predictably reduced serum circulating levels of aldosterone by 60% in those on one milligram and by 65% on two milligrams. By the time we got to week 24, the beginning of the withdrawal period, you can see that in those patients on baxdrostat at that stage, it remained suppressed out to 24 weeks, and then after withdrawal, there was a slight increase in the circulating aldosterone level, but it never returned to the baseline level by week 8, and you can see continued suppression out to week 32 on baxdrostat. Now, this is the ambulatory blood pressure sub-study. This is an exploratory analysis. It involved 59 patients. It was actually quite a reasonable number of patients for an ambulatory blood pressure study. And we look at the mean 24-hour and nighttime blood pressure differences. Now, the first thing to note is that there was very little effect of placebo on ambulatory blood pressure. Having done a lot of ambulatory blood pressure measurement studies, this is what we expect to see if there has been no turbulence in background therapy on placebo. I was surprised to see the magnitude of response here: 13.7 on one milligram, 16 on two milligrams. These are huge drops in ambulatory blood pressure, and the placebo-corrected differences are 14.6 and 16.9 for one and two milligrams, respectively. Now, the other thing that we're keen to do as clinicians is to make sure nighttime blood pressure is controlled because nighttime blood pressure is the most powerful and potent predictor of outcome. Again, I was pleased to see that with the long duration of baxdrostat, good 24-hour coverage and excellent reduction in nighttime blood pressure, placebo-corrected 11.7. Now to the safety data. The adverse events were mostly mild. There was one death in the placebo group by week 12. There were no reports of adrenal insufficiency, and the most common adverse events were somewhat predictable: hyperkalemia, hyponatremia, hypotension, muscle spasms, and dizziness, which we see in many blood pressure-lowering trials. But obviously, we were interested in potassium. And if we look at any adverse events leading to discontinuation, so these are clinicians making a decision in the trial that the potassium was at a level where they needed to consider discontinuing the drug, and reassuringly, this was very low. And secondly, we're interested in significant hyperkalemia above 6, and you can see that the confirmed hyperkalemia levels above 6 were low at 1%. So this is very reassuring data about the tolerability and safety of the drug. In summary, in participants with uncontrolled or resistant hypertension, the addition of baxdrostat one milligram or two milligrams once daily to their background therapy, so all of these patients were still on the background therapy they were on when they entered the trial, led to placebo-adjusted reductions of 8.7 with one milligram and 9.8 with two milligrams after 12 weeks' treatment. We saw that the blood pressure responses were remarkably consistent across all pre-specified groups, which was good to see. This means the drug will basically everybody will respond. And the efficacy of baxdrostat persisted for up to 32 weeks. Ambulatory and nighttime blood pressures were reduced very substantially, and we are actually conducting in parallel the Bax24 study, which has over 200 patients with a similar design to this, which is completed, and we'll get data readout in the next few weeks, and we hope to present the results of that at a conference later this year. Baxdrostat was generally well tolerated, and there were no unanticipated safety findings, and the rates of confirmed serum potassium above 6 were low and 1% in both baxdrostat groups. So we concluded that the hypertension trial demonstrated the efficacy and safety of baxdrostat for reducing blood pressure in a broad population of patients with uncontrolled and resistant hypertension. Thank you, Dr. Williams. So as we've seen, baxdrostat is a potential first-in-class and best-in-class aldosterone inhibitor that addresses hard-to-control hypertension. In BaxHTN, baxdrostat demonstrated the largest magnitude of mmHg reduction reported in a primary analysis to date and reduced plasma aldosterone between 60% and 65%. We are also greatly encouraged by baxdrostat's favorable tolerability profile given no off-target hormonal effects or clinically relevant drug-drug interactions. Lastly, we look forward to the results from additional analyses that support the benefit of baxdrostat's long half-life for potential 24-hour control. We have already seen encouraging exploratory data from BaxHTN on ambulatory 24-hour and nighttime systolic blood pressure and anticipate the results from the Bax24 trial to further confirm the benefit of baxdrostat's long half-life. With that, I will now hand over to Ruud to discuss the commercial potential of baxdrostat. Thank you. Thank you, Sharon. As a broad-based and geographically diverse company, we have the ability to reach a significant number of patients globally with baxdrostat in hard-to-control hypertension, leveraging our existing foundation in primary and specialty care in the United States and maximizing our broad and diverse footprint in markets outside of the U.S. In the United States, it's estimated that over 20 million of those treated with two or more antihypertensive medicines still do not remain at goal. Of these patients, over 85% are managed by primary care physicians and cardiologists. Our well-established CVRM teams already have the potential to reach the majority of these primary care physicians and over 60% of these cardiologists. Beyond the United States, more than 75 million patients have uncontrolled hypertension in the EU-5, China, and Japan, despite receiving at least two antihypertensive medicines. With the strong foundation that we have built with Forxiga and Lokelma, now available in over 115 countries, we have the opportunity to utilize our global network to commercialize baxdrostat around the world. Our existing presence offers us a considerable competitive advantage, and we continue to invest strategically to support the launch of baxdrostat and other new potential medicines to drive growth through 2030 and beyond. Next slide, please, and back to you, Sharon. Okay, thanks, Ruud. As a monotherapy and in combination with other agents like dapagliflozin, baxdrostat represents a $5 billion+ opportunity. As a monotherapy, we've seen the robust effect that baxdrostat has in hard-to-control hypertension with BaxHTN, and we've spoken to the importance of Bax24 to demonstrate 24-hour control in resistant hypertension. To further address aldosterone-driven diseases, we're also initiating the Phase III BaxPA trial in primary aldosteronism, a major but underdiagnosed driver of treatment-resistant hypertension, which leaves patients at increased risk of heart disease, stroke, and kidney disease. In combination with dapagliflozin, three Phase III trials are ongoing to evaluate the effect of baxdrostat and dapagliflozin in chronic kidney disease and hypertension, evaluating eGFR slope as well as outcomes, and in heart failure, prevention to demonstrate baxdrostat's benefit on top of established standard of care. These trials are progressing at pace, and we look forward to data beyond 2026. With baxdrostat, our ambition is clear: to build a franchise beyond hypertension, establishing aldosterone dysregulation as a cardiorenal risk factor to be addressed across a spectrum of cardiorenal disease. Next slide, please. So now let's move to the Q&A. We have a lot to talk about with baxdrostat, so let's try to keep questions focused on this program or on our broader CVRM portfolio. Dr. Williams will join us until the top of the hour, and I'd also like to welcome our CEO, Pascal Soriot, to the Q&A. So to ask a question, please use the raise-the-hand function in Zoom. And our first question will come from Gonzalo Artiach at Danske Bank. Hello, good evening. Can you hear me? Yes. Okay, I will start with my first one. It's on the commercial potential for both uncontrolled as well as for treatment-resistant hypertension in your view. So in your studies, 75% of the patients that were enrolled were treatment-resistant, and I was wondering, how do you guys see the future commercial dynamics of both patient groups? Can we expect that doctors will first aim for treatment-resistant hypertension patients with this opportunity expanding to uncontrolled patients later on? And my second question, I would like to also hear your view on the overall treatment-resistant and uncontrolled hypertension market. And obviously, there is a huge need for new therapies, and proof of that is that you guys are not the only ones trying to enter this big market. So I was wondering if you could give us some color on how you see the market in the near term, but also in a five-year horizon, given the potential entry of at least a couple of new drugs in the space apart from yours. And more in detail, I guess that the market is focused on the comparison with Mineralys data. Critics will focus on this 12-week data comparison versus lorundrostat, despite Mineralys data being just exploratory. So how should we compare these two studies to make a fair comparison? Thank you very much. Okay, so we'll start with some answers from our commercial experts, Ruud Dobber and Mina Makar, and then to discuss the comparison with the recently released lorundrostat data, I'll hand that over to Dr. Williams. Yeah, thank you so much, Gonzalo, for the great questions. It's fair to say that we are expecting, in first instance, quite a good uptake in the resistant population. Of course, that population is smaller than the large group of uncontrolled patients, but there's a clear medical need in both groups. But our expectation internally is clearly that we will see a faster penetration. And over time, when physicians feel comfortable, of course, with the use of the drug, we expect very strong use also in the so-called uncontrolled. As Dr. Williams alluded to, the drug is very good across all the subpopulations. So I think it's a matter of building confidence. As Sharon mentioned, there's a high medical need across the world in those hard-to-control patients. So yeah, we are very optimistic that both patient groups will benefit from the advantages of baxdrostat. Mina, anything to add? Yeah, just a couple of quick things. The timing of this data and the filing, etc., lines very nicely with the update to the guidelines now that we're seeing across the world becoming much more aggressive around targets in the treatment of blood pressure, the use of as many medicines as possible to get patients to goal. So we think the guidelines will very much align with the message that we'll be taking to the market. Already in our discussions with cardiologists and primary care, we know that they're going to try first, as Ruud said, in the resistant, but very quickly move to the uncontrolled, which is why we designed a study that included both populations. So I think we'll be very ready to move into both populations right away, but we expect the uptake first in the resistant and then with time in the uncontrolled. And then, Dr. Williams, your thoughts on the six-week readout? I think we're going to compare someday to the inevitable discussion about that. But my comment would be that when we do these trials, they're never directly comparable in terms of the way they're conducted. And the thing that was interesting about the Mineralys studies is their primary outcome was at six weeks. Our primary outcome was at 12 weeks. But the overall conclusion I would draw is that they're broadly comparable in terms of the blood pressure reduction in the doctor's office, and the safety profiles look broadly comparable as well, and that wouldn't surprise me. The one difference which doesn't come out in the trials, but almost certainly would be relevant in clinical practice, is the duration of action of the drugs. As somebody who treats hypertension, I'm always keen to make sure that the drugs I use give good coverage over 24 hours because the control of 24-hour blood pressure is the most powerful predictor of risk, and it's also nighttime blood pressure, which you want to get control. Most patients take their drugs in the morning. You don't want that drug wearing off at the time in the night when the blood pressure is actually very powerfully predictive of risk. So I think that's the main difference when I've looked at the drugs. There is one other difference that I hadn't fully appreciated until recently, and that is the acidity of the gut has an impact on the absorption of Mineralys, and therefore there is a requirement for those patients to limit their use of proton pump inhibitors. And I would see that as a bit of an issue as a clinician because many of my patients are on proton pump inhibitors, particularly patients who are taking antiplatelet therapies because they have increased cardiovascular risk or patients with renal disease or bleeding risk. So there are some differences between the molecules that don't necessarily play out in the blood pressure response that we've seen in the trials, but could play out clinically in terms of duration of action and this issue around the absorption of the drug. With gastric acidity, we know that baxdrostat isn't influenced by the acidity of the gut. Okay, our next question, Peter Welford from Exane. Yeah, thanks. Peter Welford here from BNP Exane. Three quick ones, maybe for Dr. Williams. Thank you for your time. A bit cheeky, but is there anything worth noting on part two of the study? I know it's not being presented at ESC, but I'm trying my luck here. Anything worth mentioning there? And then the second one for you, Dr. Williams. One or two mgs. Do you think you need the option of both, or is one mg enough going forward when you think about using it in clinical reality? And then for the company, the New England Journal of Medicine, as Sharon was talking about, investigating the durability of efficacy with longer-term studies. Maybe this is a little bit too early, but again, trying my luck here. Are you planning to add any additional clinical programs to the Phase III program for baxdrostat to fur ther investigate this? Thank you. Yeah, maybe. I mean, the issue you raised about the part two. Part two was the open label phase where we put patients onto baxdrostat two milligrams for 12 weeks to prepare them for the randomized withdrawal. The bit of data that I did comment on was that at the end of that period, so you've now got many of the patients who will have been on baxdrostat for 24 weeks, the baseline blood pressure going into the randomized withdrawal was 133, and they started at 149. So that's a 16 mm Hg difference from baseline. During the randomized withdrawal period, we have a standard of care comparator, which is really important because in that long-term follow-up, up to 52 weeks, we have some periods which are double-blind and placebo-controlled and other periods where it's open label where we're looking at long-term safety principally, but we have included in the trial design, which I think is important, a standard of care arm so that we can compare safety across to usual care in those open label periods, and I don't think we had time in the discussion yesterday to emphasize just how important that is, so by the time we finish this study, we will have 52-week data on the durability of the effect, and we've now gone out to 32 weeks already, and we presented some of that, and we'll also have safety data after 52 weeks. So that will be really powerful information, and I hope that will be reassuring. Peter, I'll take the second question, which was about one mg versus two mg of Bax. And first, I'll say, if we look at the data, we're viewing the mean, but in fact, there is varying response among the patients who are treated with both one and two mg. And so some of those patients on two mg receive substantially better lowering of their mercury. And the second is that physicians appreciate optionality and the ability to be able to choose the right therapy for their patients, given the polypharmacy that their patients are currently taking. So we see value in having both one mg and two mg available. Yeah, I could add, Sharon, I think it would be a mistake just to develop the one milligram because we've only studied a certain group of patients. There will be others that have got higher levels of aldosterone circulating that would need more drug, and the last thing we want to do is have to get two pills instead of one. I think the other thing to emphasize is that when we designed the study, we weren't powered to actually do a direct statistical comparison between the two doses over 12 weeks. But the thing that strikes me, and I would emphasize as a clinical trialist that I don't want to put too much store on this, but if you look at the 24-hour data exploratory, it would be very interesting when we get the data on 24-hour blood pressure overall to look at that comparison between one and two milligrams because I expect we might see more of a difference than we saw in the office blood pressure at 12 weeks. Our next question is from Steve Scala at Cowen. Thank you very much. I have two questions. First, nearly 1,500 patients were screened but not enrolled in the trial. What were the most frequent reasons for failure to enroll? I'm curious how often those characteristics are seen in the general population. And then secondly, AstraZeneca's guidance is for $5 billion+ peak sales potential for baxdrostat. What is AstraZeneca's estimate for the market overall, the aldosterone synthase inhibitor market overall? So I'm curious, ultimately, what share AstraZeneca thinks it will get of this market with baxdrostat? Thank you. It's a really good question about the screen failure rate, and that's always a very frustrating aspect of any clinical trial. The reason it happens in most cases, as in this trial, is that we call these people up who've got a diagnosis of hypertension. They're supposed to be on a certain number of drugs. When they turn up at the clinical investigation unit and get their blood pressure measured in a very robust and accurate way, quite often they don't meet the entry criteria. Their blood pressure's actually better than they have it measured in a more haphazard way, quite often in the clinical setting, and secondly, patients sometimes turn up and haven't quite appreciated the entry requirements for the study in terms of being on two drugs or three drugs and being on a diuretic as part of that therapy, so they were the sort of reasons we have screen failures. I was quite pleased, actually, that the screen failure rate was quite low compared to what you see in some trials. We then had about 300 patients who didn't get randomized because once you put them into the placebo-controlled running, again, you're measuring blood pressure repeatedly under very standardized conditions. Some of those patients do not meet the criteria for randomization, which was a blood pressure above 135. So none of that was surprising to us. I mean, that was kind of what we modeled and anticipated. I think it's essential that you do it in a robust way like this. Otherwise, you start including patients whose blood pressure is not actually elevated, and then it becomes very difficult to begin to tease out the effects of a drug. Yes, thank you. Thank you so much, Steve. Regarding the commercial opportunity, and I will also ask Mina to give a little bit of his thoughts about it. First of all, internally, we firmly believe that this will be a $5 billion+ opportunity, and it's roughly a 50-50 split between the monocomponent and the fixed-dose combinations we are developing. As Sharon has mentioned, we have a large Phase III program ongoing, two studies in CKD and one study in the prevention of heart failure. Of course, those studies need to read out positively, but assuming that it will be the case, we truly believe that this product will be a $5 billion product for the company. Equally, of course, this market will be very substantial, and we are clearly aiming for market leadership. Mina, is there anything else you would like to add? Yeah, I mean, just that our assumption going in and our expectations is to absolutely be leaders in this market. We think it's a market that will grow significantly with time as new innovations are coming into it and guidelines are becoming more ambitious in terms of the expectations. The data that have played out now give us even more confidence that this is a molecule in our hands and with our commercial capabilities in cardiology and primary care and nephrology that we absolutely can make a success with it. Thanks, Mina. Okay, next question. Sachin Jain from Bank of America. Hi, there. Thanks for taking my questions. Just commercial questions. So perhaps for Dr. Williams, if you could just put this data in the context of resistant treatment practice. You said MRAs are limited by dose-dependent safety. Perhaps you could give a sense of how the 1% confirmed hyperkalemia seen in this study favors relative to spironolactone and then how problematic the side effects of existing MRAs are. What I'm trying to get a sense of is, in your clinical practice, what percentage of your resistant hypertension patients are on spironolactone and what percentage, with this Bax data, that could expand to? And is there any specific subgroups you would use each product in? And then the second question, I guess, for Ruud or Mina is a follow-up from Steve. So the peak sales of $2-$3 billion for the monotherapy seems to reflect a fairly low penetration in 100 million patients. I'm just trying to get a sense of what commercial challenges you potentially foresee in penetrating this market, I guess, linked to the question that I posted to Dr. Williams. And is safety differentiation versus your MRA enough for reimbursement? Any early payer feedback you've had? Thank you. So maybe it's Bryan Williams here. Maybe I'll take the first bit. So interestingly, I did the trial that established spironolactone as the preferred therapy at the present time for people with resistant hypertension because I'd always long held the view that aldosterone was the right target for these patients. And I think it's actually the target for even a broader group of patients, but maybe we can get to that. But so we did that trial. I've been disappointed by the uptake of spironolactone subsequent to that. And the main reason is that, and I use it a lot in my clinic because at University College Hospital in London, I run a specialist clinic where I see a lot of the patients whose GPs are struggling to control blood pressure. And I use spironolactone, and quite a significant proportion of my patients aren't able to stay on it. And it's not because of potassium issues, usually. It's more due to the fact that spironolactone has some off-target effects. So in men, it can give rise to gynecomastia. In women, it can give rise to menstrual issues or what have you. So it hasn't been as popular with doctors as the efficacy of it would justify. And it's largely related to the side effect profile. So I'm very excited about the fact that we'll have a cleaner drug that will come online, hopefully, that will enable us to get the same efficacy or even greater efficacy potentially, but without those troubling effects which have limited the use of spironolactone. There are other mineralocorticoid receptor antagonists. Eplerenone is one of them. It is substantially weaker as a drug, and I rarely ever use it anymore. It doesn't hit the mark in terms of treatment. The new mineralocorticoid receptor antagonists that have been developed outside Japan are not licensed for the treatment of hypertension. So there is a real need for a clean drug that will treat resistant and difficult-to-control hypertension. And that's why I was so excited about this study. Thank you so much, Dr. Williams. So Sachin, I think overall, there are always challenges with every product launch, but I think there are two specifically where we are working on. First of all, most of those hard-to-control patients are in the office of the GP. So it requires, of course, identification at the GP level, and we need to make sure that there's a mechanism in place, certainly for the resistant hypertensive patients, in order to get referred to specialists, cardiologists, internal medicine physicians. So that's one. And the other one is also always an obvious one. This is a patient population, at least in the United States as well, which will have an age over 50, 60 years, and that means that getting access in Part D is always a challenge, certainly currently in the current environment in the United States, but equally, of course, we have done already a lot of payer research. We're not aiming for a first-line treatment for obvious reasons, and based on the feedback we are getting from payers, is that they have a very open mindset in order to include the product when it is approved and available in the market, so those are the two major challenges I see in order to commercialize the pro duct. Okay, next question. Simon Baker, Redburn. Thank you for taking my questions. Two, if I may, please. Really just continuing on Sachin's question in terms of targeting. I just wonder if you could give us any more granularity on targeting within resistant hypertension. And really, this is a question for all of you and Dr. Williams, both from the perspective of the patient that would be amenable as an early adopter of baxdrostat, but also in terms of the prescriber. Should we think of this initially as a sort of secondary care specialty area before moving into the primary care setting? And then a second question. Within the New England Journal paper, looking at the subgroup analysis, it appears that patients with a higher BMI responded better. I just wondered if you had any thoughts on why that might be. Thanks so much. Maybe quickly, the second bit first. I mean, patients who are obese do tend to have higher aldosterone levels, but I wouldn't read too much into picking out a single group within a subgroup analysis like that. What we do is, as you may be aware, we test for heterogeneity. And basically, it was very robustly non-heterogeneous. In other words, everybody seemed to respond equivalently. But I think it's an interesting concept. And irrespective of whether it looked like they responded better, we know that obese patients generally respond well to drugs that block aldosterone. So I would imagine this drug would be used in that population because many of them have resistant hypertension. In terms of who will prescribe, like all new drugs, initially, experience will be gained by the more enlightened specialist-type groups. But ultimately, payers, in my experience, are quite keen to get hypertension managed in the primary care community. We will have to make sure that the primary care community are comfortable with this and also provide the necessary education to support implementation. But I would say this, that doctors are well used to monitoring things like potassium and doing the sort of things that you would do with a drug like this from using ACE inhibitors and ARBs in the primary care setting. So I don't see it as a massive challenge. Yeah, the only thing I would like to add, Simon, that if you look at products like Forxiga, we have a long history, of course, in order to market products both at the general practitioner level and specialist level. So this is not new for us. I I think we have, across the world, excellent teams who know how to do that. I think it's one of the key strengths of our overall commercial capabilities in order to make that happen. Okay, let's go to Sarita Kapila at Morgan Stanley. Hi, thanks for taking my questions. From a clinical perspective, how should we think about the combination potential for Bax with Farxiga for CKD and hypertension? How meaningful or practice-changing do you think the combination can be beyond just addressing the pill burden? And then just a quick one on BaxHTN and hyponatremia. The rates of hyponatremia below 132, I believe, were somewhere between 6%-8% for Bax. How much of a concern is this, and how difficult do you think this is to manage? Thank you. All right, Sarita. So your first question, it was about baxdrostat and Farxiga and the potential there. And I would suggest that the best person to really speak to our broad program would be Mikhail Kosiborod, who's heading late development for cardiovascular, renal, and metabolic disease. And regarding hyponatremia, Dr. Williams, you've had quite a bit to say about this over the last few days, so I'll ask you to take that question. So I will start. Again, thanks for the question. I think the critical thing to keep in mind when you talk about organ protection, for example, in conditions like CKD, heart failure, and truly cardiometabolic disease in general, is that these are common conditions that have multiple risk drivers. And our approach at AstraZeneca for putting together combination therapies actually goes way beyond convenience and focuses on addressing multiple key drivers of the cardiometabolic and cardiorenal disease to really maximize organ protection and outcome benefits. And a perfect example of that is a combination of aldosterone synthase inhibition and SGLT2 inhibition, which we believe may be highly efficacious in reversing the potential deleterious effects of these mechanisms and delaying the progression of kidney disease as well as preventing heart failure. And of course, we are conducting, as mentioned previously by Sharon, a very robust program that includes two Phase III kidney trials, Arctic with eGFR slope as a primary endpoint, and Pacific with kidney outcomes as a primary endpoint, and also a very large outcome trial to prevent heart failure, actually the first large adequately powered clinical trial to specifically address prevention of heart failure as a primary hypothesis. And Mikhail, I think it's fair to say that there is no company that has the diverse and deep portfolio that AstraZeneca has that sets us up to create these mechanistic combinations to really treat the interconnectedness of cardiorenal and cardiometabolic disease. Dr. Williams, do you want to speak to hyponatremia? Yeah, I mean, interestingly, and it's a really good question because hyponatremia quite often doesn't get much attention. I'm never really concerned in my clinical practice if sodium stays above 130. And you've got to remember in this study, patients were receiving background thiazide diuretic, which is one of the factors that drives down sodium. And then on top of that, they've got the aldosterone synthase inhibitor. So we anticipated a reduction in sodium in these patients. The thing that reassures me, and I think it's consistent with my clinical experience of acting on low sodium levels, is that there were very few interventions by clinicians in the trial to actually withdraw drug because of hyponatremia, and that's because they didn't see it as a significant clinical issue, but obviously, with the longer-term follow-up, we'll continue to monitor this, but at the moment, I'm quite reassured by the fact that there was a low need for any clinician-directed intervention in these patients. Okay, to make the most of Dr. Williams' time, if we could please each limit ourselves to one question. Let's go next to Christopher Uhde with SEB. You may be on mute. All right, we'll go to the next caller, and we'll come back to you, Christopher. Okay, Emmanuel Papadakis with Morgan Stanley. Thanks very much, Emmanuel at Deutsche Bank, not Morgan Stanley yet. Thanks for taking the question. Perhaps a question for Dr. Williams on thinking through the potential clinical differences with lorundrostat. Particularly interested if the 24-hour duration of action for baxdrostat doesn't reall y manifest in. Emmanuel, I'm afraid we've lost your audio. Yeah, someone muted me. It may have been intentional, but I'll try and speed up. The question was if a 24-hour duration of action doesn't really manifest any notable difference in risk-benefit and Phase IIIs for baxdrostat versus lorundrostat with the blood pressure endpoint, would you expect that to ultimately become visible in outcomes data, for example, on a MACE endpoint? And what magnitude of difference do you think that might drive? And perhaps the company could just remind us if or when we might expect to see such data. Thank you. So it's a really important question. Look, I think in a 12-week study where we've only got office blood pressure predominantly so far, I wouldn't have expected to see too much yet, but we are going to have the ambulatory data in the not-too-distant future, and I couldn't emphasize enough how important it is to see nocturnal pressure controlled, and it'll be very interesting to see that data in comparison with the available ambulatory data from lorundrostat, so I think we should wait for that, but as a general principle, Emmanuel, when we talk about treating hypertension, one of the things we talk about is making sure that we give drugs that can be given once a day and that provide good 24-hour coverage, and a 30-hour half-life for baxdrostat is certainly going to provide that, so I think that that is a potentially important differentiation. Emmanuel, you asked about the timing of outcomes. As you know, we don't guide beyond the coming year, so the outcome study is beyond 2026. But I'll take this moment to say that it is only two years post the CinCor acquisition. And so this study has truly moved forward at pace, and we are pursuing the entire Phase III hypertension and combination program with a sense of urgency. Next question is from Richard Vosser at JPMorg an. Thanks for taking my question. Question to Dr. Williams. You mentioned the newer MR antagonists, I suppose, finerenone. So how do you think the data from Bax would stack up versus finerenone in some of the outcome studies? I mean, they've shown good data in preserved ejection fraction, heart failure, and CKD. So just do you think Bax could be superior there? How do you think it will fit into that treatment paradigm? Thanks very much. I mean, there's a short answer and a long answer, but maybe the short one. But the short answer is that the expectation would be that you would get as good an effect, at least in terms by blocking the production of aldosterone. The teaser for the long answer is there are biological reasons why blocking aldosterone at its source, in other words, its synthesis, rather than at the receptor, could be potentially more beneficial because there are actions of aldosterone that occur through an ancillary receptor that will not be blocked by mineralocorticoid receptor antagonists. That's an interesting question. It's an interesting hypothesis, and it will also be one that is endlessly discussed at scientific meetings. My expectation would be that we will see the same kind of benefit in these outcome trials that are underway. Okay, our next caller, Colin White, UBS. Hi, Colin White, UBS here. I'd like to return to just the comparison with the MRAs, if I could. We've spoken to a couple of experts today about the efficacy of baxdrostat and BaxHTN and efficacy safety in terms of hyperkalemia. They thought it looked broadly similar to what they get with MRAs. They thought that it was likely that payers would insist patients step through an MRA in treatment-resistant hypertension before trying something like baxdrostat. Do you think this is likely how payers will deal with ASIs? Is there data on effects on hormones or other data that you believe would further differentiate baxdrostat versus spironolactone or eplerenone? When would that be presented? Okay, we're going to start with Mina discussing the opportunity. Yeah, thanks for the question. I mean, as you can imagine, we've done a lot of conversations and had a lot of discussions and research with payers, and what they tell us is very clear. If you are targeting the resistant and uncontrolled population, meaning your third line or fourth line in therapy, these are very expensive patients for us. These are the patients that have strokes. These are the patients that have heart attacks that move on to heart failure. It's a smaller population than the broad hypertension. We get it. We understand the challenge of treating those patients, and while, of course, there's always questions around payer access and so forth, they get it, and they understand the clear unmet need. I believe with the updated guidelines as well that make the numbers even more, the target of 130 and down to even 120 in many patients will increase that urgency and that need. So I think, as always, there's always challenges with payers, but I think the profile of this medicine and the target patient we have give us a really good opportunity to provide access for patients. And regarding the tolerability profile relative to MRAs, Mikhail, would you like to comment? Yeah, thank you, Sharon. So first, Dr. Williams already mentioned, and he conducted the spironolactone hypertension trials, as he said, that spironolactone is poorly tolerated quite commonly by patients, predominantly because of sexual side effects, which is why we need additional therapies in this difficult-to-treat patient population. The efficacy comparisons are inherently difficult, in large part, not only because of cross-trial comparisons, but remember that spironolactone trials, of course, were done in a completely different era, where the standard of care was not what it is today. The last thing I will say is we have no outcome data for spironolactone either in heart failure prevention nor in delaying the progression of chronic kidney disease. And we already mentioned the outcome trial programs that we are running with a combination of baxdrostat and dapagliflozin. And finally, Mikhail, I think it's fair to say that we had a very low discontinuation rate on this study, which really speaks to the safety and tolerability profile of baxdrostat. Christopher Uhde, we dropped you before. Let's try this again. Thanks very much for giving me a second try. I hope it's working. But yeah, so would it make sense to try to show efficacy in absence of a diuretic given the patients find it a pain to be on diuretics? I mean, for example, when they have errands to run. And then in the cardiorenal space, drugs are typically very slow to penetrate the market. But we saw that Farxiga, which was priced well below typical specialty care meds, did really well in heart failure and CKD, and maybe it wasn't a bad thing for peak sales. So could you comment on whether you could consider a similar pricing strategy or why you might rule it out? Thank you. Maybe I'll take the diuretic thing first, Christo. I mean, the patients have to be on diuretic if they're a resistant population because that's part of the standard of care for somebody who's on a diuretic, who's got resistant hypertension, on three drugs, one of which must be a diuretic. So that was inevitable. In the uncontrolled population, you're right, there will be patients who might be on two drugs out there in the community who are not on diuretic. And it's an interesting question as to how well this drug would perform in those types of patients. My expectation is it would still have a significant effect because it's blocking a fundamental mechanism that's driving hypertension. And the percentage of patients who are at risk of that mechanism gets progressively greater as their blood pressure becomes more difficult to control. So I think this drug could be used in the absence of a diuretic. I don't see a problem with that. But in people with resistant hypertension, where it will probably initially come in, they will all be on diuretic because that will be mandated as part of standard of care. Yeah, and let me quickly comment on the challenge or the question about the pricing. First of all, I think the success of Farxiga is primarily driven by the overwhelming scientific evidence, the cardiorenal protective events of this agent. And of course, we have a clear ambition to have a well-established package also for baxdrostat moving forward, both in the mono component, as we have discussed, as well as in the combination. We're not going to comment specifically about the pricing aspects because I don't think that's appropriate. But of course, we will price it in order to represent the clinical value we think baxdrostat will have for the medical community and healthcare systems. If I could ask you once more, please, one question per caller. Ben Jackson Jefferies, you're next. Brilliant. Thank you for the question. So I'm just wondering if there's any more color you can add on the observed dose response in the data or perhaps the lack thereof, if you could argue that on two points. So how important is this that you've seen for the trials, specifically those in patients with chronic kidney disease who perhaps are slightly more sensitive to electrolyte abnormalities and things like that? Is that something that you need to consider when looking forward to the trials and other indications? Thank you. So Mikhail, I'll invite you to share your thoughts on one mg versus two mgs and the results th at we saw. Right. So the important thing to keep in mind is, first of all, as Sharon already mentioned, these are main effects across populations. There is variability in patient response. Number two is when it comes to blood pressure control, every millimeter of mercury matters. And we know that, of course, from a really extensive body of data that shows that further efficacy in terms of blood pressure reduction ultimately translates into organ protection. And then finally, the clinicians like flexibility of dosing and being able to pick the right dose for the right patient. And we really believe that this flexibility will be offered by one and two milligrams. I would say it's further reinforced by exploratory data from the 24-hour ABPM analysis that were done in BaxHTN, where we also see a difference between one an d two milligrams. Thank you. Our final question from Rajan Sharma, Goldman Sachs. Hi, thanks for taking my question. It was just actually some housekeeping on filing timelines. Do you need to wait for, or do you expect to wait for the Bax24 data before you do file? And what is your base case for launch of the drug? Are you confident that you will be on the market potentially before lorundrostat? Thank you. Yeah, let me quickly address that question. What we have said is that we are aiming for filing before the end of the year. Then depending, of course, on the regulatory interactions, we hope to launch the product in the course of 2026 in the U.S. market. So with that, I'd like to end our Q&A period. Pascal, I'd like to invite you to offer your final thoughts. Thank you, Sharon. It's really a pleasure to be here. First of all, I would like to thank Dr. Williams for his amazing leadership of this study as a principal investigator, really a beautifully conducted study. Also want to thank our AZ team for a great job done. As a company, as you know, we have focused for many years on the biggest killers in the world: cancer, of course, cardiovascular, cardiometabolic disease, respiratory disease. I'm really delighted that we are back in cardiovascular disease. We've really worked hard for quite a while to rebuild the pipeline and the portfolio of products we have. As you know, baxdrostat leads the way, but we have other agents in the cardiometabolic space. I'm excited because I've long been a believer that hypertension is an unmet need, despite what many people thought for a long time. I've also been a long-time believer of the aldosterone antagonism and in particular also the link to insulin resistance. That really fits very, very well with our overall portfolio addressing obesity, dyslipidemia, diabetes, and of course, now hypertension. I'd just like to say a few words about baxdrostat itself because we compare the blood pressure reduction to the competition. I think it's important to look at the totality of evidence. The totality of evidence is, number one, a good efficacy in terms of blood pressure reduction. The second thing is that, as Ruud said before, the 24-hour blood pressure control, in particular the blood pressure control overnight and in the early morning, which is really an important aspect, the good tolerability, the lack of drug interaction. I'd also like to add something that hasn't been discussed a lot today, actually, is the reduction of aldosterone. Dr. Williams showed us a 60% reduction of aldosterone. Beyond the effect on blood pressure, aldosterone has deleterious effects across the body: endothelial dysfunction, fibrosis, also promotes adipose activity, as some studies have shown. A lot of work will have to be done, of course, to support the effect of the drug in these aspects. It's the excitement that will come with this medicine, exploring so many additional benefits. There was a discussion on MRAs, but you need to remember that very often with MRAs, aldosterone production increases. And as Dr. Williams said, aldosterone can have effect beyond the aldosterone receptor. So blocking the aldosterone receptor is not sufficient to block the deleterious effect of aldosterone on a variety of organs and tissues. And of course, all of this will have to be supported. All these aspects will have to be supported with new work, but certainly a very exciting product to work on in the next few years. And I would also say that we have the perfect organization to maximize the potential of this medicine for patients. First of all, our global presence, you know that our focus is to bring our mission is to bring our medicines to as many patients as possible across the world. And that's why we have built a tremendous geographical footprint around the world for many years now. And I'm sure you remember that Farxiga sales are more than 70% outside of the United States. That gives you a good sense of what you can achieve with a large global footprint. And I think we can do the same with baxdrostat. We have a presence in, of course, GP office, but also cardiology, dermatology, nephrology. So we have really good coverage of not only the GP, but also the specialist. And finally, we have the portfolio that we'll bring to physicians together with baxdrostat, and that will strengthen our presence in the field and, of course, benefit baxdrostat. And finally, I have to say we will continue to invest in this very exciting medicine. So all in all, really many good reasons to believe this agent can be a $5 billion + product for us for all the reasons I've listed, and a very exciting product to continue working on and developing new data for, so with this, I would like to thank you very much for joining us, and I look forward to talking about this agent more with you in the next few months. Thank you.