Good day and thank you for standing by. Welcome to the aprocitentan late-breaking science session at AHA and webcast. At this time, all participants are in listen-only mode. After speaker's presentation, there will be a question and answer session. To ask a question during this session, you'll need to slowly press star one and then one on your telephone. You will then hear an automated message advising your hand is raised. If you wish to ask a question via the webcast, please use the Q&A box available on the webcast link at any time during the conference. Please note that today's conference is being recorded. I would now like to hand over to your first speaker, Mr. Andrew Weiss, Head of Investor Relations and Corporate Communications. Please go ahead, sir. Thank you, Emily. Good morning, good afternoon to everyone. My name is Andrew Weiss. I'm the Head of Investor Relations here at Idorsia, and I want to welcome everyone to this webcast and conference call to discuss the publication of the results of PRECISION, our phase III study of aprocitentan for patients with difficult -to -control or so-called resistant hypertension, which were shared yesterday. With me on the call here in Chicago are our Chief Scientific Officer, Martine Clozel. I'm very happy to say that we have Professor Markus Schlaich of The University of Western Australia, Royal Perth Hospital, who was an investigator of the PRECISION study and who presented the data in the late-breaking session here in Chicago at the American Heart Association meeting. He is also the Lead Author on the primary manuscript published last night in The Lancet. Thank you very much, Markus, for agreeing to present to our investors and analysts. This is very much appreciated from you. Also, when we open the floor to questions, we have Parisa Danaietash, our Expert Clinical Project Scientist, who has worked on the PRECISION study. She is a lead author on the manuscript published in the Journal of Clinical Hypertension, which presented the study design earlier this year, and she's also co-author of the aforementioned The Lancet publication. Next slide. As customary, before handing over the microphone, I need to remind everyone that we will be making forward-looking statements. You have therefore been appropriately warned about the risks and opportunities of investing in Idorsia shares. With that, I hand over to Martine. Next slide. Thank you, Andrew, and good morning, good afternoon to everyone. Thank you for joining the call today. I am delighted we are able to share the data from PRECISION released simultaneously yesterday, both in a late-breaking science presentation at the American Heart Association meeting and in the primary manuscript. Next slide. The simultaneous publication is a real testimony to the importance of this compound and that exemplified largely at the AHA meeting of the enormous remaining medical need in hypertension. To our recognition for all investigators and the patients who participated in the trial. Next slide. Over the last 30 years, we have tried through our research to advance the therapeutic applications which could be related to the endothelial system and its role in certain pathologies. From this long research, several drugs have been discovered and have already been registered. The dual endothelin receptor antagonist or ERA, Tracleer, in 2001, the dual ERA Opsumit in 2013, and PIVLAZ in 2022. Today we are presenting the phase III results of a new dual ERA and its efficacy in resistant hypertension. By itself, our research in hypertension has spanned all these 30 years. My first publication on endothelin in hypertension goes back to November 1989. Next slide, please. What is resistant hypertension? A number of effective treatments exist for essential hypertension that target different physiological systems. Yet, a subset of hypertensive patients still suffer from uncontrolled high blood pressure despite the use in combination of optimal doses of antihypertensive drugs of at least three different classes, including a diuretic. Next slide. There are known risk factors for resistant hypertension, which are shown here and include older age, high BMI, ethnicity with a higher prevalence in African Americans, obstructive sleep apnea. Blood pressure is also very often difficult to control in patients with diabetes type 2 and renal insufficiency. Next slide. Hypertension is the most modifiable risk factor for adverse health outcomes. This was clearly confirmed this week at the AHA meeting. Patients who experience resistant hypertension are at much higher risk of end organ damage as compared to those with classical essential hypertension that can be controlled. The risk of cardiovascular morbidity and mortality, particularly by stroke, heart failure and end-stage renal disease, is markedly increased around twofold more. The risk is further increased when patients require multiple antihypertensive medications. Keep these risk factors and these end organ damage consequences in mind when we talk about the reasons for aprocitentan in the treatment of resistant hypertension, because all are known to be associated with high endothelin status. Next slide. The global prevalence of hypertension is estimated to be above 1.13 billion patients. In the States, using threshold of blood pressure of 130/80 mm Hg, the number of hypertensive patients is estimated to reach 122 million in 2025, and that of treated hypertensives around 87. That means that with a percentage of around 11% of all treated hypertensive patients, 10 to 12 million Americans will be suffering from resistant hypertension in 2025, and similar numbers in Europe. However, as clearly shown at this AHA meeting, the numbers are actually growing faster than expected in the U.S., precipitated by the COVID pandemic and linked to the increasing number of patients with obesity and diabetes. Next slide. We knew after all these years that dual ERA decrease blood pressure in hypertension. What spurred us to discover a new dual ERA for difficult to treat hypertension was the hypothesis that resistant hypertension is an endothelin-dependent form of hypertension, and that resistant hypertension is resistant because endothelin is not tackled by existing drugs. Indeed, the hypothesis of the role of endothelin fits perfectly with the pattern of resistant hypertension, which is often a salt-dependent hypertension, where blood pressure is particularly sensitive to salt intake. We know now that salt and endothelin levels are closely connected, that ET-1 production is dependent on salt intake, and that ET-1 is a mediator of the effect of salt on blood pressure and hypervolemia and is also causing aldosterone release, cell proliferation, inflammation and fibrosis. All of that means that ET-1 fits perfectly the profile of a key mediator of resistant hypertension and the end organ damage which results. ET-1 is not tackled at all by any of the existing classes of antihypertensive mechanism existing. Next slide. Aprocitentan is a novel dual ERA that potently inhibits both endothelin receptors, ETA and ETB receptors, both involved in mediating the detrimental effects of endothelin. Aprocitentan has a very low potential for drug-drug interactions, which is very important as resistant hypertensive patients are treated with multiple medications. In animal models of hypertension and specifically of salt-dependent hypertension, where RAS blockers do not work well, we saw that aprocitentan decreases blood pressure without increasing heart rate, which is important, even in combination with other antihypertensive drugs, and that it induced cardiac and renal protection. Dual ERAs have also been shown to decrease aldosterone, and that has been confirmed with aprocitentan in a phase I study. After demonstrating an excellent safety profile and blood pressure-lowering effect in patients with essential hypertension, it was clear that aprocitentan was the ideal compound to take forward and develop for patients with resistant hypertension. With that, it is with great pleasure, I am handing over to Professor Markus Schlaich, who did a great job of introducing the data to the medical community here at the American Heart Association meeting yesterday. Markus, can you please share your thoughts on the data of the PRECISION study? Next slide. Certainly. It's a great pleasure to be here. Thank you very much, Martine and Andrew. It has been a pleasure really to work with the Idorsia team on this exciting study. I'm a professor of medicine. I'm a nephrologist and a hypertension specialist with more than 20 years of experience, and I run a large statewide service, particularly looking at patients with resistant hypertension. Often these are patients with impaired kidney function. That's really what excited me about the study and the potential of a new kind of class of drug in the space of resistant hypertension. I would like to take the next 10 to 15 minutes to guide you through the main results of the phase III PRECISION trial. Next slide, please. As we already heard, resistant hypertension affects around 10%-12% of patients who we see with hypertension. It's a huge number, not only in the U.S., but globally. We define resistant hypertension by the inability of at least three antihypertensive drugs to control blood pressure to target. These three drug classes are usually inhibitors of the renin-angiotensin-aldosterone system, which is no doubt an important system. Of course, we have successful drugs like ACE inhibitors or angiotensin receptor blockers, which are very widely used. We usually add on a calcium channel blocker and importantly in the context of resistant hypertension, a diuretic because fluid and water retention is an important aspect of resistant hypertension, hence diuretic being part of the definition. Now, the fact that we don't control blood pressure with these three or more antihypertensive drugs, in my view, next slide, please, indicates the failure to control blood pressure, that relevant pathophysiologic pathways remain unopposed. Even with drugs that are currently considered the fourth line preferred options to treat resistant hypertension, namely spironolactone, a mineralocorticoid receptor antagonist that targets aldosterone specifically. It still is restricted to the renin-angiotensin system. From a physiological point of view, it would make more sense to target other systems that are heavily involved. Indeed, as we've heard before, next slide, please. The endothelin system is critical in this context. It has clearly been implicated in the pathogenesis of hypertension, and particularly in forms of hypertension that are characterized by increased fluid and sodium retention. If we look at how endothelin works, it's a very potent vasoconstrictor, thereby raising blood pressure. Among other important mediators, which we've heard already about before, it also stimulates aldosterone secretion. Entirety of the mechanisms really make blockade of the endothelin system, ideally with a dual endothelin receptor blocker, a very attractive therapeutic target. Now, this was exactly, next slide, please, the background to the phase III PRECISION study, where we used aprocitentan, a dual endothelin A and endothelin B receptor antagonist, specifically in the context of resistant hypertension. I would like to add that in the design of the study and in terms of the inclusion criteria, we were not shy at all to include those very high-risk patients, particularly those ones with chronic kidney disease, because this is the real world, and this is where there's really a clinical need in terms of targeting these patients and improving their blood pressure control. We know in these high-risk cohorts, even small changes in blood pressure make a significant difference in regards to cardiovascular outcomes. Let me summarize the objectives. Next slide, please. The primary objective of the PRECISION phase III study was to demonstrate the blood pressure lowering effect of aprocitentan in patients with confirmed resistant hypertension. A secondary objective was to demonstrate that the effect of aprocitentan on blood pressure is durable in patients with confirmed resistant hypertension, and that's a critical point. Management of blood pressure is not a sprint, it is a marathon, and we have to ensure that blood pressure is controlled over prolonged periods of time. Making sure that medications are tolerated not only for three or six months, which is what most studies look at, but at the longer term, is a crucial aspect, and I would like to highlight that for this specific study, where we had follow-up up to 48 weeks or almost a year. Another secondary objective was to evaluate the long-term safety and tolerability all the way out to 48 weeks. Next slide, please. Now, we have learned, and I have been involved in different studies looking, again, specifically at patients with resistant hypertension, interventional studies, other pharmacological studies. One challenge has clearly been the design of the study to ensure that we truly include patients with resistant hypertension, that we hopefully achieve a state where they adhere with their prescribed medication. We know there's usually a quite strong placebo or even sham effect, you know, if you look at interventional studies. So this design I'm pretty proud of, and it was, you know, the result of long discussions to ensure that we get this right. Overall, we had a 12-week screening phase, which is quite substantial. Patients were screened on their individual background therapy, which included at least three or more antihypertensive drugs. If their blood pressure remained above 140 mm Hg systolic, they were eligible to continue in the study. Importantly, we then switched these patients, all of the patients, to standardized background therapy with drugs that are recommended by all current guidelines, including inhibitors of the renin-angiotensin system, in this instance, valsartan, amlodipine, a long-acting calcium channel blocker, and importantly, diuretic, in this instance, hydrochlorothiazide. Also important, this was given as a single-pill combination, which has been shown to improve adherence with medication. Again, a clever study design. On top of that, patients were then entering a four-week run-in phase, a placebo run-in phase. If they still qualified, in other words, if their blood pressure was still above 140 mmHg, they then entered Part 1 of the study, a four-week double-blind part where patients were randomized to either placebo, 12.5 mg of aprocitentan or 25 mg of aprocitentan. At the end of those four weeks, the primary endpoint was assessed, which was the change from baseline to week four in mean trough sitting office systolic blood pressure. Patients then entered a 32-week, quite a long phase, where all patients were switched to the higher dose of aprocitentan to look at the tolerability and efficacy across a longer period of time. Prior to which they were then re-randomized to a double-blind withdrawal phase, during which they were switched to either placebo or continued with 25 mg of aprocitentan. The key secondary endpoint was the change from withdrawal baseline week 36 to week 40 in mean trough sitting office systolic blood pressure. Essentially mirroring the Part 1 initially, and again, an important design to demonstrate the component of blood pressure reduction achieved with aprocitentan. Another important aspect that I would like to highlight that specifically is the inclusion of ambulatory blood pressure monitoring. Despite all standardization, office systolic blood pressure or office blood pressure measurement in general is really just a snapshot at any given point in time, and is much less accurate than a 24-hour blood pressure monitor, where you usually get 72-96 mmHg readings across an entire day, and it dramatically reduces the variability. I would like to stress that ambulatory pressure monitoring is considered the gold standard, is probably the strongest way of assessing blood pressure, and that was done in this study both at week four, when the primary endpoint was assessed, as well as at week 40, when the key secondary endpoint was assessed. Next slide, please. Here are the key inclusion criteria, and this was obviously a history of resistant hypertension. They had to have unattended sitting office systolic blood pressure above 140 mm Hg. A number of key inclusion-exclusion criteria, which are quite common in the context. We were excluding patients who had major cardiovascular, renal or cerebrovascular events in the past six months, and also patients with stage 3 and 4 heart failure. We excluded patients who had an NT-proBNP level of 500 pg / mL, and we excluded patients with CKD, chronic kidney disease, stage 5, those ones with an estimated glomerular filtration rate between 15 mL/min. These patients are close to requiring hemodialysis and not appropriate to study in this context. We did include patients with chronic kidney disease stage 3 and 4, and this is really where the clinical need lies. Now, these are the baseline characteristics on the right panel, and this is stratified according to the randomization groups. You see very balanced across the groups, around 243, 244 patients in each of those groups. Mean age, around 62 years. You see the average office blood pressure clearly in the hypertensive range, 153/88 mmHg on average, and the corresponding ambulatory blood pressure levels of 138/83 mm Hg. There was a predominance of men. We had predominantly white participants, around 12%, Blacks, particularly more in North America, where the ratio was around 37%. Body mass index was in the obese range, averaging around 33-34 kilograms per square meter. That's an important aspect. Obesity is very commonly associated with difficult to control hypertension, so this is truly a characteristic cohort. Importantly, as I mentioned earlier, more than 20% of patients had CKD stage 3 or 4 eGFR levels below 60 mL/min, and roughly 40% had evidence of proteinuria in form of either micro or macro albuminuria. Again, these are features that make it usually much more difficult to control blood pressure, particularly if not all relevant pathways are targeted. To illustrate the severity of hypertension these patients had, more than 60% of the patients included were on four or more drugs at screening. This is substantial medication burden, so truly resistant hypertensives. Also, around 20% of participants had a previous history of heart failure, so we were not shy of including high-risk populations, and more than 50% of participants had a history of diabetes. Next slide, please. Now these are the main results, the primary endpoint, and would like to draw your attention to the first Part 1 here on the left side. In blue and red, you see the reduction in blood pressure with both doses of aprocitentan. They started off at 153 mm Hg, and the blood pressure dropped all the way down to around 138 mmHg. So 15 mm Hg, absolute blood pressure reduction. If I see this in my clinic, I'd be thrilled in this patient cohort to achieve such a blood pressure lowering effect. We look at the primary endpoint, which was the comparison with placebo, and you appreciate that placebo did also result in a blood pressure lowering of around 11 mm Hg. Yet statistically and clinically meaningful, there was a clear differentiation and difference between the two, therefore meeting the primary endpoint in this study. When you look at the single-blind part, I remind you that all patients were now switched to the high dose aprocitentan. You see a further reduction in blood pressure, which is beautifully maintained across the entire 32 weeks. When patients are then re-randomized prior to the double-blind withdrawal phase, very quickly, immediately, you see a rise in blood pressure with placebo, whereas those patients who maintain aprocitentan 25 mg had a very nice continued blood pressure reduction, which was maintained until week 48. Again, this met the key secondary endpoint, the change in systolic blood pressure at week 40. Importantly, also, the same was true for diastolic blood pressure. When we deal with hypertension, obviously we look at both systolic and diastolic, and demonstrating that, diastolic blood pressure reduction was almost similar in terms of magnitude as systolic. Again, that is quite unique and will help these patients to reduce their cardiovascular risk. Next slide, please. I now would like to guide you through the 24-hour blood pressure management results. As I highlighted earlier, this is quite critical in my view, and this is the view of really the hypertension community. A 24-hour blood pressure monitor gives you an idea about the profile across an entire day. What you can appreciate here on the left, if you compare the curves, black, the placebo, blue and red, aprocitentan 12.5 mg and 25 mg, a very clear separation across the 24 hours. What that means is aprocitentan is working across the full day and separates these curves very nicely. If you look at the absolute changes on the right side in the bar graphs, first of all, I would like to draw your attention to the placebo effect. With office blood pressure, this was around 11 mmHg, and this is the variability you get with this type of measurement. We do know ambulatory blood pressure monitoring is much less prone to a placebo effect, and this is beautifully depicted here. The effect is only 2 mmHg. If you look both daytime and nighttime, significant and substantial reductions, even a bit of a dose response here. If you look at nighttime, in particular, an absolute change of more than 10 mmHg, this is indeed quite unique. I would like to highlight that it has been shown that nighttime blood pressure is the best predictor of cardiovascular outcomes. Reducing nighttime blood pressure has likely additional benefit, particularly in the context of these very high-risk patients. I'm really excited about this data. Next slide, please. As I mentioned, I'm a renal physician and nephrologist, and I see a lot of patients with severely impaired kidney function, so we had a specific interest looking at pre-specified subgroup analysis. The good news, first off, it worked across all subgroups, but we had a specific look at those characteristics that are usually associated with very difficult to control hypertension. This includes elderly, this includes patients with impaired kidney function, and those who have already evidence of hypertension-mediated organ damage, such as microalbuminuria. What you can appreciate very nicely here from the slide, exactly those high-risk cohorts seem to specifically benefit from aprocitentan, those above the age of 75 years, a substantial, almost 13 mmHg blood pressure reduction with 25 mg of aprocitentan. Those with macroalbuminuria, more than 300 mg / g, you know, around 12 mm Hg blood pressure reduction. Importantly, patients with chronic kidney disease stage 3 and 4, a large proportion of patients with resistant hypertension saw almost 13.5 mm Hg reduction with the higher dose of aprocitentan. This makes me really excited about the potential of this medication in these high-risk cohorts. Next slide, please. I want to dive in a bit more into the data regarding albumin-creatinine ratio. You may wonder, well, is that really relevant? It's absolutely relevant, because one way of assessing the efficacy of a medication is not only to look at blood pressure, but also to demonstrate that the drug hopefully has the capacity to regress what we call hypertension-mediated organ damage. That may be, for example, left ventricular hypertrophy. Regarding the kidney, we use microalbuminuria as a marker of this. What you can see here very nicely and impressively, in the first four weeks, in Part 1, a mild increase with placebo. As you would expect, they didn't get any additional treatment. With both doses, 12.5 mg and 25 mg, roughly 30% reduction within a four-week period of UACR, which is, you know, quite remarkable. Importantly, once all patients were switched in the single-blind 32-week phase, this was maintained at that level throughout. Once re-randomized, when all patients were re-randomized to either placebo or 25 mg of aprocitentan, you see a sharp rise with placebo, highlighting again that it is aprocitentan and the aprocitentan-induced changes that account for the reduction in microalbuminuria. If you look at the number 0.96, that was even a bit more pronounced in the Part 3 double-blind withdrawal. I think a unique potential, particularly in the context of impaired kidney function and albuminuria. Next slide, please. We absolutely have to talk about adverse events, and this is a summary of the individual parts, Part 1, Part 2, Part 3. You see, compared to placebo in Part 1, where there were adverse events in around 19.4% of patients. Higher rates, obviously, as we anticipate with aprocitentan 12.5 mg and aprocitentan 25 mg, and a bit of a dose response in this context. Not surprising, a relatively low number of serious adverse events and only small percentages of AEs that led to discontinuation. In the single-blind Part 2, 32 weeks, you see a larger proportion of adverse events, but that is not necessarily due to the drug. It's really a reflection of the much longer period that was observed 32 weeks as opposed to four weeks. Much more time for patients to experience or develop any adverse events for that matter. This is simply the driver here is the prolonged time. If you look at double-blind withdrawal part, again, very similar numbers, so nothing really surprising here. Let me dive into this a bit more. Next slide, please. This is an important aspect. As you would know, endothelin antagonists, in general, have been associated with the fluid retention, and that has been a concern. You see here with aprocitentan in the 12.5 mg group, around 9.1% of patients did experience fluid retention. This was almost double that number with the higher dose at aprocitentan 25 mg, accumulating to around 18.4% compared to placebo, where that occurred in around 2.1% of patients. Importantly, this only led to discontinuation of one patient during that phase, perhaps indicating that this can be clinically managed. How was this managed? You see that around half of the patients on both doses of aprocitentan, 10 and 21 patients respectively, required additional diuretic use. That's a good thing 'cause, you know, the fluid retention that is caused by endothelin antagonists is very responsive to additional diuretic therapy, and this is really reflected in these slides. If we look at the longer-term single-blind week, you see again very similar numbers. Around 18.2% of patients developed fluid retention. Roughly half of those required additional therapy, diuretic therapy that is, and five patients were discontinued due to fluid retention. In my view, that is not concerning. This is what we also see with other drugs that are prone to cause fluid retention and a relatively small number of patients in the double-blind withdrawal phase 'cause they have been used to aprocitentan during that time. Next slide, please. Very importantly, from a management point of view, as a nephrologist, we deal a lot with fluid retention. When your kidneys start to fail, one of the clinical signs you see is more pronounced fluid retention. Cardiologists, nephrologists, endocrinologists for that matter, are very used to modulating fluid and usually by adding diuretics. What is really important to look at here, you see, the amount of fluid retention that occurred depending on the timeline. If you look at the steepness of these curves in red aprocitentan 25 mg, black placebo, blue aprocitentan 12.5 mg, you see the curves are steepest, particularly for 25 mg in the first four weeks. This was the clinical experience. We had a good number of patients in the trial, so I had seen them personally. If fluid retention occurs, it usually occurs within the first four weeks, so you can monitor these patients quite easily, and if required, you add on another diuretic or you uptitrate the diuretic. You see very nicely after those four weeks, the curves flatten significantly. If you look at the comparison of those patients who in the first four weeks were on aprocitentan 12.5 mg and, please remember after week four on this timescale, all patients were on aprocitentan 25 mg. Yet those ones that have been initiated on 12.5 mg still had absolute lower numbers overall in terms of fluid retention, and that may suggest that, you know, it is a smart move to perhaps initiate with 12.5 mg and then uptitrate. 'Cause it is important to block both receptors, you know, sufficiently, and we would recommend to try to get to the full dose. But again, indicating this is clinically manageable, particularly by those physicians who see these types of patients in their clinics. Next slide, please. Another concern is obviously heart failure, also associated with fluid retention that sometimes can tip off these patients. There was a total. Let me remind you. Around 20% of the patients had a previous history of heart failure. Look, a number of studies try to exclude these patients, you know, to avoid that kind of risk. I really commend the investigators and the study coordinators here in that they have not shied away from including this cohort, 'cause you run a higher risk, obviously, to cause some issues. There were eight cases of what was termed non-serious heart failure. In other words, signs that indicate some form of heart failure, but not severe enough to require hospitalization. Most cases, seven out of those eight were on the higher dose of aprocitentan. In none of those cases was discontinuation required, indicating again, this can be managed clinically by these physicians. The vast majority, again, was treated with diuretics, indicating that it is associated with fluid retention. Perhaps a bit more important is that those patients who had to be hospitalized for heart failure, and that's an important adverse event of specific interest we have to look into a bit deeper. Most importantly, there were no associated deaths. The vast majority, again, 10 out of 11, were on the higher dose of aprocitentan. Speaking to the comorbidities of these patients, all of these patients were diabetic and that again raises the chances of these patients to experience those type of side effects. Six out of the 11 had chronic kidney disease, stage 3 and 4, again increasing the risk for heart failure complications. Five out of 11 had a previous history of heart failure. Two of those patients had to be discontinued. All patients were treated with diuretics, and in all 11 cases, the AE were judged unrelated to treatment by the investigators. Next slide, please. I would like to conclude that the PRECISION study looked at patients with true resistant hypertension. We selected them very thoroughly at high cardiovascular risk, including CKD patients and patients with previous history of heart failure. A truly resistant and truly high-risk cohort. Aprocitentan lowered both office and, more importantly, 24-hour blood pressure, both at week four and after a much longer period, 48 weeks, which speaks to its capacity to control blood pressure over prolonged periods of time. As expected, fluid retention was the most common adverse event. However, this was usually manageable with addition or uptitration of diuretic, which is again commonplace in these high-risk patients. My final conclusion I really would like to propose, and that is what really makes me excited, that we now have another pathway being targeted, which was completely unopposed so far in the context of resistant hypertension. I strongly believe that dual endothelin A and B antagonist, aprocitentan, may well represent a new approach to treat resistant hypertension. With that, I thank you very much for your attention and, you know, I think we're happy to take questions. Thank you very much, Markus. Thank you very much, Martine, for your prepared remarks. Excellent delivery. We now have some time to address questions, but before, a few housekeeping rules. Please limit yourself to one question and jump back into the queue if there is more to be asked. Secondly, this is a call on clinical data, not financials. Hence, use the occasion to ask questions to our experts in their field of expertise. We will not be answering questions on financials or on funding as well. Lastly, bear in mind that Johnson & Johnson is our partner here with aprocitentan, and they are responsible for commercialization of aprocitentan. We will be receiving a royalty from them for, on the basis of their commercial success, but please address commercial questions to them. With no further ado, operator, please open the lines. Thank you. As a reminder, to ask a question, you will need to slowly press star one and then one on your telephone and wait for your name to be announced. It's star one and then one on your telephone. We are now going to proceed with our first question. The first question come from the line of Peter Verdult from Citi. Please ask your question. Your line is opened. Thank you. Peter Verdult, Citi. Just the one question to Professor Schlaich. Thank you very much for your comments in the presentation. Professor Markus, I'd be interested in your thoughts on The Lancet editorial. They applauded your trial design, setting a new standard in clinical studies in this area. But they did question the clinical significance of the efficacy results and highlighted potential safety concerns from the edema signal. I'm interested to hear where your pushback might be to that commentary. Is it just that the unmet need is huge and patients need something extra, or would you make any other points? Thank you. A very good point. Thank you very much. You know, it's always nice, of course, if you get an editorial indicating the importance of a study. While I thought the editorial is okay, I was a bit disappointed that they really did not comment on the ambulatory blood pressure data. You know, they're questioning whether the blood pressure reduction, the placebo-controlled blood pressure reduction is meaningful in this context. If I look at the ambulatory blood pressure results, I would say absolutely yes. Also, you know, the absolute changes in office of 15 mm Hg is absolutely huge. It's a big change. In the real world, of course, you don't have a placebo control. You see your patients, you put them on medication, you see their blood pressure drops by that amount. In these high-risk cohorts, you need less magnitude in terms of blood pressure reduction to achieve similar reduction in cardiovascular risk. I guess editorialists always have to, you know, pick a bit on the data and, you know, apply a bit of caution. I think with the ambulatory data in particular, the data is very convincing. The safety side of things, both editorialists have not been part of the study, and I have been able to witness and see these patients. Again, I can confirm with a lot of experience that the clinical management is relatively straightforward. Adding a diuretic is what we do very frequently. Clinically, I have no concerns, but I would agree we have to instruct physicians in the use of this medication. This is what you do whenever you introduce a new drug, but I do not see any major issues down the track. Thank you. I'll get back on the line. Thank you. Thanks to Markus. Thank you, Peter. Operator, next question, please. Sure. We are now going to proceed with our next questions. The next question comes from the line of Harry Sephton from Credit Suisse. Please ask your question. Brilliant. Thank you very much for taking my question. Given the prevalence of obesity in the treated population, I wanted to get your thoughts on whether the emergence of effective obesity medications could reduce the need for intensification of antihypertensive therapy in the future, especially if those obesity drugs show a meaningful cardiovascular benefit? Look, an excellent question, and you're referring, of course, to SGLT2 inhibitors, GLP-1 agonist, and the GLP-1 GIP combined agonists. You know, the results are quite amazing, and it's great news for the obese community. We do know that around 70% of all hypertension we see is associated with overweight and obesity. It is an important aspect, and I would anticipate that these weight loss drugs have an impact on blood pressure and, you know, that has already been shown. Of course, in patients with resistant hypertension, there's a number of other important mechanisms. Endothelin is also upregulated in obesity, so I do not think that negates at all the need to address and target the endothelin pathway. In fact, I think that even increases the need to do so because, aside from just lowering weight, which we do know, can have an impact on blood pressure, you still need to target these pathophysiological systems that are highly activated in the context of resistant hypertension. I would see that perhaps there's an ideal combination. You know, lose weight, which we usually try to do via lifestyle modification, not very successfully. Now we have better drugs to do so. That won't take away the problem of resistant hypertension. The beauty about aprocitentan, you can combine it essentially with any other drug, may that be antihypertensives or other drugs for that matter. I see really a big scope for this, and combination of the two will help us even more. It does not negate the importance of endothelin pathway in the context of resistant hypertension. That's very helpful. Thank you very much. Thank you, Harry. Operator, next question, please. Sure. We are now going to proceed with our next question. The next question come from the line of Thibault Boutherin from Morgan Stanley. Please ask your question. Hello. Thank you for taking my question. There was another molecule, which was presented at the same conference, baxdrostat. We saw, you know, a very impressive level of decreasing blood pressure in absolute terms and in placebo-adjusted terms. Just wanted to know if you could point out the key differences, either in terms of patient screening, in terms of study design or anything else, that you see between the two trials. I mean, obviously, the designs are different. I'm aware of that. In particular, I know that the efficacy was good, I think, Part 1 after only four weeks. Even if we look beyond four weeks for PRECISION, the lowering blood pressure, there's a little bit more lowering, but not much more. Just wanted to know if you could point out some key differences between the phase II trial for baxdrostat and the PRECISION. Thank you. One second, Markus, before you dive into this. We're not gonna do competitive bashing here. We're gonna highlight what are, you know, the great things about baxdrostat, and I'll hand it over to Markus for that. Well, I've seen the study was obviously presented and, you know, it is good news. It's an aldosterone synthase inhibitor and early in my presentation, I made the point that I don't think it's too useful to target the same system multiple times. That's, of course, what really differentiates aprocitentan. It targets completely different pathophysiologically important pathway. You know, the other important differentiation here is, as I mentioned, that we had a really very high risk cohort of patients which are more difficult to control than what has been looked at in the BrigHTN study. If you compare the patient characteristics, you will see that. That may, to some extent, account for the differences. I would not overemphasize. You cannot really compare the two studies. Very different design. We have been extremely rigorous in terms of ensuring that these patients had true resistant hypertension, and this was not the case in the BrigHTN study, where you still may have much more variability and more chance of people who have not been truly resistant. Purposely, they excluded chronic kidney disease patients because that is a risk with aldosterone antagonist or aldosterone synthase inhibitor in this context. They have purposely not been looked at. This is the point I was trying to make. This is where aprocitentan seems to work specifically well, and I do not anticipate that this will be the cohort that you will be looking at giving aldosterone synthase inhibitors. Again, I think aprocitentan has a very unique role to play in that context and really targets the clinical need of high-risk patients with resistant hypertension with an exceedingly high cardiovascular risk. Thank you very much. Thank you. Markus. Thank you, Thibault. Operator, next question, please. Sure. We are now going to proceed with our next question from the line of Peter Verdult from Citi. Please ask your question. Can you hear me? Yeah, Peter, you're back. Sorry. Just a question for Martine. Just one question. In light of everything that's been discussed today, Martine, is the intention to still file both doses with FDA or given the efficacy and safety profile that was presented, might you only go for the lower dose? Just filing intentions on aprocitentan, please. Okay. In terms of the filing strategy, the only indications that we've given is we're gonna be filing by the end of the year. I would say I would refer the question back to Markus in terms of what is the differentiation between the 12.5 and the 25. Because you addressed that actually in the question and answer session in the forum itself at AHA. Yeah. You know, it's really a clinical question. If you looked at the data, it seemed from the office blood pressure that there wasn't much of a difference between 12.5 mg and 25 mg with office systolic. There was an indication for a dose response with ambulatory. I think, as with many drugs, we should strive to get to 25 mg, and that most likely based on the other data we have, will render the best effect on reversing target organ damage. Again, we also seen that with the higher dose, you get essentially twice as many incidences of fluid retention. In high-risk cohorts, which is really standard for a lot of other medications, you would initiate a medication usually on the smaller dose. You make sure patients tolerate it well. You have then time to adjust if needed. In other words, you could add a diuretic if there's any indication of fluid retention. If patients are fine after four weeks, you can uptitrate to 25 mg. That is probably what I would see as a very likely scenario in a clinical context, how we use these drugs as clinicians. I don't see any concerns in that case. This is what we do with, let's say, amlodipine, with beta blockers, alpha blockers, any kind of drug you think about. This is what physicians are very used to. There won't be much change in terms of their mindset in order to prescribe this medication in these high-risk cohorts. Thank you. Thank you, Markus. I'll let you guess between the lines, Peter, what our thought process is on this. Operator, next question, please. Sure. We are now going to take the next question. It's from the line of Harry Sephton from Credit Suisse. Please ask your question. Brilliant. Thank you very much for my next question. I'm looking at the placebo response in the PRECISION study. Clearly, there was quite a strong response there. You mentioned that the absolute response from aprocitentan is what we should look at. In the phase II study, the aprocitentan response looked relatively similar, but the placebo response was weaker, hence the better placebo-adjusted outcome in the phase II. Can you maybe help us explain why the placebo response was so strong in the PRECISION study? Look, that's a very difficult to answer question. I personally have given up to try to understand placebo. As I mentioned before, I have been involved in interventional studies where you have sometimes massive sham control effects as well. I think, yeah, we had really considered and thought this through with an excellent design to try to avoid. We had a 12-week run-in phase, which usually helps to stabilize and ensure, and we were expecting a lower placebo response. Yet, and then you see that across most placebo-controlled trials that the placebo response, whatever you do, can still be quite remarkable. I think we just have to take that at face value. Again, I would like to refer to the ambulatory blood pressure data, where you see that the effect is dramatically less pronounced. Ambulatory blood pressure monitoring is much less prone to placebo effects. I think this is what we should be guided by, and that is very strong data. You know, to be honest, I don't have a great explanation for the placebo effect. I just accept that if you have a placebo control, that is what happens. It is not the real world. It's a bit of an artificial environment. This is why I'm saying, if I see a patient today and his blood pressure is increased, I put him on a med. I've seen four weeks later, and his blood pressure is 15 mm Hg reduced. I'm the happiest man around, you know, the patient will be doing fine. That's my take. I would refer to the 24-hour blood pressure monitoring data. Brilliant. Thanks. Thank you. Thank you, Markus. Operator, do we have any more questions? Yes, we have one last question. It's from the line of, Thibault Boutherin from Morgan Stanley. Thank you. Just a follow-up on the heart failure in the diabetic patients. Do you believe that, you know, based on the slide you've shown, this is meaningful enough to potentially warrant some sort of question on the label or on some sort of warning on the label? Or is it the signal is not strong enough to have this type of issue? Oh, yeah. Not at all. I mean, you know, again, I commend Idorsia to actually include this high-risk cohort because this is where the clinical need is. These patients clearly benefit from the medication. Yes, they are at a higher risk, and the key point is that we identify these patients, that we know that they are vulnerable and at higher risk, and that we put them on adequate diuretic therapy, which could prevent many of those issues. You know, not at all would I see this as an indication to put a caution on the label or anything. These patients will also benefit from it in terms of the blood pressure lowering. I personally have no concerns in that regard. Thank you. Operator, do we have anybody that jumped back into the queue? We do have one question. It's from the line of Nick Hallatt from Goldman Sachs. Hello, Nick Hallatt, your line is open. Hi, there. It's Nick o n for K here. Thank you for taking my question. Just one question. Was there a discernible difference in the blood pressure change in patients on three background therapies versus those on four or more? Thank you. No, there was not. Obviously during the trial, they were all put on standardized background therapy, but the blood pressure lowering effect was identical across all those groups, whether they had been on four or five drugs prior or just three drugs. It was very consistent across all the subgroups we looked at. Thank you. Operator, how are we doing with more questions? No more questions on the phone lines. Excellent. Thank you very much. I think this concludes our call for today. Markus, thank you very much for your time and your conclusive remarks here. We'll very much appreciate it. Martine, thank you also very much for your time. Thank you for your ongoing interest in Idorsia. We're looking forward to speaking to you again. Operator, please close down the lines. Thank you. Ladies and gentlemen, that does conclude today's conference call. Thank you for participating. You may now disconnect your lines. Thank you.