Good morning and welcome to the Mineralys Therapeutics virtual KOL event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Mineralys website following the conclusion of the event. I'd now like to turn the call over to Jon Congleton, Chief Executive Officer of Mineralys Therapeutics. Please go ahead, Jon. Thank you, Operator. Good morning, everyone, and welcome to our KOL event. Before we get started, I wanted to quickly point out that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. You may read the disclaimer here. Joining me today are Professor Rhian Touyz, the Executive Director and Chief Scientific Officer of the Research Institute at the McGill University Health Centre; Dr. James Luther, an Associate Professor of Medicine and Pharmacology within the Department of Medicine at Vanderbilt University Medical Center; and Dr. Luke Laffin, a practicing cardiologist and co-director at the Center for Blood Pressure Disorders at the Cleveland Clinic. We are very fortunate to have these three leaders in the field of hypertension here to walk us through a few topics, including the unmet medical need in uncontrolled and resistant hypertension, the role of aldosterone in hypertension, how Mineralys late-stage asset lorundrostat has the potential to change the current treatment paradigm, and how they, as treating physicians, plan on evaluating the results from the ongoing pivotal clinical trials Advance- HTN and Launch- HTN. We will then close out the prepared remarks portion of today's meeting with comments from our Chief Medical Officer, David Rodman, who will offer additional insights on lorundrostat, the two pivotal trials, and a review of our upcoming milestones. Following Dr. Rodman's comments, we will open up the meeting for your questions. With that, I'll now turn it over to Professor Rhian Touyz to discuss the unmet need in hypertension and the role of aldosterone. Thank you so much, Jon, and it's a pleasure to be here today to share with you something that is very close to my heart, certainly having been an investigator for over 30 years in the field of hypertension, the unmet needs in hypertension, so many of you may not know or realize that the number one cause of morbidity and mortality, premature death in the world, is high blood pressure, and this has been a major burden for the world for many, many years, and unfortunately continues to be so. It is not cancer, it is not infectious diseases or trauma that is the number one killer, but it is high blood pressure, and the reason for that is that high blood pressure causes heart disease, stroke, vascular dementia, and kidney disease. Now, because of this huge burden in terms of healthcare, obviously there have been enormous efforts to try and do better in controlling hypertension, and indeed, for many years, the many different professional organizations put huge efforts into doing a better job of controlling hypertension, and we can see here in one of the very big studies from the NHANES, from the early 2000s until about 2010, indeed, blood pressure control in patients with hypertension was indeed improving. However, over the past 10-15 years, both in the U.S. and elsewhere, the control of blood pressure is now declining, and this poses an additional burden on our health system, especially since our patients are getting older and there are more comorbidities. Let's look a little bit deeper in terms of blood pressure control in both men and in women, and very importantly, how many of those people who've got high blood pressure are aware that they have hypertension, how many of those that are aware are treated, and how many of those who are treated are absolutely controlled based on international or major guidelines. So what we can see by the light blue graphs in both men and in women, it's only about 40%-50% of adults in any community that are aware that they have high blood pressure. Of those 50% that they know they've got high blood pressure, only about 30%-40% are actually treated. But even worse, of those that are treated, as we can see by the dark blue turquoise graphs, about 10%-15% of them are treated to target. So there's a huge unmet need, both in terms of the number of patients who are not treated and in terms of the patients who are not treated to target, in other words, to a blood pressure level that is indicated or recommended by guidelines. So we talk about this hypertension paradox. We have more uncontrolled disease despite improved therapies, and this was something that became evident in 2009 by Chobanian. And in 2009, he presented this concept of the hypertension paradox. However, where are we today in 2024? Well, we're not that much better. Our prevalence continues to increase. I've just told you that hypertension still remains a major problem in that it is suboptimally controlled. In fact, blood pressure control is worsening, especially in women. And I have just told you that it is still the major risk factor for morbidity and death, especially in patients with comorbidities such as obesity, diabetes, dyslipidemia, et cetera. So why is it that we have this hypertension paradox? We've got lots of treatments, and yet we're doing so badly. Well, one of the reasons is because hypertension is actually a very complex disorder. There are many physiological systems, as we can see here, the heart, hormones, the kidney that contribute to the cause of hypertension, but there are also many genetic factors, behavioral factors, environmental factors that also contribute to an increase in blood pressure. And why is it that it is the major cause of morbidity and mortality? Well, the reason for this is that high blood pressure affects every organ in the body. The brain, where it causes stroke, in large arteries, where it can cause aortic aneurysm or atherosclerosis, in the microcirculation, in the kidney causing kidney disease, in the heart causing heart disease, and even the eye. If your blood pressure is uncontrolled for long periods of time, one can have the condition of hypertensive retinopathy. So high blood pressure causes target organ damage across multiple systems, and this is why it is so important to treat blood pressure so that it prevents these cardiovascular adverse events. Now, in terms of what is being recognized more recently, is that we're having more difficulty in treating patients with hypertension because many more patients are now presenting with what we term resistant hypertension. These are patients who are on multiple therapies, and despite being on these therapies, they remain hypertensive. About 15%-20% of our patients have what we define as resistant hypertension. Very interestingly, if we look more deeply at what constitutes these patients with resistant hypertension, many of them will have a condition related to an excess production of a hormone called aldosterone. These patients are what we term having primary aldosteronism. Let's just look at exactly what resistant hypertension means by definition. It is high blood pressure that remains uncontrolled on maximal or near-maximal therapy, including many antihypertensive drugs, including a diuretic. As I said, many of them will have high levels of aldosterone. Why is aldosterone so important? Aldosterone is what we would determine as a major final product of activation of this renin-angiotensin system, which is a very important system that plays a role in many processes that regulate the cardiovascular system, the kidneys, but also blood pressure. Activation of the renin-angiotensin system ultimately results in the production of aldosterone. Aldosterone itself regulates blood pressure, and it does this primarily by regulating the salt and the water balance. I'm sure you've all heard of salt not being good for people with hypertension because you get a retention of water. Aldosterone plays a critical role in these processes. In addition to these classical features of aldosterone, we're beginning to appreciate now as researchers that aldosterone also has what we call non-classical effects. In other words, effects that work beyond the kidney. We know that aldosterone can have an effect on the vasculature directly by influencing vascular cells and endothelial cells. Aldosterone can directly influence heart cells, what we call cardiomyocytes in the heart. In addition, it's becoming increasingly evident that aldosterone can actually regulate fat cells, which are responsible for what we would term adipogenesis because it is the adipocytes that play a very important role in body mass index and in obesity. It is these processes that also contribute to hypertension and all those other conditions that are associated with comorbidities, especially diabetes, metabolic disorders, as well as obesity. In addition to the classical aldosterone effects on the kidney, aldosterone has effects on many other systems causing fibrosis, inflammation, oxidative stress, and so one can see that together the effects of aldosterone are really quite injurious in terms of cardiovascular, cardiorenal health. When we look at the association between aldosterone and other comorbidities, and I'm showing you here the association between aldosterone and adiposity or obesity. A number of clinical studies have shown us that as individuals become fatter, as they become more adiposity increases, or as they become obese, so too is there an increase in plasma and urine aldosterone levels. We can see this both for men, as indicated by the white graphs, and black as indicated by the black graphs. This quartile is a number four, is where we have the most obese or those individuals who've got the highest body mass index, and they have got the highest aldosterone levels. There are more and more of these studies now showing a relationship between hyperaldosteronism and obesity. We and others have done a number of preclinical as well as clinical studies to try and understand this relationship between aldosterone, the fat cells, and cardiovascular risk. We know that not all fat is bad, and in normal healthy individuals, we need some functional fat to allow us to control metabolism. Indeed, an active renin-angiotensin system in these adipocytes plays a very important role under normal healthy conditions. In the context of obesity or in patients who've got cardiovascular risk, the adipocytes, the fat cells, become very dysfunctional. They start reacting more aggressively to activation of the renin-angiotensin and aldosterone system. It is these processes that we believe contribute to the exacerbation of cardiovascular risk in patients with obesity, as well as in those who have hypertension and diabetes. I also want to highlight to you at this point how we define hypertension, because I've spoken about hypertension, but haven't really defined what we mean by this. And we have just come out with the new 2024 European Society of Cardiology guidelines on hypertension, and have categorized blood pressure as normal blood pressure, less than 120 over 70, what we've termed elevated blood pressure, 120- 139 over 70 to 89, and classically hypertension, 140 over 90. We believe that the patients who are in the elevated blood pressure group are particularly important in terms of management, and we are targeting now blood pressures to those of 120 over 70, which is a healthy blood pressure. So you may ask why? Why is it that we're targeting 120 over 70 and not 140 over 90? There is very, very clear evidence from many studies long ago and more recently that actually cardiovascular risk or cardiovascular events actually start increasing from blood pressure as low as 120 over 70. You can see this across all age groups, as we can see, and this is for ischemic heart disease mortality. As blood pressure increases, so too is there an increase in the risk of cardiovascular events or MACE. With that, I would like to just sum up, and the take-home message from this is hypertension is a killer because it causes heart disease, stroke, kidney disease, and even vascular dementia. We know today that the control of hypertension is suboptimal, and this is what is leading to our major adverse cardiovascular events, the burden of health across the world. Resistant hypertension is becoming more prevalent, and this is due in large part to hyperaldosteronism, a major health burden. I've shown you that hyperaldosteronism is associated with adiposity, and therefore aldosterone has become a very attractive therapeutic target in hypertension and resistant hypertension, and may indeed have added benefit in patients with obesity. And we've seen this more recently with the new discovery of new therapeutic agents targeting the aldosterone system. And with that, I'll stop here. Thank you, Professor Touyz. I'll turn it over to Dr. Matt Luther to discuss the lorundrostat and the Target-HTN data. Matt. All right, thank you, Jon. So Dr. Touyz has covered the background of the importance of hypertension, and we do have treatments for hypertension, but it hasn't been for very long. These were developed in the 1950s, and many of these drugs that were developed back in the 1950s and 1960s are no longer in clinical use, largely because of side effects, not so much because of benefit, but disabling side effects, and the development of drugs for hypertension really kind of stalled out around 1995 when losartan was released, which is the last huge clinical development in hypertension, but as a hypertension specialist, we're pretty excited about the newfound interest in hypertension and the new drug classes that are being developed, especially aldosterone synthase inhibitors, which I'll discuss further today, so this class of medications were first found clinically to be relevant with fadrozole. Fadrozole is an estrogen inhibitor or aromatase inhibitor, but it was found that the mechanism of this drug actually was pretty selective and inhibited aldosterone synthesis. Other drugs came along, including fadrozole, which is just another version of fadrozole. And more clinically relevant is osilodrostat, which was developed and went through clinical stage trials as LCI 699. It's pretty selective for aldosterone, but not entirely selective. It does have some effects on cortisol, also has a short half-life. One of the reasons that it has been difficult to select, to completely selectively inhibit CYP11B2 or aldosterone synthase, is that it's a complex enzyme. It has a multifunctional, multi-step synthesis process for aldosterone that includes not just the later 18-hydroxylase and 18-oxidase steps, but there's an 11-beta-hydroxylase step that this enzyme shares with CYP11B1, which is the primary enzyme that converts the main glucocorticoid in our bodies, cortisol. So these are 93% homologous enzymes, so it's made this more difficult to get a highly selective aldosterone synthase inhibitor. There are three that are now in development, including lorundrostat, which I'll talk further about today. Lorundrostat and also baxdrostat and vadadustat have been through at least early phase and are in phase II and phase III studies. Lorundrostat, of these, looks like it has the most selectivity for aldosterone synthase. It also has a 10-12-hour half-life, which is amenable to once-daily dosing and has favorable otherwise kinetics. In phase I studies, this was the first-in-human studies, lorundrostat dose-dependently inhibited aldosterone or decreased plasma aldosterone in humans. This goes all the way up to much higher than the targeted dose of lorundrostat. They'll be using 50-100 milligrams daily in the ongoing clinical studies. Most importantly, or just as importantly, there was no effect on plasma cortisol measured as a 24-hour area under the curve with any of the doses even exceeding the currently used doses in the trials. Those background studies led to the first phase II clinical study in humans. This was done in patients that had uncontrolled hypertension, which was defined as greater than two medicines, and they had above-target blood pressures on these medications measured by ambulatory or AOBP, which is a standardized in-clinic blood pressure. Patients were enrolled in both a low and a high renin cohort. You could hypothesize that low renin hypertension patients are more like primary aldosteronism and could respond better to this drug. Later on, the high renin cohort was added. These patients were screened, then they underwent a run-in period on their background medications that they were taking for hypertension to ensure that they truly had resistant or uncontrolled blood pressure, which is one of the main difficulties in studies of this type. Once they qualified, they were given a dose, one of the multiple increasing doses of lorundrostat or placebo, randomized in a one to six ratio, six to one ratio versus placebo, and underwent treatment for eight weeks to examine blood pressure at the end of the study. As I mentioned, another arm looked at high renin patients, and they were assigned to 100 milligrams daily, which is at the upper limit of the higher dose of the lorundrostat. So as you can see here, there was a significant drop in blood pressure in the higher doses, the 25, 50, and 100 milligram doses of lorundrostat at the end of the study. Baseline, of course, placebo also had a small drop in blood pressure measured by AOBP. But when you had placebo adjusted this drop in blood pressure, there was still a significant drop in blood pressure in the 50 and the 100 milligram once-daily doses. These doses were otherwise also well tolerated, had a low incidence of potassium, sodium, hypotension, and other relevant side effects. So this was a small study, but it was also important to demonstrate that there was no effect on cortisol, not just on the random cortisol, which is not a really good, not a very good measure of cortisol response. But there was also a good demonstration that if you stimulated cortisol response with ACTH, this lorundrostat shown here at the highest dose given did not impair the cortisol response compared to the baseline or the placebo arms. We uncovered also the importance of obesity and not only hypertension, but stimulating aldosterone production, and that was one of the pre-specified subgroup analyses, and looking at patients that were obese, so the BMI over 30 versus the group of patients who had a lower BMI or who were not obese, there was a more significant drop in blood pressure in the patients that were given either 50 or 100 milligrams daily, stratified by BMI, so there was a 12-16 mm Hg drop in blood pressure, which is a pretty significant effect of a blood pressure medicine. Anytime we get a response of that magnitude, we're pretty happy. In conclusion, this early phase study showed that lorundrostat potently and selectively inhibits aldosterone synthase, has an acceptable safety profile, although in a small cohort of patients. It reduced blood pressure in these patients with uncontrolled hypertension. And there could be a significant greater response in obesity. There certainly was in this early trial. So these are questions that will be asked and looked into further in the studies that are ongoing that Dr. Laffin will present further. Thank you, Dr. Luther. I'll now turn it over to Dr. Luke Laffin to provide his perspective on Advance- HTN and Launch- HTN. Luke. Good morning. Good morning, everyone. Thank you, Jon. So my name is Luke Laffin. I'm a cardiovascular clinical trialist and co-director of the Center for Blood Pressure Disorders. I'm going to talk about Advance- HTN and Launch- HTN, the ongoing trials of lorundrostat that are going to give us a nice idea about its efficacy going forward. What's the objective today? It's to describe these ongoing trials. Really, I want to focus the next 10 minutes on the differentiating features of these trials compared to prior trials and the key data that they are going to provide. Why are these important trials for lorundrostat, Advance and Launch? The first is, of course, as Dr. Luther just described, we have Target- HTN, which was a dose-finding study for lorundrostat. Although the data are promising there, particularly at the 50 and 100 milligram daily dose, the numbers are small. We need more data to actually support how much blood pressure-lowering lorundrostat provides. Of course, any of these studies are important for providing comprehensive safety data and longer-term data for regulatory filings. But then I think most importantly, clinicians and payers, and this is more in the medium to long term, use this trial data to inform decisions about applicability to individual patients. Okay? As Dr. Luther alluded to earlier, there's newer hypertension solutions coming up, and so what trials need to do is they need to differentiate themselves and provide useful data for clinicians and ultimately payers when they're thinking about coverage, and so that's what we're going to talk about a little bit here, so Advance-HTN. So it's a randomized, double-blind, placebo-controlled, parallel arm, multi-center phase II study. And it is going to evaluate, or it is evaluating, the efficacy and safety of lorundrostat in patients with uncontrolled hypertension on a standardized medication regimen. Okay? I really want to highlight that standard medication regimen. That's very important. Why is this important? Well, there's really three major factors that I feel are important here. Number one, it limits interpatient variability in background treatment and clearly reflects guideline recommendations. I'll talk about that in a couple of minutes. But important to understand that, as was alluded to earlier, clinicians in general do a real bad job at treating hypertension. So we wanted to reflect guideline-recommended treatment as the background and lorundrostat on top of that. Additionally, what a standardized regimen does is it limits clinician and payer hesitancy to ultimately second-guess results. Okay? Hypertension is a disease dominated by therapeutic inertia. Right? We have someone who learned how to treat it in medical school or during their residency and hasn't changed the way they treat it in 15 or 20 years. Unfortunately, they teach the next generation the same thing. So high-quality data needs to be provided in this setting. Then finally, and most importantly to me, and I think to most clinicians, is that lorundrostat studies hypertension in patients that could truly benefit from a new blood pressure-lowering drug. As many hypertension specialists will tell you, we can tweak the current generic medicines. Right? Coming in on a little bit of losartan and a little bit of hydrochlorothiazide, that's not going to be an appropriate patient necessarily for this drug, for low doses, things like that. So this is studying it in patients that really can benefit with uncontrolled and resistant hypertension. So what does Advance look like? Okay? So this is the design, as many of you have probably seen. Projected enrollment, which has been completed, is over 261 participants in the United States. It includes a screening period of a couple of weeks. Then patients on two drugs start a standardized background regimen of olmesartan and indapamide. Those individuals on between three and five drugs, three or more drugs, get olmesartan and indapamide, so a very potent and long-acting ARB, a potent thiazide-type diuretic, but they also get amlodipine as well at the maximum doses, 10 milligrams. They're on the standardized antihypertensive regimen for three weeks. Then if they meet certain thresholds, which we'll talk about in a second, they're randomized in double-blind fashion to continue the standardized treatment, but then to either placebo every day, lorundrostat 50 milligrams a day, or lorundrostat 50 milligrams per day with the possibility of increasing to 100 if they meet certain thresholds on their week four testing. That includes blood pressure continues to be uncontrolled, etc. They're followed for 12 weeks. And then the primary efficacy endpoint of Advance-HTN is 24-hour ABPM and the systolic blood pressure of that and the change from the time of randomization to week 12. Okay? And then ultimately end of study. We talked a little bit about this standardized background. When we go into it, it's important to understand that this is a precedent in many recent hypertension trials. On the left side of the screen, we see the data from the PRECISION trial, which was a trial and ultimately the pivotal FDA trial for aprocitentan, which is a dual endothelin antagonist for resistant hypertension. And they used amlodipine, valsartan, very similar to olmesartan in terms of works, and then hydrochlorothiazide at fixed doses. And then also in the device space for hypertension as well, the Radiance-HTN Trio study, we're looking at renal denervation, used amlodipine, valsartan or olmesartan, and then hydrochlorothiazide at fixed doses as well. So this is a well-worn path. One thing that I want to point out about Advance-HTN and how it differs is when we look at the amlodipine and the valsartan or olmesartan, quite similar, right? And that reflects guidelines. But when we look at the diuretic, a little bit different. Okay? Everyone in Radiance-HTN and PRECISION got hydrochlorothiazide. Now, not everyone in Advance-HTN is getting hydrochlorothiazide. Okay? Now, those patients that entered on hydrochlorothiazide could continue, but if they weren't on a diuretic or were on a different diuretic, they were switched to indapamide. And there's going to be a significant percentage of patients within Advance-HTN that are on indapamide. And why is this important? Well, when we think about resistant hypertension, most people, clinicians, they automatically say, "Oh, treat with spironolactone." But this table right here is taken directly from the AHA scientific statement on resistant hypertension. And that's not until step three. What you want to do at step two is optimize the thiazide-type diuretic with chlorthalidone or indapamide. So Advance- HTN is going to study a significant percentage of individuals who are on indapamide as well, which is going to be helpful for us, okay, to take a look and see. All right? When we look at the other parts of Advance that are important, really looking at how well selected these patients are for different thresholds of blood pressure because it differs a little bit as well from some ongoing trials. You need to enroll the right patients in blood pressure trials. We've seen that with other drugs that have failed recently in terms of some of their trials or at least had negative trials. It wouldn't necessarily fail, but negative trials. Is that when we look at this diagram, so the X-axis is office blood pressure. The Y-axis is out-of-office blood pressure. And we have to remember that if you're going to really treat the right patients, they're going to be up in this red box, okay? High office blood pressure and high out-of-office blood pressure. You don't want a discordance, okay? You don't want someone with white coat hypertension in particular impacting results. Now, most contemporary hypertension trials focus on this, okay? They're measuring office blood pressure. And that's fine if your numbers are high enough, okay? Because you're going to get a smaller percentage of white coat hypertension, and you're going to get it equally distributed amongst the placebo and then the active treatment groups, okay? But if it's a smaller or medium-sized trial, what you don't want to do is end up with a bunch of people with white coat hypertension, and you're not truly treating sustained hypertension. The nice thing about Advance-HTN is they're getting their office blood pressure at the time of screening, the AOBP. They have to be above a certain threshold. And then the primary endpoint is the gold standard, which is ambulatory systolic blood pressure. And if they're on that background regimen and they're controlled with their systolic, with their ambulatory blood pressure, then they were not randomized, okay? Those are patients that don't necessarily need the drug. They're controlled on a good background regimen. This is the most important data that's clear and valid for patients and clinicians. These are some of the thresholds that are in advance that we use at screening: office blood pressure 140-180, and then at the time of randomization, a systolic blood pressure between 130 and 180. Still uncontrolled, which is really, really important. This idea of out-of-office measurements in advance, we talked about 24-hour ambulatory blood pressure monitoring being the primary efficacy endpoint. This is the gold standard for blood pressure measurement. Also, it has the ability to assess nighttime blood pressure and nocturnal dipping. We know that patients that don't have appropriate nocturnal dipping have increased cardiovascular risk. There's a very clear correlation between that and major adverse cardiovascular events. This trial will get a sense of that. In addition to the ambulatory blood pressure monitoring, there's a segment of the population who gets home-based blood pressure monitoring, and everyone gets office-based blood pressure monitoring as well to really augment and supplement the data that's important to patients. We can talk about it, but also to clinicians as well. Okay? And then in Advance, there's also assessment of adherence with a tool called AiCure to make sure patients are taking their drugs, which is really helpful on a daily basis when we think about these trials. Some of the key characteristics of randomized participants in Advance- HTN are as follows. Okay? So it's enrolled more than 50% Black or African-American patients, okay? Which, I mean, I probably don't have to tell this audience that that's really important. That demographic, particularly in the United States, carries a large burden of excess cardiovascular risk from hypertension. Advance is going to do a great job representing that group. Interestingly, that's also a group that tends to have more low renin hypertension. So theoretically, we may see a little bit more blood pressure lowering amongst them. As was alluded to by our prior speakers, obesity and dysregulated or autonomous aldosterone production, there's definitely an association between those. And over two-thirds of individuals enrolled in this trial have obesity or are living with obesity. So they have a body mass index over 30 kg/m². And then additionally, women are well-represented, right around 40% of the population in the trial at this point. Okay? So that's a little bit about Advance, which is an exciting trial to look at. Now, Launch, a bigger trial, projected enrollment of 1,000 participants worldwid. We can see not necessarily a dissimilar setup to Advance-HTN in terms of two weeks of screening. Then there's a single-blind run-in with placebo. Now, these patients are kept on their standard background regimen. Okay? And this is reflective of the real-world practice, right? You're on two, three, four drugs. What will lorundrostat do on top of those? Patients are randomized, again, this time in a 1:2:1 fashion to placebo, lorundrostat 50, or again, lorundrostat 50 with the potential to increase to 100 at week six if certain parameters are met. Okay? This has a lot of similarities with other ongoing large phase III trials of other aldosterone synthase inhibitors, other blood pressure medicines. Of note, patients are on two to five blood pressure medicines at baseline, which is going to capture the vast majority of patients with uncontrolled or resistant hypertension. The primary endpoint is office blood pressure at six weeks, which is reflective of clinical practice, particularly worldwide. What does this all mean? In a disease that is dominated by therapeutic inertia, okay, hypertension being the chief example among any chronic disease that we see, new treatment strategies are clearly, really desperately needed given the cardiovascular morbidity and mortality associated with hypertension. Advance- HTN and Launch- HTN were thoughtfully conceived and well-designed trials that should provide clear data about the blood pressure-lowering effect of lorundrostat in patients with hypertension. We look forward to seeing what the results are. Thank you very much. Thank you, Professors Touyz, Luther, and Laffin. I'd like to take a few minutes to put the information you've shared with us today into context for where we are at Mineralys in the development of lorundrostat and where we expect to be in the first half of 2025 when top-line data from the pivotal trials are anticipated. You've heard from our three speakers that despite a burst of innovation in hypertension therapies in the 1990s, even into the early 2000s, uncontrolled hypertension remains the greatest single contributor to increased cardiovascular risk, with approximately half of all hypertension patients continuing to have difficulty. A reduction in blood pressure seen after four to 12 weeks of placebo-controlled treatment, when maintained during longer observation in an open-label extension, is a good surrogate endpoint predicting reduction in major adverse cardiovascular events, sometimes termed MACE. In the Advance-HTN trial, we're optimizing the treatment regimen and ensuring adherence, which you just heard about, to confirm that the subjects have verified rather than what's referred to as apparent uncontrolled and resistant hypertension. Simply, they do not respond to standard of care. Significant reduction of systolic blood pressure is likely to predict a positive outcome on reducing cardiovascular risk and events in patients in whom lorundrostat is added to that standard of care. With over 50% of treated patients not achieving their optimum blood pressure goal, we believe that the most impactful inadequately addressed node in the RAS pathway is aldosterone synthase. As you heard from Professor Touyz, targeting aldosterone has benefits well beyond simply reducing blood volume and blood pressure. Multiple trials have demonstrated that aldosterone-targeted therapy results in significantly greater reduction in MACE than a calcium channel blocker or other third or fourth-line alternative, despite the same reduction in blood pressure. The superiority of targeting aldosterone is explained by direct adverse effects of aldosterone on small blood vessels, thrombosis, and stroke, the heart, kidney, and importantly, adipocytes. In our Target-HTN trial published in JAMA last year, a prospectively specified test of the association between obesity and blood pressure reduction with lorundrostat showed that individuals with greater BMI demonstrated a greater response to lorundrostat, as Dr. Luther showed you. This is likely due to elevated aldosterone production known to be present in obese individuals, and consequently, the robust reduction in blood pressure is due to selectively inhibiting aldosterone synthase. It's worth mentioning that 30%-50% of individuals taking an ACE or an ARB will initially respond well, then lose much of the benefit weeks to months later. This phenomenon, known as aldosterone breakthrough, is the direct result of autonomous increase of aldosterone synthase activity in response to chronic upstream RAS pathway inhibition. We believe that obese individuals are predisposed to autonomous aldosterone production, uncontrolled hypertension, and aldosterone breakthrough. We were excited to announce this morning that enrollment in the Launch-HTN trial was completed ahead of schedule. As a result, we have accelerated our timeline and expect the trial to be completed earlier than planned, with top-line data now anticipated in the mid-first half of 2025. We are excited to have been able to announce that both our pivotal clinical trials are now fully enrolled. In terms of the demographics for the two trials, we took special steps to help ensure a good representation of minorities, Black or African Americans, including our site selection and diversity monitoring. Dr. Laffin reviewed the specific information there and the importance, particularly in including African Americans and women, where the need is greatest. We believe that on final enrollment, the Advance-HTN trial, which, as Dr. Laffin mentioned, had more than 50% of the enrollees as Black or African American, should achieve our goal and the requirements and recommendations of the regulatory authorities. Next steps in our pivotal program are completion of the treatment phase and rollover of those subjects into the Transform-HTN open-label extension trial. In parallel, we will be executing on the process of data cleaning, database population and lock, and finally, statistical analysis using the FDA-approved statistical analysis plan. In the Advance- HTN trial of approximately 261 subjects, we're using the comprehensive 24-hour ambulatory BP technique as the primary, which allows us to evaluate the effect of lorundrostat throughout the day, including during sleep, when the normal pattern of BP reduction or dipping is often lacking. While we are using ABPM as the primary method of measuring BP in the Advance- HTN trial, we're also measuring automated office blood pressure, AOBP, and standardized home blood pressure monitoring in that trial. The AOBP provides a bridge between the Advance- HTN trial and the Launch- HTN trial. AOBP is an optimized office-based approach that is directly translatable to a practical real-world medical office approach, as Dr. Laffin mentioned. Launch- HTN, with enrollment of approximately 1,000 subjects, was designed to be a confirmatory trial for the Target- HTN trial. It will also, in combination with the Transform-HTN trial open-label extension, provide the enlarged safety database required for the NDA submission. Both trials will explore the relationship between obesity and the efficacy of lorundrostat. We believe this is a novel aspect of our development plan, and lorundrostat may provide significant additional clinical benefit for obese patients who have achieved some degree of weight loss with or without GLP-1 receptor agonists, but continue to have a significantly elevated cardiovascular risk profile. As you can imagine, the entire workforce at Mineralys is excited to see the upcoming results of several years of intensive work. I'd like to take a moment to recognize the commitment and hard work of our outstanding Mineralys employees and contractors who went above and beyond to achieve operational excellence. I would also like to extend my thanks and those of the company to the trial participants and trial site staff for their enthusiasm and commitment to the lorundrostat development program. Let me end my comments here and turn the call back over to the operator to start the question-and-answer portion of this call. Thank you, David. So at this time, we will be conducting a question-and-answer session with our speakers. Please hold for a brief moment while we pull for questions. So our first question comes from Rami Katkhuda at LifeSci Capital. Please go ahead, Rami. Hey, guys. Thank you for taking my questions. I guess for the KOLs on the line, what level of blood pressure reduction would excite you in Advance? And how do you envision utilizing lorundrostat in the clinic if it reaches that level of blood pressure reduction? Yeah, let's go ahead and we'll do a round robin. We'll go in order of presentation. Professor Touyz, do you want to answer Rami's question on level of blood pressure reduction that would excite you? Then we'll go to Matt and then to Luke. There we go. Thank you very much. Yeah, this is an important question. Obviously, it always depends on the starting blood pressure that one has as one's baseline. But I guess always in these types of studies, a sustained reduction, at least in systolic blood pressure, of 10-15 millimeters of mercury would be hugely advantageous. Matt? Obviously, in epidemiologic studies, if you just achieve a blood pressure reduction of three to five millimeters, that's enough to impact the population's health. But when I'm dealing with patients on a personal one-on-one level, of course, I want as much as I can get. 10- 15 points, which was seen with the drugs in the first study that I showed, I mean, would be fantastic. I don't really expect that that necessarily will be seen across the board in larger studies, but in selected patients, that would probably be achievable, and that would be huge. From my perspective, I think it's important to put into context which modality we're measuring blood pressure and talking about reductions in blood pressure. So office blood pressure, I agree with the two others here. Double digits, right around 10 or more, is appropriate. We're going to see, theoretically, in the vast majority of studies that do 24-hour ambulatory blood pressure monitoring, you see less reduction because they're starting off at a lower blood pressure over the 24-hour period because it encompasses the nighttime nocturnal dipping, all of that. So I think if we see somewhere in the at least six, but probably more in the six to eight for ambulatory systolic 24-hour mean blood pressure, I think that's definitely a win. And more than that is appropriate as well. You compare it directly to the Advance- HTN trial, where it wasn't nearly that. And so that would be what I would think. To, Luke, and Matt, and Rhian, I presume you're talking about a placebo-adjusted change within all of your numbers, or were those absolute figures? Those are placebo-adjusted. Yeah, those are placebo-adjusted. Okay. Thank you. Rami, thank you for the question. One more, if you don't mind. I guess on the flip side, what potassium levels do you start to be concerned about hyperkalemia with an MRA or an ASI? Rami, thanks for that. Matt, do you want to give a perspective and then Luke or Rhian? Yeah, my perspective is that I'm a nephrologist, and I deal with a lot of hyperkalemia. So I'm much less concerned than a PCP and often cardiologist because I deal with potassium, 6.5 or 7, which definitely I'm concerned about. I usually adjust other medicines. I use RAS blockade, aldosterone synthase inhibitors, spironolactone, medicines like that to balance other medicines. I usually kind of use them to keep potassium in the normal range. It's kind of rare that I run into problems, but it does occur. Anytime it's approaching 5.5, that's really when I kind of have to go beyond maybe the lifestyle changes, the diet changes, adjusting up the thiazide diuretic, things that I can usually do to mitigate that, or backing off other medicines that aren't working as well. We do have some potassium binders. I try not to use those, but those are pretty effective as well. So that's my perspective. Others are probably a little more cautious. Yeah. Matt? I wouldn't say necessarily more cautious. I'd say 5.5, right, is when you start to make some adjustments. The likelihood is that most of these patients that are going to be getting the ASIs, lorundrostat, are going to be on a decent dose of a thiazide-type diuretic anyway. So the likelihood of getting above 5.5, if they're following a low-potassium diet, is pretty darn low. I should say I have a lot of patients with primary aldosteronism, and I deal with a lot of hypokalemia. Basically, I'm trying to keep my patients off potassium supplements, which are very large and difficult to swallow, and not many of my patients need to take potassium pills because I use the medicines to balance the potassium. Rami, just to frame what we've heard in the market and the primary care voice, it's usually incidence of 5% or lower. Physicians are very comfortable with. Just as a reminder, and I think Matt covered it, we saw about 3.7% incidence above 6, and with the 50 milligram, even going down to the 5.5-6 range, really modest changes. So it's something we'll definitely be looking at in the pivotal program. Got it. Thanks so much. You bet. Thanks for the questions, Rami. Our next question comes from Richard Law at Goldman Sachs. Please go ahead, Richard. Thank you. I want to start with the three experts. Who do you think are the patients that will benefit the most or suitable for lorundrostat or the ASI class broadly? And how do you think about using this class of drug in a third and fourth-line setting ahead of calcium channel blockers or MRAs such as spironolactone? And then I have a follow-up too. Yeah, maybe we'll go reverse order. Luke, then Matt, then Rhian. Luke, what do you think? So yeah, so I think it can be used both, probably as third or fourth-line, depending on what the data show. I think there's a clear role for it in resistant hypertension. So patients already on the ACD combination. We know, as Matt's slide showed, spironolactone has been around for 65 years, and people still don't prescribe it, right? And there's a reason for that. There's side effects, antiandrogenic, etc. So there's a clear role there, I see. Amongst patients with uncontrolled hypertension, let's just say they're on a fixed-dose combination, like a thiazide-type diuretic and a RAS blocker, particularly in that patient phenotype, perhaps it's those patients with obesity with autonomous aldosterone production, I could see this being used as a third-line drug. Yeah. Well, first of all, all my patients have resistant hypertension. So obviously, resistant hypertension is the obvious group of people. Patients that don't, I also have a lot of patients that have adverse reactions. Spironolactone, obviously, gynecomastia. Some people don't even want to take it because of that. I still use quite a bit of it and have issues with it. The patients that I really can't wait to get my hands on this in clinic are for people with bilateral primary aldo that will not benefit from surgery, and that's a much bigger population than we identify. There's such a screening rates are less than 5% in most people that should be screened or screened for it, and then 50% of those people with primary aldo would not benefit from adrenalectomy. They need to be treated with medicines. So those are the people that I'm dealing with. and there's other populations as well I think would benefit. but those are the big ones. Very good. Rhian? Yeah, I'm in total agreement. Also, the patients I see in my clinic are those with complex hypertension, usually resistant hypertension referred by cardiologists or family doctors, and indeed, I concur with what has been said. I think there's huge potential for this drug for third-line treatment, and I think it will be very interesting to see as these studies emerge in terms of the relationship to obesity, whether there is indeed added benefit in patients who've got comorbidities, knowing that aldosterone has these pleiotropic effects, so I think with time, it will be, we'll know more from the trials as to whether there is an added indication, but at the moment, there's huge benefit in resistant hypertension, as Matt said, in those patients who have bilateral hyperplasia and primary aldosteronism. Very good. Thank you. Rich, you had a follow-up question? Yes, I do. Yeah, thanks for letting me ask my follow-up. So Dr. Laffin mentioned that 66% of patients have BMI greater than 30 in the Advance- HTN study. It seems like the study is skewed toward obese-related hypertension patients. Is there anything that you want to learn between the obese and non-obese populations, and how do you think about the treatment effect between these two different patient populations? Yeah, Rich, let me maybe make a comment and turn it over to Luke. We clearly saw a linkage between elevated BMI and response to lorundrostat. It fits the biology that I think you heard all of the speakers opine on this linkage between visceral adipocytes and dysregulated aldosterone. But we didn't restrict the inclusion criteria for either Advance or Launch. Both have BMI inclusion of 18-40 because we want to continue to investigate it. We believe it's a continuous variable that we'll be able to see. But Luke, if you want to add anything to that, it's something that we're excited about. We believe the science is there, but need to validate it within the larger studies. Yeah, I mean, I would agree with that. It needs to be validated, right? It was pre-specified in Target, which showed potential interest. I wouldn't necessarily say it's skewed toward that. I mean, that's just when you run a blood pressure study in the United States, almost everyone has a BMI over 30. You look at PRECISION, the aprocitentan, which is a good 30% of those had a BMI under 30, and then the rest were 30-40 or greater than 40. So it's pretty much in line with clinical practice, definitely in the United States. Yeah. Thanks, Rich. I thank you. Thanks for the questions, Rich. Our next question comes from Seamus Fernandez at Guggenheim. Please go ahead. You might be on mute. Okay, great. Can you hear me? Yeah, we can. Yes, we can. All right, great. Thanks, so just wanted to follow up a couple of questions. Maybe first off, for Dr. Laffin, can you maybe give us a sense? It sounds like there's a high percentage of patients who are African American. In the Advance-HTN study, over 50% are African American. Are there any potential concerns or issues around the performance of aldosterone inhibitors or upside case where you've seen MRAs or other aldosterone inhibitors perform better in an African American patient population? Just trying to get a better sense of, I know that these are patients that are affected by resistant hypertension, but wanted to just better understand what you've seen from drugs with a similar mechanism in that setting. Yeah. Look, real quick, just Seamus, thanks for the question. To remind, race was a pre-specified analysis we did in Target-HTN, and we didn't see a differential as far as predictor for response, whether Caucasian or African-American. And that's actually a positive, frankly, because a lot of the agents that are currently available don't work as well in Black or African-American population. But it's something we'll continue to look at. But Luke, maybe the scientific thought to Seamus' question. Yeah, I mean, I think that patient population responds very nicely, right, to MRAs when we treat them clinically. One of the factors that is also associated with likely the high proportion of African-American or Black subjects is the stringent blood pressure criteria for entry, right? We know that population is the one with truly uncontrolled hypertension, particularly when we do a cuff in the office, and then we do a cuff with ambulatory systolic blood pressure monitoring. So I think that's why, as well as operationally, from a Mineralys perspective, finding sites that had a significant proportion of potential African-American subjects. But we should see very good response to them, particularly in combination with that background therapy, I would imagine. Great. And in terms of some of the competitive agents that are out there, we know baxdrostat is conducting an extended clinical program almost slightly behind where Mineralys is. Can you just do a little bit of a compare and contrast of your thoughts of the benefits or limitations of a 24- 30-hour half-life with baxdrostat versus a 10- 12-hour half-life with lorundrostat? Where do you see the efficacy and safety potentially shaking out between and among the two products? And does half-life play a meaningful role, in your opinion, on potential impact on 24-hour ambulatory versus AOBP? Matt, do you want to maybe start off? Yeah. Luke and Rhian, the comment? Yeah. I mean, I've thought about that. It's mostly theoretical discussions that I've had. The thoughts that could favor lorundrostat, the shorter half-life gives you a little bit of an off period, which is, I think, obviously still good enough to achieve blood pressure control, but potentially maybe give the kidney a little extra time to excrete some potassium. Maybe it could alleviate some potassium hyperkalemia risk. Also, I think the ASIs compared to mineralocorticoid receptor antagonists could potentially also leave the MR open a little bit to enable potassium excretion. So we'll see. I mean, it's obviously still a concern. The other, I think, liver versus renal clearance and whether you get into trouble with patients with lower GFR is a question that's of relevance as well. So we'll have to see about that. But I like the selectivity over cortisol, I think, for the lorundrostat. Looks like it's really good, but I haven't seen the data on all of the agents that are out there for ACTH response, so. Luke or Rhian? Yeah, I would agree with Matt, and I think sometimes some of the longer-acting agents may have less benefit in terms of too low blood pressure effects, but again, we'll have to see how this all pans out with the trials. Again, as Matt said, I think some of this is probably academic, but yeah, I don't think it's a major issue at this point. Yeah, I agree with Matt. I mean, to your question, Seamus, about efficacy, what we know, at least that's in the public domain, is that baxdrostat has one positive trial and one negative trial, right? Lorundrostat has one positive trial for blood pressure lowering, and then we'll have to see what the data shakes out for the upcoming year. Very good. Thanks, Seamus. So our next question comes from Mike Di Fiore at Evercore. Please go ahead, Mike. Hey, guys. Thanks so much for hosting this event and for taking my questions. Can you hear me? Yeah, we can, Mike. Great. Thank you. I just want to revisit the powering of the Advance-HTN trial. I think in the past, you said the trial is powered to detect an 8-10 placebo-adjusted reduction in blood pressure. Is that 8-10, does that refer to AOBP or 24-hour ABPM? And I have a follow-up. Mike, the Advance-HTN has 90% power to detect 7 mm Hg placebo-adjusted change, and that's with 24-hour ambulatory. Okay. Okay. And for the KOLs on the line, you said that if the trial does, in fact, achieve a 6- to 8-mm ABPM reduction, that would be deemed appropriate and clinically meaningful? Luke, do you want to? I think you were the one that made that comment with the ABPM, Luke. Yeah, in that ballpark, right? I mean, and that's taking into account what we would typically then expect from an office blood pressure as well. So in that sort of 6-8. And that's just comparing it to other current therapies that have been recently approved, right? Like aprocitentan, which is in the 4-mmHg range. You look at renal denervation in the 4- 6-mmHg range. You want to see something more than that, essentially. Got it. And I have a follow-up question with regards to hyperkalemia. When you think about the temporal dynamics with regards to hyperkalemia, say, in Target-HTN, the trial was only eight weeks long. By contrast, the Advance-HTN trial is 12 weeks long. So given the longer follow-up period of about four additional weeks in Advance-HTN, could we, at least theoretically, see potassium levels come down, or does the potassium remain increased over the entire period of time? Luke, do you want to give your thoughts? Sure. Probably it's going to stay in the same range after the drug gets to steady state, unless patients make significant lifestyle changes. We may see a slight shift downward, but probably going to stay in a very similar range compared to, say, six, eight weeks versus 12. Okay. Mike, that fits the profile we saw in Target. Within the first couple of weeks, you saw the 0.25, 0.3 millimole per liter increase, and then it stabilized over the remaining six weeks. Congleton, I was going to suggest that when we take aldosterone-producing adenomas out of a patient, potassium is the quickest thing to change. The next day, you take away the potassium supplement. So I view it like a switch. I mean, it happens quickly. The blood pressure takes a little bit longer. So I think the people that are going to get into trouble tend to get into trouble quickly. Or if you give them years of it, life happens and other things come up. Got it. And it's a quick follow-up question. It's very helpful. Could you review the, I guess, what's the protocol implementations? Like, say, if a patient gets up to 5.5, that 5.5 potassium level, I mean, is the dose held? Is it decreased? And if so, is the patient data censored from that point on? Any color there would be helpful. Dave, do you want to address that one on the design? Yeah. Yeah. Good question. So if it's between the upper limit of normal, 5.1 and 5.5, we just observed. If it was 5.6- 6, we held the dose until it was below 5.5 or so, and then we started at a lower dose. The one thing we didn't do was to adjust the background regimen because we really wanted to know what lorundrostat did. But we heard earlier, that's really the approach people take in the clinic. Leave the lorundrostat the same and adjust the other medicines to get that goal. So that would mean that we can maintain the dose of lorundrostat, although we did reduce it in that circumstance in this trial. Okay, so if it's between 5.5 and 6, you just hold the lorundrostat dose and observe? Hold and then restart at half the dose. At 6.5. Okay. Very good. Mike, thank you. Thank you. So our next question comes from Annabel Samimi at Stifel. Please go ahead, Annabel. Hi. Thanks for taking my question for hosting the call. So I want to direct this at the physicians. Just practically speaking, when a patient comes in and has or has not responded to a high-dose diuretic or a high-dose calcium channel blocker, and they are compliant, I guess, what is the likelihood that that patient has an aldosterone mechanism at play? Are there many other mechanisms that could be at play other than aldosteronism? And I guess what I'm getting at is, from a diagnostic perspective, do you think it would be a big leap for physicians to identify without any major tools who that ideal patient would be who would respond to an ASI versus adding any other mechanism, an ACE or ARB or calcium channel blocker? So I guess that's my first question. Maybe we'll go in new order. We'll go Matt, and then Luke and Rhian, just really kind of quick responses to Annabel's question. Yeah. Thank you. I'm very primary aldosteronism-focused. And patients with PA are pretty refractory to pretty much any medicine that doesn't target aldosterone or the MR. And then in some people that just have pure PA, you may only have to give them spironolactone or an MR antagonist or this drug alternatively. So you'd hypothesize that low renin patients would respond better. But I was surprised that in the initial study, the patients with high renin and patients that were treated with thiazides actually responded just as well or better. So I mean, that broadens the reach of the medicine, but it was surprising to me that maybe those other agents increased the response. I shouldn't be surprised, I guess, but. Rhian? Yes. Thank you. What we do know is that those patients with resistant hypertension, a large majority of them do seem to have hyperaldosteronism as an underlying pathophysiological mechanism. I call spironolactone or agents that would target the aldosterone system my wonder drug because the effects are so profound. But what I can say, and this is included even in our 2024 ESC guidelines, is I think we're going to be seeing much more screening upfront for hyperaldosteronism. And so we're likely to be picking up many more patients with hyperaldosteronism, even those who may not have resistant hypertension. So yeah, I think the component of those patients who non-responded to our usual treatments or as diagnosed as resistant hypertension, a large percentage have aldosterone-sensitive mechanisms. As I said, as we screen more, and the trend will be for screening more based on guidelines, we will be picking up more of these patients. I agree that we should be screening more for primary aldosteronism. I think the best data comes with two points of data I'll point to. Pathway-2 trial was patients with resistant hypertension, okay? And even across high levels of renin, so not suppressed renin, MRAs still were much more effective than alpha blockers and beta blockers. So that's a very important point. Addressing that aldosterone system, even in non-low renin hypertension, so just essentially hypertension, is effective. Number two, your question about what percentage of patients have aldosterone amongst those uncontrolled or resistant hypertension. So that's observational data from four major hypertension centers published, I think, about four years ago. And amongst uncontrolled treated resistant hypertension patients, you're looking at least 20-25% in that range that have a true diagnosis of PA, primary aldosteronism. There's also those ones that may just fall, because it's a spectrum of disease, just below that threshold. They're also going to respond nicely. So we're talking at least a quarter, maybe probably more. Okay. And I guess to follow on that in that vein, does that give you increased comfort in the Advance-HTN trial, I guess, from the inclusion criterion that the population could be naturally enriched for patients who have hyperaldosteronism? Luke, do you want to maybe hit that one real quick? Yeah, because I mean, we know that on a very standardized, very strong guideline-recommended regimen, they're still uncontrolled. So naturally, yes, you're going to see a significant percentage of patients, and we can call it enriched for autonomous aldosterone production. But I will point to the fact that in Target, it didn't matter if your renin was suppressed or not. With that 100-milligram dose, you saw a pretty similar blood pressure reduction. And that speaks essentially to that Pathway-2 trial data that I alluded to earlier. Thank you, Annabel. Thanks. So our next question comes from Saadia Rahman at Wells Fargo. Please go ahead, Saadia. Hi. Yeah, Saadia on behalf of Mohit Bansal. Thanks for taking my questions. So a question on the trial design differences between Advance and Launch, particularly with regard to the standardized background regimen that's used in Advance. How do you think about how that could impact maybe the differences in the effect size between these two trials? Could that influence the outcome at all? And also related to that, do you see maybe some limited read-through because of these trial design differences from one trial to another? Yeah. Luke, given your engagement with the advanced study, do you want to just talk about the distinction of the populations between the two pivotal studies? Yeah. I mean, I wouldn't necessarily. They're definitely not conflicting. I think they're complementary, right, in terms of what they're providing. And as I alluded to in my presentation, what is really focused on is providing data for clinicians and payers. And Launch reflects essentially a real-world experience. You're on whatever medicines you're on, two-plus medicines. Take the drug. This is how much office blood pressure lowering you get. Whereas Advance gives us a little bit deeper dive to say, "This is the 24-hour blood pressure on this optimized regimen." And that's important for clinicians, but that's also important for payers too, when they're thinking about a market that's highly genericized to say, "How much blood pressure lowering?" So when you look at it, again, the primary endpoint's different. It's office versus ambulatory blood pressure monitoring. And it's not necessarily apples to apples there when you're talking about it. Thanks, Luke. Thank you. Do you have a follow-up, Saadia? Yeah. So also on the subgroup analyses, can you discuss, apart from obese patients, are there any specific subgroups that you are focused on, which are most important? And will that analysis drive your clinical decision-making at all in patient selection for this drug? Thank you. Yeah. Thanks, Saadia. I'll go ahead and address that. We are going to continue to pre-specify various indicators, markers. In our effort to identify an endophenotype, you can certainly expect we're going to look at race again, as we did in Target, look at gender, some of those other elements. We'll definitely be pre-specifying analysis for those subjects on two meds or those on three in advance or three or more in launch so that we get a really clear picture of the resistant population versus the uncontrolled, and certainly, as we share top-line data either in press release or in future publication, we'll further clarify what other markers or endpoints we looked at. Thank you. Thanks. Thanks for the question, Saadia. Our last question comes from Matthew Caufield at H.C. Wainwright. Please go ahead, Matt. Great. Thank you. Can you guys hear me okay? Yes, we can. Awesome. Thanks a lot for taking our question. So there is the distinction for Advance having the four-week analysis with patients uniformly at the 50-milligram dosing and then the 12-week primary analysis, obviously. Can you remind us of the best way to frame expectations between these two time points? And then also, what is sort of the best perspective for considering read-through to the 12-week top line for Advance? Thank you. Dave, do you want to take that? Sure. So the difference between four and 12 weeks, well, there's really two parts to your question. The first part would be, will four weeks read through to 12 weeks as I understood it? And it will. We see the majority of the response in our trials occurring by four weeks. However, as you go longer, some of those non-traditional effects on blood vessel, particularly the endothelium, may start to improve as well. The four-week will not overestimate the response. It may underestimate it at 12 weeks and even beyond, but it won't be a big difference at 12 weeks. The other thing is, at four weeks, every subject in the trial, in the launch trial, is on 50 milligrams. In the third cohort after that, if they haven't achieved their target, they'll be increased to 100 milligrams. At four weeks, we have just the comparison between 50 milligrams and placebo with a larger sample size. At 12 weeks, we'll have two comparisons: 50 milligrams versus placebo and the escalated population versus placebo. Somewhat subtle differences. We're superpowered for all of them. Thanks, Dave. And thank you, Matt. Thank you. Thanks for the questions, Matt. So this concludes our Q&A session for today. I'll now turn it back over to Jon for closing remarks. Yeah. Thank you, operator. And thank you to everyone for joining us today. A special thanks to Professor Touyz and Doctors Luther and Laffin. Clearly, very busy schedules. We appreciate your time. I know the audience appreciated your expertise in addressing their questions. We're very excited about the progress we've made in advancing our pivotal clinical trials, and we remain enthusiastic about the upcoming data announcements in Q1 and in mid-first half 2025 for Advance- HTN and Launch- HTN, respectively. Thank you, and we appreciate your attendance. This concludes today's conference call. You may now disconnect your lines. Thank you for participating and have a great day.