All right, good morning, everybody. Thanks for joining us for another fireside chat here at Guggenheim's second annual Healthcare Innovations Conference. I'm Seamus Fernandez, one of the senior biopharma analysts. To my right is Mineralys CEO Jon Congleton. Really excited to have you here talk about the program. It's been a very big year for Mineralys and the ASI class. Yeah. Of drugs, for sure. Maybe just, before diving into the lorundrostat data, maybe you can just kind of talk to us a little bit about the unmet need in hypertension, and the opportunity for lorundrostat and the overall ASI class. Yeah, happy to do it. I really appreciate the opportunity to be here with you, Seamus, at the Guggenheim Conference. For those of you that do not know me, I have been in the industry 38 years, started my career carrying the bag, selling antihypertensives. All these drugs that are generic now, I am old enough to remember when they were launching. This has been an issue that we have been dealing with in the 40 years I have been in the industry. I was recently at the American Society of Nephrology meeting this past week, as well as the AHA, and this continues to be the leading modifiable risk factor that we are dealing with globally. About 10.8 million lives per year are lost to hypertension-related comorbidities. We have seen over the last several years the goal for getting the blood pressure progressively come down. What that has translated to is, if you look at in-hands databases, we've gone from about 40% of the patients not getting, about 40% of the patients treated getting to goal to now it's about 20%, because the goal is now at about 130 over 80 for the majority of patients. Those with other comorbidities, it's actually down to 120. The challenge is, we're progressively seeing the benefit of getting your blood pressure controlled, but we haven't had a lot of innovations in the last 20 years to help patients do that. I would say a lot of the existing treatments, while very good, aren't addressing what a lot of patients need to have addressed, and that's dysregulated aldosterone. That's why I'm thrilled about what we're doing. I think we have a best-in-class molecule that's targeting what needs to be targeted to help these patients get to goal. You know, at the end of the day, the need is significant, and the impact of uncontrolled hypertension is monumental. Great. Maybe just talk a little bit about the ASI class, how that integrates into the treatment algorithm, going forward. Yeah. From our perspective, you can count about 30% of all hypertension patients probably have some form of dysregulated aldosterone. It's important to talk about dysregulated. You could say overproduction or elevated, but there are certain segments of patients that it's not so much about being elevated, but it's the sensitivity to it. Black or African American hypertension patients are a case in point. They can tend to have lower aldosterone, but they're more sensitive to it. Dysregulated is the proper term. ASIs have been a class of drug under development by industry for over 10 years. Some of the first-generation ASIs really struggled with selectivity and the proper half-life. Selectivity becomes critical because aldosterone is one of our ancient evolutionary hormones. It has tight homology with cortisol, about 93% similarity. If you are not a selective aldosterone synthase inhibitor, you end up inhibiting both cortisol and aldosterone. You clearly don't want to inhibit cortisol. Lorundrostat has best-in-class selectivity for aldosterone, about 374 to 1. We think it has an ideal half-life of 10- 12 hours. Aldosterone is one of those hormones that surges pre-wake, peaks mid to late morning, and then tapers off in the afternoon. Really ideally matches lorundrostat's half-life, as far as 10- 12 hours through the course of that day. We also believe that aldosterone, while it drives volume, which is important for hypertension, it also has other mechanisms through non-mineralocorticoid receptor pathways, GPR30 being a case in point, that can drive inflammation, fibrosis, oxidative stress. That's why we think there's utility beyond hypertension in a lot of the overlapping comorbidities, such as CKD, OSA, that we have programs in, but also in things like heart failure. There's a lot to these ASIs beyond just hypertension. I think that's kind of the beachhead. That's the beginning of the journey. I think the promise of these molecules far extends beyond that. Great. You know, let's talk about lorundrostat data. You know, on its own, before we get to some of the competitor data sets, you know, ADVANCE HTN, maybe just remind us from a starting point there, what that study was geared to understand and what it showed? Yeah. We've always been really mindful of the biology of this class of drugs and then the pragmatic market presence for it. The biology, we know that with the ASIs, and we see it with our molecule, with the other contemporaneous molecules in development right now, when you lower aldosterone, you see renin increase. We think you'll have a need for an ACE inhibitor or an ARB that inhibits that pathway. Diuretics drive volume. Volume is such a big component of hypertension that we think that combination of an ACE, ARB, diuretic, and an ASI biologically makes sense. We have always studied lorundrostat going back to the proof of concept in the third line or later position. We think biologically it makes sense. From a pragmatic standpoint, from a payer, from a physician's vantage point, that's really the ideal entry point. and really moving forward into a launch position, and I think resistant hypertension, fourth line is where there's really open field running. There's a lot of confusion about what to do, what to use, dissatisfaction with what's available. I think that's going to be a clear entry point in the marketplace for a novel innovation like this. Moving to third line is going to very effectively do that. We have, through our proof of concept, our pivotal studies, ADVANCE and LAUNCH HTN, always looked at patients that are failing to get to goal on two or more meds. Generally, the mix that we've had in all of those trials is almost a 50/50. Some trials a little bit higher, 60/40, as far as the mix of uncontrolled and resistant. I've been really pleased to see in the data that the team has generated that regardless of using a third line or fourth line, you're getting really robust response. I think it just speaks to the fact that those are subjects that are dealing with that dysregulated aldosterone. If you target it with a kind of molecule like lorundrostat, you're seeing really robust reductions in BP. You know, typically third or fourth line agents, calcium channel blockers, alpha blockers, beta blockers, you get about a 5 millimeter, 6 millimeter mercury improvement in BP. We're seeing absolute changes here of 15-19 millimeters of mercury. I mean, those are transformative. Those are the kind of numbers that get patients to goal and ultimately help with their cardiovascular risk. Great. Can you also walk us through a little bit of the sort of differences in the endpoints, the, you know, absolute, you know, ambulatory blood pressure monitoring for 24 hours, you know, versus the sort of point-in-time estimates? Yeah. There's really three ways to measure blood pressure. The standard that we're all probably accustomed to, that's the in-office measurement. You can do 24-hour ambulatory, which is a cuff on your arm. It takes readings about every three times an hour while you're awake, two times an hour while you're asleep. Then you can do in-home measurement. We've used all three in AdvanceHTN. We've reported out on the 24-hour ambulatory for that. For our larger LaunchHTN study, our real-world study, we're measuring it the way that it's measured right now in practice, and that is in the office. The challenge typically is that, unfortunately, we probably all do this when we go in for our physical checkups, they'll put a cuff on, do one measurement, say that's your blood pressure. There were guidelines out from the AHA in 2019 that said the worst thing you can do is use your first measurement, because think about your experience. You're running late, you're in a doctor's office, you're anxious about that, your BP's naturally elevated. We have, from the beginning, followed the guidelines recommendation and taken five measurements and averaged the last two. The goal of that is you want to get rid of those false reads upfront, because there's a big issue with white coat hypertension and reading that in-office blood pressure. We want to make sure that we're getting the true sense at baseline and through the time course of the study, what is that patient's true BP. That, I think, has worked very well for us. I think we've controlled the background noise. All three are important, are informative. The 24-hour is a very informative measurement. The challenge is nobody really uses it in the real world. To really get a good sense for that in-office measurement, we've just always efforted to do it proper and control for white coat. You know, maybe we can talk a little bit about the primary endpoint, of, you know, of 24-hour ABPM. You know, we also saw the AstraZeneca's baxdrostat data. I mean, this is an opportunity for us to maybe understand a little bit of the compare and contrast. Right. you know, how are, how is that study different from Advance, from AdvanceHTN? How's the primary endpoint measurements different? And then how might the data analysis also be different? Right. First, it's important to delineate the study participants. What were the participants like between BAX24 and AdvanceHTN? BAX24, the study participants look a lot like BAXHTN, look a lot like LaunchHTN. In other words, they were kept on their existing background meds. They had a run-in period where you're ideally trying to get them compliant to their medications so that when you do your measurement for randomization, you've got a sense for, are they truly uncontrolled if they're compliant to their medications? AdvanceHTN is a completely different design and construct that we did with the Cleveland Clinic. We went to Steve Nissen and Luke Laufen, who, Steve's the Head of the group and Luke's the Head of the hypertension division there at Cleveland Clinic, and said, "All right, we have these thoughts about how to develop this molecule." They said, "If you want to put it to the most rigorous test, do this design of a study." The design of AdvanceHTN is we basically take patients off their background medications and we harmonize everybody to an American Heart Association prescribed treatment guideline at max dose and use smartphone technology for three weeks and then through the course of the study to ensure compliance. What that basically does is it eliminates what's called apparent hypertension and gets your population to be confirmed hypertension. The distinction is apparent is your existing world population, which is fine. It does not mean it is not a good study, but those patients may not be on the right drug, may not be on the right dose, may not be fully compliant. If you were to get them on the right drug, right dose, compliant with existing meds, they may be able to get to goal. There is some space for improvement within that kind of a population. Within an AdvanceHTN population, I mean, they are on high dose olmesartan, the most potent ARB. They are on high dose diuretic, either indapamide or hydrochlorothiazide. If they are on three meds, they are on high dose amlodipine, a dihydropyridine calcium channel blocker. These patients are getting the best of the best. If they filter through that, fully compliant and are still hypertensive, those are the patients that went into Advance. A completely different population that I think needs to be the starting point for any kind of contrast between, because I don't think you can compare, you can maybe contrast. You look at that and then look at the baxdrostat or the BAX24 data, AdvanceHTN data, absolute change on 24-hour ambulatory was roughly the same. I think it was 16 millimeters with one, 15, 15 and a half with AdvanceHTN. Even then that's difficult to compare because in AdvanceHTN we have all of the patients in there. We know with 24-hour ambulatory, we're asking the patients to do a lot. In the case of AdvanceHTN, we did a baseline measure, a week four measure, and a week 12 measure, which means they're wearing this device for 24 hours. They're sleeping with it. They're wearing it through the course of the day. You know, you allow an allowance like maybe an hour to take it off for the shower or an activity or whatever. There are challenges with that, just getting patients to comply to that. Does the cuff stay in the right position? Does it move around? You have to account for some level of data missingness. It does not necessarily mean patients dropped out or discontinued. It is just the logistical challenges of that device itself. We knew that would be the case. How you handle data missingness is you do proper imputation. Those imputations are based on, is data missing at random? Is it not at random? I am going to get to the deep end of the stats pool. I do not want to go there because it is not my expertise. The key is you have got to account for the data. That proper accounting from my perspective is what we did, what we did with AdvanceHTN, when it was accepted as a preliminary presentation at ACC, when it was published in NEJM. I'm comfortable with how we've done the imputation based on the dialogues we've had with the agencies. We've talked about the inclusion of AdvanceHTN into the NDA. In the case of BAX24, there was about an 18% exclusion of data, and what was presented was at least square mean. It is difficult to say, well, if I do back of the envelope calculation for most rigorous imputation, might their data be this? We just cannot do that. It is not interpretable from our perspective. It would be interesting to see the publication and see how the missing data is accounted for, how it is imputed, and what that translates to from an effect, efficacy standpoint. Even when that's done, it's still not a comparable data set because they're just vastly different populations. Not the least of which, 50%, 53% specifically of the AdvanceHTN population was Black or African American, which we know is a higher risk population, harder to treat, tends to have more intransient form of hypertension. Both in design, in study participants and in demographics of that population, Advance is really kind of the ultimate challenge. I think lorundrostat met that very well. What's also interesting, I think, is as we look at the absolute number, and I know placebo-subtracted is the standard here, but the absolute number consistently seems to be in that mid to upper teens for both products in class, pretty consistently, especially at the 12-week data point. Right. Can you just help us understand, you know, what can happen with placebo even when you do it as, as rigorously as you did in AdvanceHTN? Yeah, there's, you're right. These drugs tend to have an absolute reduction. I think baxdrostat, baxdrostat 24 were about 15-16. LAUNCH HTN, we had about a 19 millimeter absolute change. ADVANCE, LAUNCH was with in-office measurement, ADVANCE 24-hour ambulatory about 15. I mean, these are, these are transformative numbers. On the one hand, you would think, all right, scientifically, let's focus on the placebo-adjusted number, but we go out and do market research with physicians who are prescribing in this space, and they're like, I don't do placebo tests in my office. I want to know what is going to be the absolute change. That's where they're really motivated. I think that's what's meaningful. If you look at the placebo change, that's where you can have some variability as far as the measurement, the response. ADVANCE HTN, it was kind of interesting. Again, we took these patients off of their background meds and put them on an optimized treatment regimen, did a three-week run-in. There may have been some residual benefit into the early part of Advance post-randomization, because what we saw was at week four, the placebo-adjusted change was about 7 millimeters of mercury. That stabilized. At week 12, it stayed about 7. Getting caught up in, all right, what's the placebo-adjusted figure? Again, there's a lot of nuances in the study, what's going on in the background, how are you doing the measurement? You know, we're very comfortable with what we've seen in the absolute figure, the rigor of that study. In Launch HTN, I think we saw about a 7 millimeter mercury change in that background population as well, if memory serves. It's noise that you try to control for. I think what we've done, what the team has done really well is control for that so that we get a true sense for what is the drug doing separate from that, but what's it doing in absolute change? Maybe we can talk a little bit about just sort of the market opportunity, and, you know, how you think about the sort of scale of the opportunity. We talked about it a little bit, but, you know, the competitors now talking about this as a $5 billion-$10 billion potential market opportunity. You know, and I presume that's more talking about the ASI class as a whole. Right. Help us understand, you know, how you guys are thinking about the size of the market opportunity, and the consistency with that, and, you know, basically how you would market into, you know, this population? Yeah. The numbers that I'll reference here are really U.S.-based. We think about the market opportunity, that third line and later is about 20 million patients. You can kind of split it into two buckets. Fourth line or later, the resistant population, about 10 million, those that are uncontrolled, about 10 million as well. There are 20 million patients there. There has clearly been a lack of innovation in the hypertension space for 20-25 years. How this condition is treated is no different than when I was a rep 38 years ago. As far as ACE inhibitors, diuretics, calcium channel blockers, there is this kind of rote, just keep adding medications on. That is, I think, an opportunity that we can change. The reason I think we can change is because of the magnitude of effect that we've seen, which I think that blood pressure reduction that we see with lorundrostat is indicative of the fact that these patients that can't get to goal, aldosterone is their problem. You know, we've seen some really nice innovations with renal denervation, with endothelin receptor antagonist, even angiotensin-agent-directed SR RNA treatments, but they don't have the magnitude of effect that this class does. I think that fundamentally means we're hitting the right target at this point. I think that's critical. Why I say that is because I think that's what breaks up a little bit of this inertia within this treatment space. I think when you get to resistant patients, that is where physicians really struggle with, how do I help my patient get to goal? Because fundamentally, I know they're on a path that's either going to lead to a stroke, a heart attack, progressive kidney disease, dementia. The list goes on and on. If you don't dam this river, you're going to have end organ damage, without a doubt. I think the size of the market, I think where we're targeting this market opportunity, where the need is most evident, and most clear, creates that market opening. We've seen that with the research we've done, not only with physicians. I would say for that third, fourth line target, it is largely cardiology and high volume primary care that are driving that. There's some nephrology and endocrinology there, but those are the two big specialties driving that. They are keenly interested based on some of the market research we did with our data, 95% probability or intent to prescribe if this drug's available. Those are huge numbers that speak to the desire for innovation, the unmet need. I think that creates the opportunity. We've talked to payers as well. You know, access is never easy. I'm not going to say it's easy, but there's a clear path when you get to third and fourth line, with right price, right rebate structure to minimize utilization management so that you don't have these massive hurdles to access. At the end of the day, it does kind of come down to what does the data look like? What are you doing for the patients? If it's that robust of a story, then you can create the demand and you can create the access. Again, thinking about who are the prescribers in this space, if you think of or look at IQVIA data and say, all right, who has put pen to pad and prescribed something, it's big. It's a million docs. If you begin to narrow that, say, all right, let's look at who's prescribing third line or later and where's that, say, top 50% of the market, suddenly that narrows very tightly, about 60,000 doctors, again, largely made up of cardiology and primary care. It becomes a much more targeted market opportunity, market entry. I think that's where the demand and access is. That's why I think there's an efficiency with this that on first blush, people think, oh, it's hypertension. You've got to have this massive commercial footprint. I just don't think that's the case. Let's talk a little bit about just one of the concerns with this class, has been, you know, potential for safety issues. You know, where are we with lorundrostat versus baxdrostat from your perspective? And is this sort of one thing that you would say is comparable in the class, or do you feel lorundrostat differentiates there? I think there's a differentiation. I think this class has a nice safety profile. Pretty much what you're seeing from an adverse event standpoint is all related to mechanism. It's frankly similar to what you see with other RAS inhibitors, ACE inhibitors, ARBs. That is electrolyte changes, so potassium retained or hyperkalemia and sodium depleted hyponatremia. You also see slight reduction in eGFR, but again, that's viewed more as a benefit because you're reducing blood pressure, you're reducing pressure on that kidney. eGFR goes down. It's a bit of an artifact, but that's ultimately a benefit. Then hypotension that you can see in some patients. As we look across these studies, again, at the risk of looking across different studies, different populations, the rate of potassium above 5.5% favors lorundrostat. That's what's considered mild hyperkalemia. The rate of hyperkalemia above 6% favors lorundrostat. That's your moderate. Again, this is where I think the half-life that we know works for 24-hour control may also be a benefit, that if you do have a patient that goes to an extreme above six, six, five, you could reduce either the dose or just discontinue, let the patient stabilize, and then do a restart. I think from a safety standpoint, it's well characterized. It's similar to ACEs and ARBs. It fits within the existing workflow of prescribers. They start a dose, have the patient come back in two- four weeks, and you're going to see these changes in that first two- four weeks. They tend to stabilize over time. I would say collectively, owing to probably the selectivity and the half-life, the on-target adverse event profile favors lorundrostat. We also just, you know, maybe just to wrap up, we did learn that, or at least there's strongly suspected that the filing may have already occurred at AstraZeneca. Can you just remind us the timeline for filing of lorundrostat, and, you know, perhaps where, you know, directionally, how separated the launch timeline might be, assuming a, you know, a standard 12-month review? Yeah, we're looking at filing by the end of this year, Q1 of next year. I've not, the most recent that I got from AstraZeneca is they had intent by the end of the year. I think at the end of the day, presuming a 12-month review cycle, you're talking months as far as separation between the two. A lot of people talk about first mover advantage. In my years in this industry, first mover advantage is not measured in months. It's usually a much longer timeframe. From my standpoint, these are very much going to be overlapping review cycles, approval cycles, launch cycles. Great. Unfortunately, we're out of time. Twenty-five minutes is never enough to talk about this category or lorundrostat and certainly baxdrostat as well. I really appreciate you spending the time with us, Jon. Yeah. looking forward to, you know, a lot of success, going forward. You're already on the path for sure. Yeah, I appreciate it. Thanks, Seamus.