All right. Good morning, everyone. Thank you for joining us for the Mineralys Therapeutics presentation. Happy to have Jon Congleton, CEO, little frazzle. I'm so excited. So sorry. So maybe we can just start. Tell us about yourself. Yeah. No, Jon Congleton, CEO of Mineralys. Great to be here. Appreciate the opportunity to present. Obviously, we're really excited about the work we're doing with lorundrostat. Clearly, significant unmet need. I mean, coming off the heels of the AHA that occurred this past week, and we continue to see a focus on cardiorenal metabolic. What are the drivers of that? We know hypertension is a huge component of that. As we've talked with you in the past, we think there's a clear linkage with obesity. Dysregulated aldosterone is a key component of what's driving that. We've been efforting this past year on the clinical programs that we have underway, leading them to a really exciting first half of next year with three different data readouts. So very excited to be here and talk to you about Mineralys Therapeutics. Okay, great. So first, why don't we look big picture and talk about the hyperaldosteronism population, whether it's broadly recognized today, whether they're easy to identify. And as far as the uncontrolled and resistant patients, are they broadly recognized as likely having hyperaldosteronism? So what are the factors that go into a diagnosis for them? Yeah, I think the overriding thought right now is that we're underdiagnosing hyperaldosteronism or dysregulated aldosterone. So that is one. Two, I think specialists are beginning to recognize that even when optimally treated, patients still not getting the goal, still resistant, that aldosterone may be a component of that. There's a lot of literature that looks at as you progress through stage two, stage three, and into resistant hypertension, the percent or prevalence of dysregulated aldosterone is much higher as you get into those resistant populations. It was interesting that the European Society of Cardiology meeting this past August, two things were of note. One, the European authorities lowered goal for systolic BP from 140 to 130, acknowledging the linkage to poor outcomes of BPs not below 130. But they also recommended that all hypertension patients get tested for aldosterone. Now, they're using an aldosterone ratio. It's not the most stable marker, but it was clearly an acknowledgment by the European Society of Cardiology that we're underdiagnosed and aldosterone driving the disease, and we need to do a better job of that, so I think there's this growing appreciation for aldosterone, for trying to identify it and then trying to match therapies to those patients in need. So the Europeans are there. How about the Americans? I think the Americans are likely to move in that regard. If you again talk to specialists, cardiologists, nephrologists, endocrinologists, I think they're progressively appreciating this linkage of the obesity epidemic to the aldosterone epidemic. But I don't know that they're quite there from a diagnostic standpoint. Okay, great. So maybe you can just share with us before we get into the trials, you can share with us what your key takeaways are from Target and how that's sort of allowed you to design the appropriate trials for Advance and Launch in the pivotal studies right now. Yeah, Target-HTN was really the first in an affected population. So if we go back to preclinical and Phase I, we had a real clear sense that lorundrostat could effectively lower aldosterone 60%-70% without affecting cortisol. And that was kind of job one for an ASI because historical, maybe first generation ASIs were inhibiting both, and you don't want to inhibit cortisol. What Target-HTN did for the first time in a hypertension population was give us a proof of concept that that reduction in aldosterone had a correlate reduction in blood pressure. It showed us that the safety profile was well within what we had hoped for as far as the effect on potassium. It also showed us or guided us to dose to be utilized because prior to doing Target-HTN, we were still debating QD versus BID. We know the half-life of 10-12 hours, on the one hand, gave us thoughts that it may be ideal for once daily dosing, but we needed to confirm that. And so Target-HTN really confirmed for us that once daily is effective 24-hour control and to do it safely. And then I think the other thing that Target-HTN was informative for us in the pivotal program were just some of the operational challenges in doing hypertension studies. So how we measure in-office blood pressure, how we capture potassium, how we track compliance, and the use of 24-hour ambulatory. So there were operational lessons for us beyond just understanding the molecule itself. Okay, great. So maybe we can talk about the Phase III program and what it is specifically that you're trying to draw out of each one. There's two studies that are designed differently. You have Advance, and then you have Launch. And maybe you can just help us understand both of those a little bit. Yeah, I think at the end of the day, Advance-HTN is a standardized background of medications that we're enrolling truly uncontrolled, truly resistant. Launch-HTN is, in essence, a confirmatory study of Target-HTN. Now, these are patients that may not be on the right dose, may not be on the right drug, right dose of that drug. So there's something called apparent versus true hypertension, if you will. And so I think what Launch-HTN and Advance-HTN does for us is it addresses that question for both of those populations of patients that are frankly treated by two different groups of physicians. So if you think about Launch-HTN, it's really a real-world study targeted at generalists, adding lorundrostat to maybe what is not an optimized background treatment, what may be apparent uncontrolled or resistant hypertension, but will be how the drug would be used within a generalist population. Conversely, Advance-HTN is really built targeting the specialist. So the specialist, these are cardiologists, nephrologists, endocrinologists. They're getting difficult to treat patients. They are the physician group that are most likely using the right drugs at the right dose and truly dealing with that true uncontrolled or true resistant population. And so in that case, we're going to be able to give them kind of a state-of-the-art, best-in-class data set that says, right, when you take patients and treat them with the right drugs at the right dose, ensure compliance, and yet they are still uncontrolled or resistant, this is what lorundrostat does for that subset of patients. Okay, great. So for Advance, obviously this is the next data set coming up. That's the first quarter. So what are the components there that give you confidence that, one, you have at least as good an outcome as Target, and second, that you have comfort that you're not getting that placebo response that has sort of derailed some other programs in the past? Yeah, I think it's a couple of things. It's the construct. So in Target-HTN, we saw that 8-10 millimeter mercury placebo-adjusted change for the ITT. We did pre-specify an analysis because we anticipated some level of synergy with the diuretic. Half of Target-HTN's patients were on a diuretic, half were not. Those that were, we saw about a 10-13 millimeter mercury drop. It was very informative for us. We've applied that to both Advance-HTN as well as to Launch-HTN. So thinking about how do we get from that 8-10 in Target-HTN and replicate that in Advance-HTN, I think that's a component of it as far as the diuretic as part of a background. Another part that is a little bit theoretical, but there's some data that would support it. That is when you optimize standardized treatment in that three-week period and still have subjects that are uncontrolled or resistant. There's a high likelihood that we will be enriching the Advance-HTN study population for an aldosterone-dependent form of hypertension. If that is the case, we know what lorundrostat does to aldosterone. So I think that gives us another comfort that we could see a replication of that eight to 10 that we saw in Target-HTN. As far as avoiding the white coat hypertension or placebo response that has been an issue with some of their contemporaneous hypertension studies, in Advance-HTN, the primary endpoint is 24-hour ambulatory. 24-hour ambulatory, just for those that don't know, it takes this device that has a cuff you put on your arm. It's like a little device you put on your belt, and it does three measurements per hour while you're awake, two measurements per hour while you're asleep. There are about 70-80 measurements over that 24-hour period, and it averages them. It takes white coat hypertension out. It takes masked hypertension out of the equation. It's the gold standard measurement. You typically see a placebo response of one to two millimeters of mercury, and so from our standpoint, using that gold standard as the primary endpoint really quiets that background noise, coupled with the fact that standardizing treatment during the active period, we have a lot of homogeneity as far as background treatment during the study period, so all of those things are built to quiet the background noise. But even in Launch-HTN, we're using in-office measurement, but using the technique that we used in Target-HTN, where we saw about a four mmHg change from a placebo standpoint. So we're going to continue that in both studies, but in Advance-HTN, the 24-hour ambulatory really does quiet placebo. Okay, so I guess I heard two things here, so for advance, two components. One, everyone's on diuretics, so not 50%, but 100%. Correct. If you have these patients screened during that period and they're still hypertensive after two to three drugs, then they are most likely aldosterone patients. There's a higher prevalence of it. Higher prevalence of it. So I guess to that point, how many patients? Well, again, I'm giving you complex questions. So let me just break them apart. On the diuretics, what makes the diuretic? What makes this so synergistic with diuretic mechanistically? So we can understand the importance of all these patients being on diuretics. Yeah. In its simplest term, you can break hypertension and the treatments into vasoconstriction or volume. Vasoconstriction, ACE inhibitors, ARBs, beta blockers, things like that. Volume tends to be diuretic. Now, volume is all about how do you just reduce blood volume, which is water, and the way the diuretics work is they basically help excrete sodium. Water follows volume, comes down, blood pressure comes down. The problem is there are multiple points in the kidney where that sodium can be reabsorbed. Even though it may be blocked with a hydrochlorothiazide, there are other places in the kidney where sodium can be reabsorbed. Now, in the case of an aldosterone-directed therapy, that's a different part of the kidney, so in essence, what you're doing is you're now blocking two points of reabsorption of sodium. That's why we anticipated that there'd be a synergy there. That's why we pre-specified the analysis in Target and then ultimately saw that benefit. And so just mechanistically, it makes sense as far as giving yourselves two distinct shots on controlling volume. And I think that's why we were very comfortable with the data we saw in Target. I was glad we had kind of a 50/50 split to show us that and confirm it. And now we're doing that for both Advance and Launch per protocol. Everybody's on a diuretic. Okay. Now, the second point is that most likely patients with hyperaldosteronism in the trials. So that's usually correlated with obesity. What% of the population in Advance has greater than 30 BMI? Yeah. We announced October 30th just a few baseline characteristics. The BMI was the most critical one because even though we saw a correlation to obesity in Target-HTN, we kept BMI inclusion criteria wide, 18 to 40 for both Advance-HTN and Launch-HTN because we want to confirm that finding. But we did note baseline BMI over 30 is two-thirds of the population in Advance-HTN. So in Target-HTN, the mean BMI was 31. Very comfortable that the mean BMI is going to be above that for Advance-HTN just based on the fact that two-thirds of the subjects are above 30. Okay, so that gives you, I guess, a little bit of an extra push or powering or not powering because that's using a statistical term. Yeah, I think it's de-risking. It's very favorable. Yeah, exactly. I think it's de-risking. But again, we want to confirm what we saw in Target-HTN with that correlation. The science supports why that is. There's a clear link between rising obesity, rising aldosterone levels in patients. And again, if we can identify those subjects, we know what lorundrostat does to aldosterone, and we think that's what yields an enhanced clinical response. Okay. And I want to just go back to this 24-hour blood pressure monitoring that you have in Advance. That's not what you had in Target. That was the AOBP, which is the office monitoring. So I guess one of the questions that we get is that when the secondary in Target was a 24-hour blood pressure monitoring, but that didn't quite show a difference in Target. So what makes you comfortable that it will show a difference here? Yeah. So in Target-HTN, we had office as the primary, as you said, 24-hour ambulatory was the secondary. As we got the data, there were out of the five doses tested in Target-HTN, four were active. The 50 and the 100 milligrams are obviously the ones we're moving into clinical development. But if we looked at the 25 BID, it had really good clinical response as well. When we looked at in-office measurement, 25 BID, 50, and 100 were all around that eight to 10 millimeter mercury reduction. When we looked at the 24-hour ambulatory, the 25 BID and the 100 looked great, and the 50 was this anomalous outlier. We've partnered with the Cleveland Clinic on the design of our pivotal program. We went to the experts there and said, "Help us sort through what's going on," and the 50 milligram, for whatever reason, had an abundance of patients, about half of them, that while they were hypertensive in the office, they weren't hypertensive on the 24-hour ambulatory, and that's what confounded those findings, so as we teased that apart, as well as some improbable outliers, we got really comfortable that the 50 milligram, 24-hour ambulatory data was concordant with the in-office and very supportive of efficacy. Coming back to what is the intent of Target-HTN, that was an exploratory dose range finding proof of concept to really inform what is this drug doing? How does it inform how we think about the drug moving into pivotal development, and we got really comfortable with the 50 QD as likely the predominant dose and the 100 as the titrating dose. Got it. Okay. So we should be able to get some comfort in the 24-hour BPM based on the different criteria that you provided. Yeah. I think we're very comfortable with it. Okay. All right, so now Advance, you said, is powered for a minus seven mm Hg drop in blood pressure, which seems achievable given Target, and I guess maybe you can frame that for us. The KOL community, we've often heard them say that greater than 10 mm Hg is something that would be really meaningful to them and game-changing in their minds, so how do you square seven mm Hg with what the community wants to see, and how should we think about what seven mm Hg means? Yeah. I think the community, specialists particularly, will tell you, "Give me 2 millimeters reduction sustained, and that will have a meaningful impact on outcomes." What breaks through the inertia of, "I'll just keep trial and error on the drugs that I'm using right now," I think is the 8 to 10. We had our KOL call. I think you listened in on that. We had KOLs that said 10 to 15 would be great. Had Luke come in and be a little bit pragmatic and say, "And the study is rigorous as Advance-HTN." From his standpoint, if you see 6 to 8, that's transformative, to use his term. We've done, at this point, market research with over 1,000 docs in the U.S. We always test the same base case TPP, and that is 8 to 10 millimeter mercury reduction, systolic placebo-adjusted, and a 5% incidence of hyperkalemia. That's kind of right down the lane of transformative for these docs because they don't currently have that. You and I have talked about meta-analysis of the existing treatments. When you add a third agent, you get about a 5 millimeters of mercury reduction in systolic BP. So whether it's a beta blocker, a calcium channel blocker, whatever, that's what you get. Renal denervation delivers about 5 millimeters of mercury improvement in a resistant population. Aprocitentan, a recently approved drug, does about 3.8. 8 to 10 is effectively doubling what's currently available, either from an existing generic treatment or some of the newer innovations that are out there. Clearly, our goal is not only that 8-10 at the top line, but to do what we did in Target-HTN, and that's continue to dig into the data and say, "Are there subsets that have even a greater response?" Because that's what we want to bring to the market, is not just best-in-class molecule, but a toolkit to help physicians identify a priori, "Here's who's going to respond to the drug, and here's what you could expect from a response." And that's why we're going to pre-specify analysis around things like obesity, number of background meds, and just continue to try to inform the community where to use this to get the best response. Okay. Great. So if I remember correctly, that you said the study is powered to show statistical significance in both an uncontrolled population as well as a resistant population. Is it statistically powered to show a difference between obese population versus a non-obese population or any other kind of subsets that you're looking at in a pre-specified fashion? Yeah. We'll have statistical power. Thinking back to Target-HTN, we pre-specified about six different endpoints. We looked at age, race, gender, number of background meds, obesity, and diuretic. Now, obviously, diuretic, we're not going to do the analysis because everybody's on it, but we're comfortable that we're powered for really the two key elements that we want to look at, and that is that correlation to BMI, and we want to be able to dig in deeper on this uncontrolled versus resistant. Okay. All right. And then maybe we can talk about Launch-HTN a little bit. That's the real-world trial. It seems like it's a little bit trickier just because you have a whole host of background meds, different populations, a little bit less stringent as far as what that background med is. So maybe you can just, again, talk about that. And now you're measuring AOBP. So what does that mean as far as what you might see in terms of the drop in blood pressure? Yeah. The good news about Launch-HTN is, in a lot of ways, it's confirmatory to what we did with Target-HTN. So there is some variability as far as background. In Launch-HTN, we keep people on their existing background regimen, which means they may not be quite on the optimized drug regimen or the optimized dose. But in fairness to the prescribers, it's not a bad regimen, right? In Target-HTN, we saw roughly 80% of the patients were on an ACE or an ARB, which is recommended by the AHA. Are they at the right dose? That may be a bit of the variable question. But again, we saw a pretty stable background population within Target-HTN. We saw that 8 to 10 millimeter mercury reduction in Target-HTN. And so moving into Launch-HTN, we still have that variety of the background, but we've added that one component. They all have to be on the diuretic as part of that existing regimen. So that's beneficial. The fact that it's over 1,000 subjects, I think, allows us to absorb a little bit of noise on the edges. But at the core, presume that we see a replication of Target-HTN. The primary endpoint is in-office measurement that does create potentially a little bit more noise around the placebo response. But again, what we saw in Target-HTN, our in-office measurement placebo response was about 4 millimeters of mercury, and the 24-hour ambulatory was about 2. We're using that same technique for in-office measurement in Launch-HTN that we used in Target-HTN. And so taking five measurements over 30 minutes, average the last two, I think, is what helped really compress the placebo response for our study, certainly relative to some of the contemporaneous studies like the CinCor programs where you saw nine and 16 millimeters of mercury placebo response. Even though launch is a global study, I mean, I've been to the investigator meetings for the U.S. meeting as well as our European investigators. We spend a great deal of time training all of these PIs, all of the site coordinators on the technique, the approach. Our staff, not just CROs, are in those sites continuously retraining, educating the sites on proper technique. So I feel comfortable that we've managed that risk around the variability. Okay, and the endpoint on this trial is six weeks, not 12 weeks. Correct. Why did you choose a six-week time point? The six-week time point, both Advance-HTN and Launch-HTN are taking advantage of a titration schedule in the third arm of each study. In other words, everybody is on 50 milligrams through either four or six weeks. And then we measure their blood pressure and their electrolytes. And if they're not at goal and their electrolytes are in a normal range, we titrate up because we think some patients may benefit from additional dosing. In the case of Launch-HTN, that time point is at week six. Launch-HTN is randomized 1 to 2 to 1. So those 1,000 subjects, about 750 are going to be on 50 milligrams of lorundrostat. That gives us superpower to do subset analysis relative to placebo. We feel very confident in the profile of this drug that we're not going to be missing any efficacy signal between week six and 12 or even week four and 12. In Target-HTN, we saw by week two, you get about 70% of your clinical response, and by week four, you had the majority of the blood pressure reduction. From our standpoint, knowing how important some of these subset analyses were, it was beneficial to move that endpoint in Launch-HTN from week 12 to week six. Not for the primary. I mean, we're at this point on 98% power for a 7 mm Hg change, but it's for the subsets that'll be really informative for the label specifically. Okay. And then one of the questions we get a lot is around safety and hyperkalemia issues. That's a little bit more prevalent for these aldosterone-type mechanisms. So how are you managing that? Yeah. What we learned, so what we saw in Target-HTN was about a 3.6% rate of hyperkalemia across all the cohorts. That falls well within the range that the market finds really kind of modest. So in other words, 5% hyperkalemia or lower is going to be a real benefit for this class of drugs. There are unique things about how to collect potassium that we learned from Target-HTN that we're going to play into our pivotal program to help us continue to really manage factitious or false readings. But really critically, and Target-HTN wasn't quite big enough to do this analysis, we know that there's a potassium wasting component to the diuretic that could relieve that. And so having all patients on a diuretic, we think is going to manage that risk to a degree. And then really the last thing, in Target-HTN, we allowed potassiums of 5.1 or lower. We've reduced that to 4.8 just because 5.1 is basically the upper limit of normal. So we've tightened up that range for inclusion criteria. So we feel very comfortable that the profile we saw in Target-HTN is likely to replicate within Advance-HTN and Launch-HTN. Okay, and I guess for what is the level that patients or physicians are concerned about? It's 5.5 or it's 6? We've heard both numbers. I think it's 6 is where physicians would probably want to do a dose discontinuation and then potentially restart. In the 5.6 to 6 range, it's going to be more about monitor and consider dose reduction. And that's typically what you see with ACE inhibitors and ARBs because both those classes of drugs do a slight increase in potassium. And the labels, I think, recommend in that 5.6 to 6, just monitor and maybe dose adjust accordingly. Okay. And one other point of clarification. In Target, the patients who showed elevated or hyperkalemia, were they on the population that were not on background meds of diuretics? Did you notice a correlation? No, we haven't noticed a correlation. Again, it's small numbers. We know the majority of those patients were on an ACE or an ARB. And that was an important finding. We know there were some studies done in the late 1990s, early 2000s about combining ACE and ARB, and that was too potent as far as hyperkalemia. But knowing that 80% of our subjects were on ACE or ARB, and then to be able to look at the benefit of lorundrostat on top of that without exacerbating the hyperkalemia, that was a key finding for us. Okay. Great, and then one last trial, Explore. Just remind everyone what Explore is. Yeah. Explore. We have two seconds. Two seconds. Explore-CKD is looking at hypertension with CKD. We're going down to eGFR of 30. The key takeaway of that study is the potential for dual benefit. Can we see continued reduction in blood pressure as a benefit, but also having a benefit on proteinuria? And we believe that's a white space right now. There are a lot of interesting agents for CKD, but don't have a benefit in blood pressure. And so being able to do two benefits with one drug, we think would be a nice benefit and could be informative for what we do next.