Okay, welcome to the last session of the B of A Healthcare Conference on day two. My name's Jeff Meacham. I'm the Senior Biopharma Analyst, and I have Mary Kate Davis from my team on the stage with me as well. We're thrilled to have Mineralys. And speaking on behalf of Mineralys, we have Jon Congleton, who's CEO, and Adam Levy, who's CFO. Guys, thank you. Thank you. Good to see you. Yeah. I think, Jon, you're gonna just give a bit of a high-level view, and we'll get into some questions after that. Yeah, no, happy to. I appreciate the opportunity to share the story. Mineralys, in simplest terms, is focused on targeting aldosterone as it's related to cardiorenal metabolic syndrome. Our first beachhead indication is hypertension, but we think there's potential for this molecule in things like CKD, heart disease, and beyond that. The purpose that really drives this organization daily is to create more better days. I personally have started my career carrying the bags of sales rep in this space. So I've seen the value of innovations, but we haven't had that in about 25 years. The ability to address unmet need, to get patients to goal, to avert things like dialysis and stroke and heart disease is what we mean by creating more better days. Mineralys itself was formed in 2020, shortly after the licensing agreement for lorundrostat. Lorundrostat was developed through discovered and developed through phase one by Mitsubishi Tanabe. We set out, in 2020 to really build the company, do the tech transfer, do our proof of concept study that really demonstrated a robust effect, on systolic BP. For me, what was enticing about coming back into the organization was not only the novelty of the molecule, but also our approach in targeting, and bringing a level of precision to the treatment of cardiorenal diseases that has not existed before. But really, frankly, is the unmet need. We just in the US, there are about 118 million people with hypertension. About half are treated. Of those treated, about half cannot get to goal. And there's a lot of reasons for that. Some of it is, are they on the right drug, right dose, are they compliant? But fundamentally, we think there's something else going on, and that's dysregulated aldosterone. And why that matters is globally, from the WHO, we know about 7.5 million people die per year in things related to or attributable to hypertension. So we're nowhere near done with this mission of addressing unmet need and hypertension. And aldosterone, interestingly, has kind of silently ridden the coattails of obesity. Everybody's aware of the obesity epidemic, but few appreciate the link of obesity and dysregulated aldosterone. Probably about 25% of all hypertension patients have abnormally elevated aldosterone, and there are really limited alternatives to address that. Really, the main drug was developed in 1959, a mineralocorticoid receptor antagonist called spironolactone. It's, frankly, underutilized because it has a lot of off-target effects. And we think there's the need for better, improved ways to address aldosterone. And that's kind of the path that we're on right now. Lorundrostat, we think, has the means, and the potential to do that. It's, from our standpoint, best in class. ASI has the best selectivity, for, inhibiting aldosterone without affecting cortisol, which has historically been the issue in the development of aldosterone synthase inhibitors. Has an ideal half-life to deliver efficacy once daily, but to do so safely. All of that's been validated at this point in preclinical phase one and now phase two proof of concept study, where we showed a double-digit reduction in systolic BP relative to placebo with modest impact on potassium. And that's really potassium's really the kind of on-target adverse event you wanna look for. That's where our selectivity and half-life, we think, gives you the ideal mix of efficacy and, and safety from that perspective. Again, owing to how we're trying to bring a level of precision within that proof of concept, we pre-specified some what we thought would be determinants of enhanced response. The two that really stood out, was, one, a synergy with a diuretic. We saw even beyond the ITT reduction, a more enhanced response when a diuretic is used in combination with lorundrostat. And then very clearly, and it's based on the underlying biology, the obese population showed a really enhanced response. So these are things that have informed our pivotal development program. Right now, we're, executing two pivotal hypertension studies. One is called Advance-HTN. The other's Launch-HTN. In support of that, we have proof of concept studies in, hypertension and CKD. Advance-HTN, and we'll probably talk about it a little bit in the Q&A, but Advance-HTN is likely the most rigorous hypertension study ever done, just as far as getting subjects on a standardized background regimen of the right drugs, right dose, compliant, gold standard 24-hour ambulatory as the means of identifying are they truly uncontrolled before we even randomize. That study, I think, will be a seminal data readout for us. It's Q4 of this year. Launch-HTN is really kind of a replication or confirmation of the proof of concept. It's a bigger study. It's global in nature, up to 1,000 subjects, probably generating real-world data for us. And then Explore-CKD is the hypertension CKD study that will really kind of fully inform what's the benefit not only in hypertension but also in comorbid CKD, and proteinuria is the primary endpoint with that. The position that we're ultimately looking to bring lorundrostat into the market, and it's what is the basis of our clinical development program, is really a third-line agent for uncontrolled hypertension. So we're not looking to be a monotherapy. We're not looking to displace ACEs or ARBs or diuretics. But when you get to third line, we want to be able to, frankly, deliver a toolkit or a means to guide prescribers and payers in where are those responding populations, and that's tested well within the market research we've done. So the clinical development program really supports that positioning. And then, you know, beyond hypertension, we think there's a, a great deal of utility for lorundrostat given how pervasive aldosterone is in cardiorenal metabolic syndrome. So very excited to, to be on the path that we're on. We think the need's there. We think we've got a really significant opportunity with lorundrostat, and happy to address any questions you have. Yeah, perfect. Well, let's get into Advance-HTN. So, you know, what would you say, Jon? What does, you know, success look like? How predictive, you know, would you feel based on the results of the larger Launch-HTN study? Yeah, we have to put into context what good looks like, we kinda need to think about what's available right now. So typically, and this was from a meta-analysis of about 143 studies, when you add a third-line agent of the existing armamentarium, you get about a 5-6 mm Hg improvement. Yep. What you typically see is monotherapy, you know, the first treatment. You'll get a 10-15 mmHg, and then everything else is incremental. We think by targeting, and creating that toolkit to help identify, but by targeting aldosterone, we can get to that 8-10 mmHg change that we saw in Target-HTN. That's what we're guiding towards with Advance-HTN that we think would resonate. Again, as we've done market research with physicians and with payers, that becomes more transformative. It's not just a little bit of a bump, but it's a significant move, and in a targeted way. Talk about the kind of background therapy and what that could do to introduce some, you know, some variability. Yeah, we were fortunate, and we did it by design. So it was kind of predestined fortune. But Target-HTN, because we were studying patients, this is the proof of concept study. Because we were looking at patients failing on two or more meds, we actually had a good mix of those on two meds, those on three. It was about 50/50. We also had a good mix of those on a diuretic and not on a diuretic. Yep. So we got to see that interplay with lorundrostat and a diuretic. So as we think about our pivotal program, Advance-HTN, which is the one that reads out Q4 of this year, we're actually taking people off of their hypertension medications, and we're putting them onto a standardized regimen that follows AHA-recommended guidelines. So if people coming into the study are on two meds, they get an ARB called olmesartan, and a diuretic both at kind of a maximal dose. If they're on three to five meds, those are taken off. They get the olmesartan, the diuretic, and amlodipine, a calcium channel blocker at maximal dose. What that basically enables for us is a couple of things. One, it is gonna generate class one evidence that'll help get lorundrostat into the hypertension-treating guidelines. But two, it addresses that question of, hey, if patients were just on the right drug or the right dose and compliant, do we really need new innovation? And I can tell you we do. You know, that regimen is not solving the problem for everybody. And what we're gonna see through the course of Advance-HTN is that through that three-week run-in, some subjects are gonna get to goal. If they do, they're out of the study. You know, we just won't randomize them. But if they do not get to goal on that rigorous regimen that's tracked for compliance, then we randomize. And what I think that creates for us is two things. One, it's as close as you can get to a truly confirmed uncontrolled and resistant hypertension. But I think also, by definition, it's likely to be an aldosterone-enriched population. Because that standardized regimen's hitting a lot of different drivers of their blood pressure except for aldosterone. And there's some literature that would support a more uncontrolled and resistant population has a higher prevalence of aldosterone. Now, Launch-HTN, again, is confirming of our proof of concept. We're gonna keep subjects on their background meds. We're gonna try to help them be more compliant. Again, if compliant on their meds, they're still uncontrolled, we randomize them. So that's probably built more for the PCP. It's the real world. We're using in-office blood pressure measurement. But Advance-HTN is really probably targeting cardiologists, endocrinologists, nephrologists that are really getting into the tough-to-treat patients, and will be really considered to the data that we're creating. Great. I guess, looking at the Advance-HTN readout later this year, going into potentially third line here, could you talk a little about your expectations for safety for this readout? Yeah, the on-target. There's really two potential on-target safety things we're looking at. One is cortisol, which has been a challenge with this class of drugs historically, now through preclinical, through phase 1, through phase 2. We have a lot of confidence that the selectivity is bearing out, that, you know, we're seeing about a 70% reduction in aldosterone and really no inhibition to cortisol. And that's basal and that's stimulated. So that's. We do these stimulation tests with ACTH, and there's no inhibition. So that's one. We're continuing to monitor that, continuing to track it. The other one is around electrolytes. And so that's sodium and potassium. That's really where aldosterone has its effect. Aldosterone in elevated state retains sodium, retains water, increases blood volume, increases blood pressure. We're going the other way, where we're basically pushing sodium out. Blood volume goes down. Blood pressure goes down. But you're retaining potassium. And so you wanna make sure that in exchange of that big blood pressure reduction, you're not seeing a big spike in hyperkalemia. We didn't really see it with the 50 milligrams in Target-HTN. We think the combination of its selectivity and its half-life, which is about 10- 12 hours, really is kind of an ideal profile to get the efficacy but potentially allow a little bit of an aldosterone inhibition escape period during the sleeping hours. Because we do see pretty much complete suppression of aldosterone through about 14 hours, and then it begins to rise, comes up about 30% from the baseline level. Did I get that right? You always have to correct me. Yeah, so about 70% suppression, after 24 hours, right before the next dose. Yeah. And so we think that actual allowance of aldosterone to kind of build back up allows a little bit of a clearance of potassium. But that's really the main thing. So cortisol, potassium, sodium, and what we'll be looking at from a safety standpoint in both studies. Just a quick follow-up on your payer work. So if you look at the two settings, right, a refractory population and more of a primary care front end, does a payer value getting to goal differently between those two settings? Have you done that kind of analysis? Yeah, we've done that research. And, you know, sorry. So the most recent payer research we did, we had 30 payers. And as you're well aware, Jeff, you know, there's not a payer. We looked at about 10 IDNs. We looked at 10 PBMs. We looked at 10 health plans. The IDNs were actually when we showed them the profile of about a 10 mm Hg drop in systolic BP, modest impact on potassium, reasonable price, and all that, the IDNs said, third line, yeah, maybe even second line. The PBMs, the health plans were a little bit more circumspect, and it varied between third and fourth line. So I think where our goal of third line is how we're building out the profile, how we're doing the clinical development, I would anticipate we'll see some resistant hypertension. Fourth line by some payers initially. Some will be at third line where we think it's ideal. Then that'll build over time with experience. Okay. Makes sense. Right. I guess, just following up on, on the Launch HTN study and how you've, you've already talked a little bit about how the background therapy is different from Advance to Launch. Right. I guess, do you expect this to kind of change your goal of maybe 8-10 millimeters of mercury for the efficacy, for the Launch-HTN? Yeah, I don't really think so. To a large degree, Launch-HTN is a replication of Target-HTN writ larger and a bit longer, right? So, Target-HTN, we had about 200 subjects. Launch-HTN, we're up to 1,000. Target-HTN was 8 weeks. Launch-HTN is 12 weeks. What gives us comfort that we're gonna be able to replicate that 8 to 10 is we're taking the learnings from Target-HTN. Again, where half the patients were on a diuretic, half weren't, we know there's a positive interplay with the diuretic. All subjects in Launch-HTN will, even though they're on existing meds, one of those existing meds needs to be a diuretic. So we're bringing that advantage from Target-HTN into Launch-HTN. And so we're fairly confident with everything that we learned from Target-HTN, not only about lorundrostat but about how to conduct and construct the study. We've done that in Launch-HTN. So we're, we remain pretty confident that 8-10 placebo-adjusted figure is what we're gonna see with Launch-HTN. Great. I guess just one more for me right now about, just the ongoing clinical trials. Could you touch upon your open-label extension trial and what you're looking to see from that? Yeah, so the open-label extension study, it's omnibus. So subjects not only from Advance and Launch go into that but also Explore CKD. And the main purpose of that is just the long-term safety. You know, we've had good dialogues with the FDA really from the beginning. We're confident that the size of the pivotal program, you know, barring any unforeseen safety signal that may pop up, is probably appropriate. But that's why we're collecting that longer-term data. Now, within that, we're gonna continue to monitor blood pressure. We're gonna continue to monitor other markers. You know, looking at the durability of the response is gonna be a key component of that. So those are really the main things. The safety's really the big primary driver. From a market perspective, I always have to ask the sort of GLP-1 kinda question on. I mean, they haven't the drug company, the pharmas haven't necessarily officially gone after hypertension as an indication. Right. It probably is a matter of when, not if. But we had, you know, a dinner last night with Lilly, and, you know, that it's on their radar. But with that as a backdrop in the marketplace, like, how do you see that, the impact kinda settling out for lorundrostat? Yeah, you know, I think we know and have known for decades, if you lose weight, your blood pressure's gonna come down. Yep. You know, at this point in time, I think the predominant benefit of the GLP-1s, at least as it would relate to hypertension, is probably that benefit, right? You lose weight with GLP-1, you're gonna see a reduction. I think one of the tirzepatide studies tracked and followed that showed about a 6-7 mm Hg drop in systolic BP. That's kind of in line with historically what we've seen with diet, exercise, things like that, which is great. But the fundamental goal is not lowering the BP. It's getting the BP to goal. Right. The goal is 130 just in kind of a standard hypertension subject. But if you have any comorbidities, the goal is 120. And I think in due time, 120 is gonna be the number for everyone. The U.S. is a little bit more advanced in that than Europe is. But with that said, the benefit you see with the GLP-1s is great, and it's meaningful, but it's not sufficient. You know, there's gonna be more there. I think fundamentally, we actually see the GLP-1s as more collaborative than competitive. I think there's gonna be, you know, for an obese subject where we've seen a clear correlation of response, their weight loss is gonna be great for them, but it may not get them all the way down to a BMI below 25 or 22. And so we think there's clearly gonna be a fit of getting the benefit of the GLP-1 but also needing the benefit of lorundrostat given its specificity within that population. Yeah, I think even in the case of the SELECT study for, or for semaglutide, you saw, you know, obviously good weight loss but very varied effect, you know, on stroke was only 7%. Yeah. You know, like, there's so and even, you know, I don't remember off the top of my head what the, you know, what the blood pressure benefit was. But I know you the cardiac benefits are, you know, are not consistent. So having. Yeah. You know, a clear pressure effect would help. Well, and to your point, I think the cardiac benefit. I don't know if it was SELECT or SURMOUNT. It seems like every week, there's a new study coming out. But the cardiac benefit of 20%, again, meaningful. Yep. But there's still residual risk. I think you know, the placebo group had 8% risk of cardiovascular event, and the GLP-1 had 6.5%. So a good, meaningful reduction, but again, not sufficient. Right. So that's where, you know, it's good. We need better. Right. Right. Yeah, totally. I guess just looking at, again, like, the market opportunity here, I guess, what feedback have you been receiving from patients and physicians regarding unmet need and hypertension and how lorundrostat could potentially fill that need? Yeah, I think, you know, first, just from a clinical study standpoint, we've the sites are very engaged. You know, the subjects that they bring in to screen are very interested in this. They wanna see something new. You know, this is a field, again, I started my career in when it was transformative. And then it went nascent. And there's just been a dearth of innovation for a quarter century. And so I think the energy, the enthusiasm, the excitement for new innovation and, and there's a host of it, right? There's ASIs, MRAs, agents, and synagen vectors, and endothelin receptors. So we're seeing a lot of great innovation. And that reflects the unmet need. I think that's being greeted well by patients as we do the market research, and really talk about how we're trying to bring a level of precision, and to help them identify responders. That's greeted with enthusiasm as well. I think the best example of it is think about asthma that maybe a decade or so ago was this just big, massive syndrome that's suddenly beginning to be broken up into subtypes, so eosinophilic asthma. I think fundamentally, we have the opportunity to help drive that as far as how we're targeting. 'Cause right now and this was a surprise when I came back and joined Mineralys in 2020. We still have 90% of those 100 almost 20 million subjects. It's idiopathic hypertension, which means we don't know what's causing it, which to me is kinda shocking in 2024. We have the means and the ability to say, "No, actually, there's. Cardiac biomarkers and. Yeah, I mean, we know aldosterone is a big chunk of that. Aldosterone itself's not a good marker, but we've got the means within our program to help say, "These are telltale signs that aldosterone's likely the driver," and then begin to break that idiopathic down into some bigger chunks, at least initially. Understood. I guess another aspect to touch on here is compliance as well. Could you talk a little about how you're following compliance for the clinical trials, then maybe also your expectations if approved for lorundrostat? Yeah, so in our proof of concept, we do the standard stuff. You do pill counts, daily diary, you do blood tests. But we've actually continue to do that in the pivotal program, but we've added a component that we're really excited about. And it's basically smartphone-enabled technology. It's with a company called AiCure. They've done over 300 registrational studies. Subjects on a daily basis take a picture of not only their background meds but their study drugs. They video themselves consuming that. We have the means to intervene and interject when subjects are not compliant to their medication. So it solves one of the big issues that, frankly, has been a problem in some of the recent hypertension studies. And that's just ensuring patients are taking the study meds, taking the background meds, and just create a really good quality data set. So we're applying that to our clinical development program, all of them. But we're also beginning to have dialogues with them about how can we take that technology and learnings from it and apply it into a potential commercial model, you know, things like gamifying the technology to really get people to go beyond just what should be a natural inclination to take a medication that's helping them and just give them additional incentives beyond that. Beyond the registration phase 2 and phase 3s, to what do you think would incentivize, you know, maybe cardiologists or primary care to sort of elevate, you know, hypertension in terms of increase the, say, the urgency to treat? I think based on the dialogues that we've had and we do a lot of qualitative market research where we can really the moderator, it's not us, but the moderator can really dig in and really articulate what we're trying to do. And I think as particularly cardiologists understand how we're trying to reveal those subjects that are best inclined to respond to this drug and really give them the science behind that and give them the tools to do that and have, again, not just an incremental benefit but something that for a subsegment they're dealing with has a meaningful reduction. Yep. And that's new, right? That's something that in the past, you know, hypertension drugs have been developed, you know, for one for all. And by definition, what we're willing to do as a company is to say, "We're gonna highlight negative predictors as well. We're gonna carve out and say, 'For this group, use what you have or use some of the other new technologies.'" But for a defined population that we're gonna be able to articulate, you're gonna see the kind of response that is gonna be meaningful. And I think that element of it is what really gets hypertension back into the forefront of, "All right, I can really begin to think, you know, have a level of curiosity as opposed to empirically just keep adding drugs and then wonder why on the fifth drug, patients aren't compliant." Well, all right, they're taking a bag of M&Ms every day. Right. They get tired of it. Right. So reduce the pill count, target the treatment, and let's get them to goal. So I think algorithm obviously would be an easy, you know, way, but that, that may take a little bit of time, right? Yeah, and that's, I mean, if we had several hours. We're actually doing, within our pivotal program, we're working with a partner on AI and machine learning to build out that teaching data set out of Advance-HTN and validate it at Launch-HTN that could potentially have as an outcome an algorithm of, "Here's the responder. Yep. And I think for us, as we're trying to think forward into the, you know, the commercial opportunity, it's a matter of time before AI begins to get in the hands of the payers in setting their formularies and their step edits and their PAs. And so we will have the data set to say, "Great. Here's where to say no, but here's where to say yes, and here's what you get as a clinical benefit. Makes sense. I think we should also touch upon your CKD programs as well in, I guess, the final few minutes. Yeah. Talk a little bit about the Explore-CKD trial and then, your expectations for the data, I think, later this year or early next year. Yeah, the Explore-CKD really has two purposes or objectives. One is to give us a sense for the benefit on kidney function via proteinuria for the hypertension profile. And I say that because as we go out and ask physicians, "What are the main attributes for an new antihypertensive that's or number one, blood pressure reduction, number two, safety," but invariably, in the next one or two is effect on proteinuria, which makes sense. There's a huge overlap. Two-thirds of your CKD subjects have hypertension. A quarter of your hypertension patients have some form of CKD. So we wanna have that data set to really bolster the hypertension profile. But then secondarily, we know that kidney function CKD is a significant part of just the broader cardiorenal metabolic syndrome. So having a real sense for what does lorundrostat do not only for blood pressure but also kidney function could really inform our next steps as far as where we wanna go. And we think there's a bit of a white space within that concomitant hypertension CKD space, right? SGLT2s, which are a mainstay of our Explore-CKD as part of background, are standard of care at this point. Rapidly became so. But they don't do really anything to blood pressure. Finerenone, a really nice innovation brought in, is designed to have no effect on blood pressure. So it's all CKD. We think having a drug that can give you both in one med is the beginnings of our opportunity in the broader cardiorenal metabolic syndrome. So Explore-CKD, we're looking at lorundrostat on top of SGLT2, primary endpoint change in systolic BP. Explore would be the change in UACR or baseline proteinuria. What do you think is clinically meaningful in that population? I think, too, from a BP standpoint, it's probably still in that 8-10 millimeter mercury change. You know, I think given the exploratory nature, if we see something that's akin to what BI showed last fall, they showed some nice evidence with their ASI, as far as reduction in proteinuria. You know, that's where we think the class to a degree is de-risked, but we wanna generate some of our data. So, in that realm, possible. Yeah. But that's a population with more comorbidities, a sicker population, would you argue? We are going lower in eGFR. In our proof of concept, eGFR was down to 60. Okay. In the pivotal program, we're going down to 45. Feel very comfortable with that. And in the CKD study, we're going down to eGFR of 30. So it is a sicker population from a renal function standpoint. But again, we think that's where the profile of lorundrostat tends to play very well, not only the selectivity of the half-life, but also we're about 87% hepatically metabolized. So we're not renally metabolized. You don't have to worry about adjusting dose within this more compromised population. Okay. That's a good summary. Any final takeaways? No, we're look, we're excited about our opportunity, you know, back to the purpose, create more, better days. We think we've got a molecule that can do that. We're trying to do it in a more targeted 21st-century way. We're excited about the next 12-18 months, a lot of data readouts that'll tell us a lot about what this molecule can do and the benefit we can provide. Awesome. Yeah. John, Adam, thank you. Hey, you bet. Thank you. Appreciate it, Jeff.