All right, well, good afternoon, everybody, and thanks so much for joining us for a fireside chat discussion with Mineralys CEO Jon Congleton and CFO Adam Levy. I'm Seamus Fernandez, one of the senior analysts here at Guggenheim. So again, super excited to have Jon and Adam here with us today. You've got some pretty big readouts coming fast, so this is exciting times. Maybe Jon, if you just want to start us off, give a quick overview of Mineralys to those who may not be familiar, and we'll jump into questions.
Yeah, happy to do it. I mean, Mineralys we're really focused on how do you target dysregulated or elevated aldosterone to the benefit of cardiorenal metabolic conditions like hypertension. That's our beachhead indication. We know that we haven't finished the job, we being collectively the treatment of hypertension. We know that it's correlated to poor outcomes. 10 mm Hg reduction in BP gives you 20% reduction in CV risk, 30% reduction, 35% reduction in stroke, 40% reduction in heart failure. These are leading global burden of disease conditions, so we're excited about really the transformative potential of lorundrostat to bring a targeted approach. So in those patients that can't get to goal, we're trying to identify those where aldosterone's driving it. That's the way the proof of concept study began that journey.
The pivotal trial will continue to look at what are predictive determinants of response, what are predictive of where aldosterone's dysregulated, and where can we yield the most robust benefit that's safe and then help these patients get to goal and then ultimately alleviate the risk down the road.
Great. And obviously a fairly heavily generic category in general, but talk about the approach that you're taking and how do you view it as a challenging payer environment in particular, or is your strategy really built to sort of give the payers actually what they're looking for?
I think it's more the latter. I think we acknowledge that payer control access to the market is a key and critical part, but payers acknowledge that there is unmet need, that there is exposed risk with patients who truly cannot get to goal. So you're right, we've got a host of generic drugs. They're good drugs. I actually started my career selling calcium channel blocker that's now generic. The problem is even with free and easy access to a host of different mechanisms, over half the patients treated cannot get to goal. Now part of that is, are they prescribed the right drug and the right combination, right dose, and are they compliant?
But that's where our Advance-HTN study, I think, is really going to generate the kind of data the payers want because we take patients off of their existing meds, we put them on an AHA prescribed background, make sure they're compliant, right dose, truly treated appropriately. And if they can get to goal, we don't randomize, but we then randomize those that can't. So Advance-HTN not only is going to show us what lorundrostat can do where the existing drugs can't get patients to goal, but it'll help map out who are those patients, what % of them can get to goal. And then that's how we've positioned the drug as we've done payer research. We're not looking at first line, we're not looking to supplant all their patients.
We actually think third line with a targeted approach, likely the obese hypertension patient or the resistant hypertension population is where we can generate the kind of value the payers would create access for.
Great, so let's talk about Target-HTN and how it informed the design of Advance-HTN and then obviously the Launch-HTN clinical trials that are underway.
Yeah. Target was our dose range finding proof of concept study. The first time we had studied lorundrostat in an affected population, it was really our first step in trying to bring a targeted approach to the treatment of hypertension because that proof of concept had two parts. The first part was using renin as a bit of a guide and a marker for an aldosterone dependent form of hypertension, low renin. We also had an arm that looked at normal to high renin. Long story short, renin's not the predictive marker. Lorundrostat worked equally well where their patient had low, normal, or high renin. But we also began to pre-specify analysis that was following the biology to really help us think about, all right, if renin's not the marker, how do we find that?
A lot of great research had been done linking visceral adiposity to dysregulated aldosterone. Said another way, as BMI increases, aldosterone increases. And so we pre-specified an analysis in Target-HTN that showed about a 12-17 mm Hg reduction placebo adjusted in systolic BP in those subjects with a BMI above 30. We also pre-specified an analysis looking at with and without a diuretic. About half of Target-HTN population was on a diuretic, half were not. We thought there'd be an interplay given the different mechanistic approaches to volume in a hypertension patient. So a lot of those pre-specified analyses were done with the intent of how do we continue to try to identify what's going to predict a more enhanced response? Where is aldosterone really the culprit in this patient's uncontrolled hypertension that we could then apply into Advance-HTN and Launch-HTN?
So the BMI finding, we chose not to narrow the BMI criteria. In other words, just study patients above 30. We wanted to confirm that finding. So the BMI is still a wide range of 18-40. We did incorporate the diuretic finding though. All subjects in both of the pivotal studies will now have a diuretic required as part of their background. And then there were a host of other things just as far as operationally. We did both in-office and 24-hour ambulatory study in Target-HTN. We're applying that to Advance-HTN. The technique we used for measuring in-office blood pressure measure, we're applying to both Launch-HTN and Advance-HTN. So I think there were a lot of learnings from our program and then frankly from other contemporaneous studies, both pro and con.
Great. Can you talk a little bit about just the mechanism of action for why diuretics would have an impact in this setting and why it's actually so important to kind of sequence the therapy and to optimize that therapy before adding an ASI?
Yeah. I think in the simplest terms, you can break hypertension treatments into either vasoconstriction or volume. So what's working to dilate the garden hose, if you will, and what's working to reduce the amount of volume in the garden hose? If I can overly simplify this, ACE inhibitors, ARBs to a degree, beta blockers, renin inhibitors all work on dilating the vessel, so reducing pressure that way. On the volume side, it's really more diuretics, mineralocorticoid receptor antagonists, sodium channel blockers. In the case of the diuretics, they work really well on volume, but they're not complete. You need more. And we know within the kidney there are multiple points where you can have a release of sodium into the urine or reabsorption into it. And where an ASI versus a diuretic works are on different mechanisms.
It's giving you two shots on that effort to excrete sodium. And by excreting sodium, water follows, volume comes down, pressure comes down. And so that was the rationale behind why we thought there'd be a synergy between the two, and we wanted to pre-specify the analysis, and then it bore fruit within the Target-HTN study. As far as thinking about the treatment paradigm, we don't have an illusion broadly of let's prove that lorundrostat can work great as a monotherapy. We actually think probably the triplet that would work ideal follows generally current practice. And current practice is if you go in and you're identified as having elevated blood pressure, you're likely to get an ACE or an ARB. So either an ACE inhibitor or an ARB that works on the vasoconstriction side. They're really good drugs. They're fairly well tolerated.
You'll come back in four weeks. If you're still elevated, you're likely to get a diuretic for the most part. You may get a calcium channel blocker, but generally it's a diuretic. It's at that third point where we want to bring in not just lorundrostat writ large, but to bring in lorundrostat and say, and here's who. We've called it an endophenotype in a simpler term. It's a toolkit. How do we arm physicians and payers to say, if you're at a third line consideration of a treatment, here are the type of patients that'll respond to this? Why we think that triplet works ideally is we know with the ASIs when you reduce aldosterone, you see a slight increase in renin.
And so you're going to want to have an ACE or an ARB on board with that because it may actually create a level of synergy there. You're creating more substrate for the ACE or ARB to have a more pronounced effect. And then the diuretic just simply we know that volume's a big component and we've seen a synergy there.
Great. Let's talk a little bit about the pivotal program. Two very different, maybe not dramatically different, but different programs. One a little bit more carefully engineered, which is the Advance-HTN study. Can you talk about Advance-HTN as a starting point because that's our next sort of readout?
Right.
Remind us the timing of the readout and where we are today with Advance-HTN.
Yeah. So after the Target-HTN data read out, we met with the FDA post phase 2 meeting, laid out the program that we're affecting right now that has Advance-HTN and Launch-HTN as the drivers for an NDA enabling package. The simplest way to look at it is Advance-HTN is really geared towards and built for specialists and for hypertension guidelines. It has a great deal of rigor, frankly beyond what the FDA requires. Launch-HTN is probably more the real world study. So for a primary care doc, how he'll treat hypertension is probably replicated within Launch-HTN. And Launch-HTN is to a degree a confirmatory from a design standpoint to what Target-HTN was, existing background meds. So Advance-HTN, I want to spend a few minutes on because I think this likely is going to go down as the most rigorous hypertension study ever done.
Patients have to come in at screening, have a systolic BP above 140 in the office. If they have that plus some other inclusion criteria, we take them off their background medication. We know it's just a hodgepodge of what patients have as an existing background med. We take them off of that and we standardize them to one of two regimens. If they were on two existing antihypertensive treatments, we put them on high dose olmesartan, an ARB, high dose diuretic, either indapamide or hydrochlorothiazide. If they were on three to five meds, we put them on the ARB, the diuretic, and then high dose calcium channel blocker, amlodipine. These are AHA recommended mechanisms. They're at near maximal doses. We then are partnering with a company called AiCure.
It's a smartphone technology where patients have to take a picture of those pills daily and video themselves consuming it daily. That goes to the cloud, it goes to the CRO, to the site, and to us, and we actively call patients if they're missing doses. So during that three-week run-in period, we've got patients on the right dose or the right drug, the right dose, and we're ensuring they're compliant. And these are three of the biggest reasons why with existing medications, patients can't get to goal. So we're knocking out those pain points doing that. The fourth pain point that we knock out is we basically, or not basically, we use the 24-hour ambulatory blood pressure monitor, which is the gold standard. They put this device on, it's a cuff, a little device they put on their belt.
It does three measurements per hour while they're awake, two measurements per hour while they're asleep, averages those, and that determines whether they get randomized or not. If that three-week run in being on the right drug at the right dose and compliant, they get to goal, we don't randomize. If even though they've had all of those things done, and this gets to your question about, hey, we've got all these great drugs, we know that picking the best ones at the right dose and ensuring compliance, they're not all getting to goal.
And so then we randomize to either placebo or 50 milligrams alone for the 12 weeks, 50 milligrams with the chance to titrate at week four out through 12 weeks, and use the same compliance tracking, use 24-hour monitor for the primary endpoint on week 12, comparing the 50 milligram to placebo and the 50 titrated to 100 to placebo. And again, fundamentally, I think this study is truly going to be. These are affirmed uncontrolled hypertension patients. They're affirmed resistant hypertension patients. It creates the kind of evidence that, again, beyond the FDA, it gets us into the hypertension guidelines. I think it may create a population that could be trending towards more aldosterone enriched because we've used a lot of different treatments that hit other mechanisms that could be driving their hypertension except for one, and that's an aldosterone-directed therapy.
Great. Baseline characteristics of that patient population that could impact the efficacy of an ASI in one direction or another.
Yeah. We got a lot of questions when we had the finding of the correlation to BMI and response in Target. Had a lot of people ask, aren't you concerned you've kept the BMI range really wide with Advance-HTN? Are you handicapping against the study? And contemporaneous studies in hypertension in the US, BMI is above 30. I mean, our study was 31. The two baxdrostat studies in the US, I think were 31 and 33. The prevalence of obesity, we all know what that is in the US, but when you look at a hypertension population, it's even greater. So we didn't have a concern with that, but we wanted to, once enrollment was complete, wanted to share that information as somewhat of an assurance that, yes, in fact, this is a good distribution. Fully two-thirds of the population has BMI above 30.
So we'll really be able to investigate that. And that's what we wanted to do. It's why we kept the BMI inclusion wide. We want to really confirm that finding. And then we also wanted to make sure that we replicated what we did in Target-HTN and that was have diversity within the study. So in Target-HTN, we had about 39% of the population was Black or African American. Advance-HTN is just over 50%. And that's important because we know there's disparate responses based on race to hypertension treatments. And we wanted to have a good diversity within that study to show that there's equivalency as far as response to lorundrostat.
Great. So I think maybe you can clear up one point of confusion, which was with Advance-HTN. There was sort of this announcement in the middle of the summer that there might have been some questions around the timing of when the primary endpoint would be assessed. So there was a kind of question around, was it going to be four weeks or 12 weeks? Can you just remind us what happened there and then where did we end up? And then that'll kind of lead us into Launch-HTN.
Yeah. So I'll start with Launch because Launch was the first meeting we had with the FDA for the statistical analysis plan in May. Kind of regular order of business, you go meet with the FDA, you finalize your statistical analysis plan. We had that meeting for the Launch study in May. Bigger study, randomized one to two to one placebo, 50 milligrams, 50 titrated to 100. Week six is the titration point. We went to the agency. They knew that we very much wanted to specify responder populations. The agency said, yeah, that could be part of section 14, the clinical data section. We said, all right, we'd like to move the primary to week six, not for the powering of the primary because the primary at week 12 was 95% power for a seven mm Hg change.
It's now 98% at week six, but for the power of the subset analysis, things like BMI, number of background meds, so they aligned to that, so that makes sense. We went to the market, notified the market of that change, and said our intent is to do a similar change with Advance-HTN, move it to week four for the primary analysis, so met with the FDA in August about Advance-HTN's statistical analysis plan, and in that dialogue, they said, it's our recommendation given how far along you are in enrollment that you don't do that because of the perception of a change that late in the game. Did you see something? Are you concerned about something? And we said, we haven't, we aren't. They said, agree. Let's leave it at 12.
So we created, in an effort to be as transparent as we could, probably created a little bit of noise that at the end of the day, the story is nothing changed from what was designed in the study a year and a half ago.
Okay. Perfect. Difference between AOBP and 24-hour and how we should think about the thresholds of benefit in terms of the absolute change or placebo, just rather than the absolute change, the placebo-subtracted change and what the study's power to show on 24-hour in Advance and then what the study's targeting in Launch.
In Advance-HTN, where we use 24-hour ambulatory, 90% power for a seven millimeters of mercury placebo-adjusted change. When you compare ABPM to AOBP, the goal for the 24-hour measure is 125 millimeters of mercury. The goal for the office is 130, and that's just standardized. The reason they're off by five millimeters of mercury is that 24-hour includes nighttime, where typically like a normal hypertensive patient does something that's called dip. Your blood pressure should come down. It's part of the restorative aspect of sleep. That's an important consideration because not all hypertensive patients dip. That's why you see the goal is a bit lower. We had a KOL call. I know you and your team had a chance to listen to on October 30th.
Luke Laffin, who's the PI for the Advance-HTN study, talked about how the reduction may be off by one or two millimeters of mercury as far as more compressed in the 24-hour ABPM because of the more extensive measures with that, the factoring of the nighttime. I think he alluded to a six to eight millimeter mercury reduction in that study. The way it's designed with that measure to him would be, I'm trying to think, was it transformative? It was a nice positive word, but would be meaningful just simply because they are truly uncontrolled, truly resistant. From our mindset, I don't disagree with Luke that there may be a one or two millimeter difference between the placebo-adjusted reduction between ABPM and AOBP, but what we saw in Target-HTN was a fairly equivalent placebo-adjusted reduction of eight to ten millimeters of mercury.
The 50 milligram QD on ABPM had some anomalies, but if we look at the 100, if we look at the 25 BID, AOBP, ABPM lined up pretty tightly. So we'll see. I think fundamentally the profile we've tested that resonates with physicians and payers within this population, that eight to ten millimeter mercury, if we can deliver on that, then that's transformative relative to what you can do now with currently available treatments.
Great. And then with launch, can you talk a little bit about just sort of the dynamics? And I guess the first program is called Pivotal phase 2b and the others a very large phase 3, without question. Do the definitions even matter? They're both pivotal studies.
They don't. Yeah. If there was something I could go back and change, I would just say Advance as a phase 3. At the end of the day, the FDA doesn't get caught up in nomenclature of phase 3, 2b, 2a. It's do you have well-controlled, well-constructed, and in this case, replicate studies. So both reviewed as pivotal in the mind's eye of the FDA. Launch is, as I said, it's super powered. It's really built for that size simply to help augment the safety data set. Hypertension is a large indication. Obviously, the FDA wants to make sure that we've got a well-characterized safety adverse event profile. Target HTN had a really nice safety profile. The on-target adverse events that you would look at, like hyperkalemia, hyponatremia, I think were well-characterized.
The agency has said, based on the size of these two studies, presuming the profile that we saw on Target-HTN is replicated, that should be a sufficient safety data set, barring any unforeseen adverse events. So we feel good about the size of the study. Again, Launch-HTN is really built for real-world primary care docs. It's keeping patients on their existing background meds, typical two-week placebo run-in to get them compliant on their meds. We're using an in-office measurement. We're using the same technique we used in Target-HTN. So it's a more quieting, if you will, way to measure BP. It gets a tighter placebo response. We saw a 4 mm Hg reduction in Target-HTN, taking five measurements, averaging the last two. We're doing that again in Launch-HTN. I've been at the investigator meetings that we had for Launch-HTN in Atlanta and in Madrid for Europe.
I've seen the training that we do and continue to do. It's kind of the boring meat and potato stuff of what we do, but we know others have had challenges with execution on this study. And we've been very mindful of that as far as how we train, educate, and communicate with our sites. And so that'll be a 12-week study, six-week for the primary, but we'll have the 12-week as the secondary endpoints. And again, the size and scale of this study lets us really dig into some pretty cool subset analysis to continue to identify where we target patients with lorundrostat.
So, limited time left. The competitive landscape, there's differences in your product versus the effort at AstraZeneca and potentially some other programs. I think the focus from investors has been on AstraZeneca's baxdrostat program. Interested to just know, how are you thinking about the competitive landscape? I've always thought of classes as better things at the end of the day. So more products in category up to a point is a good thing. If you can just maybe talk about that.
Yeah, I agree with you. I think having the validation of AZ, BI, their focus on aldosterone and specifically with an ASI, I think is important for the class, for how the medical community gets excited and enthusiastic about what's coming. Right now, there are two hypertension studies that AstraZeneca has with baxdrostat. They have a hypertension CKD study. BI is looking at combining with their SGLT2 and CKD and heart failure. And we've got our hypertension program and then Proof of Concept Explore-CKD looking at that. And I think what we've done to date continues to validate that aldosterone is probably at this point one of the top targets in cardiorenal metabolic disease, just based on the amount of work being done here. I think we've got a best-in-class molecule for that. I think we're doing a best-in-class study to generate class one evidence.
I think all of that will be very informative to the data readouts in the first half of 2025 and then how we think about further development beyond that.
Great. And Adam, I apologize, just to wrap up, the sort of cash needs and financing of the opportunity and just sort of maybe the scope of the opportunity that you see for lorundrostat going forward?
Yeah, we feel really good about our balance sheet. We just reported approximately $264 million in cash, and that will bring us into 2026 and allow us to get through the readouts in each of the clinical trials that we're running now.
Great, and just the size of the market opportunity, I know, Jon, you talked about it a little bit, but how do you think about the sort of scale of the opportunity?
Yeah, it's enormous. I mean, there's probably at least 10 million patients in the target opportunity just in the U.S. alone. And then around the world, hypertension and some of the other diseases that we're looking at, chronic kidney disease, eventually potentially heart failure, are all really big indications with high value. Well, and that's why we're unabashed about trying to narrow in target. Let's identify those patients where it's really driven because it's a big enough market, you can cut it down. Let's find the patients that have the biggest response. It's going to create uptake, access, and ultimately success for patients.
Great. Fantastic. Well, it's great seeing you guys again. Thanks for joining us at our conference and really looking forward to a very exciting first half of 2025 for Mineralys.
Yeah, agreed. Thank you. Jamus, appreciate the invite.