Thank you very much for joining us today. My name is Mohit Bansal. I am one of the biotech analysts, biopharma analysts here at Wells Fargo, and I have Jon Congleton. He's the CEO of Mineralys, the new company, with us today, and we would love to learn more about Mineralys and the ASI that you have right now. Jon, let's just start with the journey so far. It has been, what, eight months since the IPO or seven months? Yeah, seven. Seven months. Yeah, better. How it has been, and then for those who are new to the story, could you briefly talk about the program you have, the platform you have, and the data you have generated so far? Yeah. No, happy to do that. So first of all, thank you. Appreciate the opportunity to chat and update you on Mineralys, barring the slide to my right. No, to answer your first question, it's been a busy seven months. Right. We were obviously thrilled with the success of the IPO, the funds that it enabled us to continue our journey with lorundrostat. You know, we were, about the same time as that, we were coming off the heels of an end-of-phase 2 meeting with the FDA that was very productive, that informed the pivotal program that the team has been actively enabling this year. The first of two hypertension pivotal studies began enrolling in April. That one will read out in mid-2024. The second study will get underway before the end of this year. So it's been a very energetic and active year, as you can imagine, with a lot of really key studies getting started up. Taking a step back further, you know, Mineralys is really focused on, I think, critical areas, that I think we're beginning to see pharma come back to, and that is cardiorenal metabolic. If you look at the, really the top eight burden of disease conditions globally, three of the top eight are CKD or heart failure and stroke. Right. All of those have an underpinning as related to hypertension. All of those also have a correlate to some degree of dysregulated aldosterone. So from our standpoint, we're very much focused on how do we create more healthy days for subjects that are dealing with these conditions, but do it with a targeted treatment. What we mean by targeted is how do you identify where aldosterone is in the dysregulated or abnormally elevated state? Because what we can say at this point now about lorundrostat after the preclinical work, the phase 1 study, and the phase 2 proof of concept, is that we have a highly selective aldosterone synthase inhibitor. So our job right now is how do we identify those patients where aldosterone is really the driving force behind that? It was part of our proof of concept study that we executed in 2021 and 2022, where we were using different markers to inform the enrollment. We used renin. Unfortunately, we determined that renin is not a predictor of differential response, but we also put another pre-specified analysis. And obesity was very much one that, based on the research and the literature, seems to be linked to dysregulated aldosterone. We're seeing really profound effects in our proof of concept studies related to obese hypertension. And so from our perspective, we're continuing to endeavor how do we, through our pivotal program in hypertension, through our CKD proof of concept study, how do we create what we call a toolkit? A means for a physician and frankly, payers, to identify responders to lorundrostat, and that would be populations where aldosterone is in a dysregulated state. That's what we began doing when the company was formed in 2020. It's what we're going to continue to effort to do, just bring that level of precision and targeting into cardiorenal disorders. Got it. Maybe let's just start with ASI as a mechanism. I mean, if you look back at the literature, it has been a mechanism of interest for a while, but I think the safety needle, so to speak, was difficult to thread. So can you talk a little bit about the previous efforts and then how these second-generation drugs are better or safer? Yeah in that regard? No, it's a, it's a great question, and aldosterone has been a target for cardiorenal intervention for decades. I mean, really, one of the first antihypertensives developed was an MRA called spironolactone- Right -in 1959. So we've known aldosterone is a driver of pathology. But it was really over the last 15 years that aldosterone synthase inhibitors became a really interesting target. You had companies like Merck and Lilly, Boehringer Ingelheim, and Novartis that at one point or another had an ASI in their pipeline. The challenge is, in inhibiting that synthetic pathway, you have to make sure you're not inhibiting cortisol. Both aldosterone and cortisol, the CYP11B2 and CYP11B1 pathways, have about 93% homology. So you've got to be highly selective at just inhibiting the aldosterone pathway. If you don't, frankly, you have a non-approvable drug because you cannot inhibit cortisol. Right. That's our flight or fight hormone. So fast-forward to where we are now. There were really two compounds that got into the clinic over the last several years. One from CinCor, now AstraZeneca, baxdrostat, and our drug, lorundrostat, that are highly selective relative to the previous assets. The baxdrostat asset is about 100-to-one selective for aldosterone over cortisol. We're about 374-to-1. Time will tell, is that fourfold improvement in selectivity, will it manifest in a clinical outcome? I think it's too early to tell. We'll see down the road. I think one of the key distinctions between baxdrostat and lorundrostat is really the half-life. Right. It was maybe initially perceived as our shorter half-life might be a liability because we may require BID dosing. We now know that once-daily dosing is ideal... And so suddenly that perceived liability is actually a benefit, particularly for a prescriber. Because Baxdrostat has a half-life of about 25-31 hours. That drug will stick around in the system for three-five days. If you have any kind of adverse event, like a hyperkalemic state, it's going to take longer to get the drug out of the system. In the case of lorundrostat, 10-12-hour half-life, the drug's out of the system in about 24-36 hours. Right. No, that's, that's super helpful to understand. And then, you did briefly touch upon the data you have generated so far. Can you help us put this data in context with current drugs that are on the market? Because you're seeing -point-plus improvement in terms of placebo-adjusted improvement- Mm-hmm. in terms of blood pressure reduction. CinCor also in one trial, they showed that. So can you, can you help us understand how powerful these data are compared to what is out there? Yeah. From my standpoint, I think they're potentially transformative. We know from the FDA standpoint, the requirement for approval is a 5mm mercury improvement over placebo. So that's kind of the bar. We also know from countless meta-analysis that when you get to the point of adding a third agent with the currently available treatments, you typically see a 6-7 mm mercury improvement, and that's not really placebo-adjusted, but it's what you see in the meta-analysis. So for this class of drugs to deliver the potential of a double-digit, placebo-adjusted reduction, really is something that's not currently available. I think it is also indicative of the fact that we're probably seeing more dysregulated aldosterone than we really appreciate. There have been a lot of studies that have looked at just abnormally elevated aldosterone across hypertension populations and posit it's about 25%-30% of the population. And so that's why I think you're seeing these kind of really robust responses, because aldosterone is a big part of the pathology- Right. Both of these agents reduce that very effectively. I think there's some interesting distinctions. One of the things that we built into our proof of concept study was the flexibility of patients either being on a diuretic or not. About half of our subjects in our proof of concept study were on a diuretic, half were not. When we looked at that population on a diuretic, we actually saw an even more enhanced response. As you noted, our top line phase 2 data was about an 8-10 mm mercury drop, placebo-adjusted, systolic blood pressure. In the diuretic background population, it was about 10-12. That was not entirely anticipated, but it was very informative. In fact, as we go into our pivotal study, we're actually requiring all patients to be on a diuretic. So from our standpoint, that's a means of de-risking the pivotal program as we move from the proof of concept into the pivotal program. Is there a mechanistic rationale that why it will work better with diuretic? I don't know that we know the full answer to that. We know that both diuretics and the initial benefit from an ASI are volume-related. Right. We know both mechanistically hit different parts of the renal tubule. We basically have a pretty strong sense that volume-driven hypertension is a pretty large unmet area. A lot of the currently available antihypertensives tend to focus more on the vasoconstrictive side and less so on the volume. Right. Does it make it better combinable product because of this? I'm sorry, say it again. That, does it make it better adjunctive product because of a different mechanism here? Different than a diuretic or different from the ARBs? Different. Would it be easy to combine with these, ACE and ARB? Oh, I think so, and that's... You know, from our standpoint, we're not looking at lorundrostat as a monotherapy- For sure. -as a first line. You know, hypertension, CKD, heart failure, for that matter, they're not monogenic. They're not silver bullet conditions. It's, it's a complex- Right. Compensatory system. You know, from our vantage point, if we fast-forward to where does this drug get placed in the treatment armamentarium, we think third line is the ideal spot. This is a highly genericized space. We acknowledge that payers are going to want to continue to use generics in this space. We've done research with payers and basically said, "All right, when you've got a patient that's on an ACE or an ARB, on a diuretic, but failing to get to goal, that third line is the time to really begin to try to bring a targeted, potentially branded approach into the marketplace." We think an ASI like lorundrostat with a diuretic and an ACE or an ARB is really the ideal triple therapy that's going to get a patient to goal and maintain them at goal. Got it. Can you remind us why something like Spiro, I mean, it has been out there, but it doesn't—it is not being used a lot in hypertension management. Why is that? Yeah, it's interesting. The MRAs, and then when you think of a mineralocorticoid receptor antagonist, you might as well think of spironolactone. Right. That's the main one prescribed. Right. And so in Spiro's case, it's got some compelling clinical data. Even the guidelines recommend in a resistant hypertension patient to consider spironolactone, and yet it's not used. Again, this drug's been around since 1959. It, unfortunately, is somewhat of an indiscriminate blocker of the mineralocorticoid receptor. What that means is you get a lot of off-target effects. You get androgenic effects, which are basically gynecomastia in men, breast enlargement, fertility issues in women. You also have issues with glucocorticosteroids because of the blocking of that. So while the efficacy data can be compelling, which really shows the value in mitigating aldosterone, the adverse event profile that I described, coupled with the risk of hyperkalemia, has just really burned too many physicians, I think, and that's just why you see it greatly underutilized. Right. No, that completely makes sense. Maybe let's just talk a little bit about the ongoing Advance-HTN trial here. What are you expecting to learn there, and how significant is the data set? Yeah, I think, I think Advance- HTN is a really interesting study. I think it's gonna be a very compelling data set. We're working with the Cleveland Clinic, Steven Nissen and Luke Laffin, in the design, the education of our sites, some of the selections of our sites. This study is very rigorous. It's really kind of beyond the standard the FDA requires for approval. It's really geared towards Class I evidence for the Hypertension Guideline Committee review. What makes it so rigorous is that we're bringing in patients at a screening who have a blood pressure, systolic blood pressure above 140 millimeters of mercury. They have to be on two-five background medications. If they meet those two criteria, we're taking them off of their background meds, and we're putting them on what would be considered optimized treatment by the Hypertension Guideline Committee. So if patients are on two medications, they're taken off those two, and they're put on an ARB, olmesartan, and a diuretic. If the patients are on three, four or five meds, they're put on olmesartan, a diuretic, and amlodipine. And you would think after all these years that everybody would be on guideline-driven background treatment. They're not. They're not. We saw that in our Target-HTN study, and so what, what Advance-HTN does is it takes patients off of a just kind of collective different therapeutics they're on, standardizes their background- Mm-hmm. - homogenizes that, and then we track those patients for three weeks on that standardized, optimized treatment, and if they continue to be hypertensive, and I believe it's over 135 millimeters of mercury, we then randomize. We know that a portion of those patients will probably get to goal. So it's gonna be really informative to answer that question that we get, "Well, if patients would just be compliant, wouldn't hypertension go away?" The answer is no. We're gonna have data from this study that I think will inform that. Compliance is a part of the issue, but it's not the whole story. So if patients continue to be hypertensive, they're then randomized to either placebo, 50 milligrams, and then a 50-milligram arm that'll be titrated to 100, depending upon if they got to goal, as well as some of the safety parameters. They'll be then tracked for 12 weeks, and the primary endpoint is 24-hour ambulatory blood pressure. So stepping back and thinking about this data set, we know that we saw an interplay between lorundrostat and the diuretic and the proof of concept. All of these subjects will be on a diuretic by design. We're using the gold standard measurement, which is 24-hour ambulatory blood pressure. We're gonna be able to see a longer duration, so the durability of the drug. The proof of concept was eight weeks. This is 12 weeks. We'll also get a real sense for titration to the 100 milligrams. You know, we saw within the 100 mg a fairly similar response to the 50 at a macro level. When we dug into the data, we saw there was variable exposure and we think benefit of the 100 mg. But by titrating through the 50, we'll get to those patients that maybe need a bit more drug, as opposed to maybe overshooting exposure if you just start at a 100. So there's a host of interesting data we're gonna be able to pull from this. We are stratifying the study by background meds, but we will be pre-specifying analysis based on BMI, as well as a host of other markers, to continue our effort to say, "Target lorundrostat where aldosterone is driving the condition." And that's gonna be the goal of the phase 2 study. That'll be a goal, which is the Advance-HTN trial, as well as the pivotal phase 3. Got it. So given that you will be putting them on standardized regimen for a few weeks before randomization, does it control for the placebo effect in some way? It does. I mean, you know, that three-week run in, A, we think is an appropriate time to get to peak response. olmesartan, diuretic, amlodipine all have pretty rapid onset, pretty rapid effects, so we think we'll get a stable background. The 24-hour ambulatory, we have experience with. We used it in our proof of concept study, something that was a little bit different. CinCor didn't use it in their studies. We saw within that proof of concept that 24-hour ambulatory, the placebo response was 1mm of mercury. So stabilizing the background meds, giving time for everybody to get to kind of a steady state with that, we think we'll have a stable background, not only in medications, but also a stable placebo response- Right. because of that, run-in period and because we're using 24-hour ambulatory. Got it. So what should be the expectations when we see the data? Should it be like, as... Again, it's a million-dollar question. I'm gonna hedge that. Okay. You never, never know what expectations you'll see. I, I think from our standpoint, we're very confident again in what lorundrostat's doing to aldosterone- Right ... The role that aldosterone plays in hypertension. I think as a team, we learned so much from our study and frankly from the CinCor studies and others as far as what to do, what to avoid, to really de-risk and stabilize the background. So you know, we're confident we're gonna see this drug continue to perform well. We think we've created a study that's gonna be enable it to really reveal its benefit, but I'm not gonna hedge on a number quite yet. Fair enough. Maybe on the same line, can you talk a little bit about the pivotal program here as well, and the Launch-HTN study? Yeah. A little bit, and if it is different or similar, how similar or different it is from the Target-HTN or Advance-HTN side? So again, this with the, with the response we saw in the proof of concept study, the pivotal program for this for efficacy could be smaller than we probably are planning, but we know we need to have a larger safety data set. So Advance-HTN, the one with the standardized background, that pivotal study has up to 300 subjects. Launch-HTN has up to 1,000 subjects. In Launch-HTN, the biggest difference really, it's a 12-week duration as well. The biggest difference is we're doing similar to what we did in Target-HTN, and that is we're allowing patients to stay on their existing background medications. In this case, we'll do similar in Launch that we did to target our proof of concept, and that is a two-week placebo run-in, get them stable on their background medications that their physician put them on. And then if they continue to be hypertensive, they'll be randomized again to placebo 50 or the 50 titrated to 100 for 12 weeks duration. So very similar construct in that regard. However, Launch, where Advance is stratified by background meds, Launch will be stratified by BMI. Okay. Again, we want to confirm those really interesting findings we saw in Target-HTN with that enhanced response in a more obese population. Advance-HTN will be a U.S.-only study. Launch-HTN will be our first global study, so it will be Europe, Canada, and potentially some other markets like Australia. It'll be largely U.S., but it will be a global study in nature. And that one will, as I noted, we'll begin enrollment before the end of this year, and we'll have top-line data readout mid-2025. Got it. Makes sense. Let's just talk a little bit about BMI, because I want to go into the trial differences with CinCor as well here. But since you mentioned BMI here, how should we think about the stratification part with BMI? I mean, do you think... Let's say the idea is that the data could look stronger among those that subset of patients. So if that hypothesis turns out to be true in a bigger trial, how would you think about the market positioning of the lorundrostat in among obese patients- Right ... versus the overall patient population? In Target-HTN, we did a categorical analysis, which means we bucketed patients, BMI above 30, BMI below 30, and we saw a clear delineation of response. In fact, we saw in that categorical analysis, really a modest effect for patients with BMI below 30, but a really profound one for patients above. Case in point, the 50 mg QD dose had about a 16.7 mm Hg placebo-adjusted drop. I mean, that's almost triple what you could currently get with available treatments. Right. When we step back and look at that response, though, it's not really that harsh of a cliff. In other words, if you have a BMI of 29, it doesn't mean the drug is going to work for you. So we know it's going to be more of a continuous variable. Launch-HTN, the bigger Phase 3, by having 1,000 patients, we're really going to be able to characterize, right, where is that cutoff? Where is that? Is it 25 BMI? Is it 26, 23? Do you see an even more enhanced response if you have a BMI of 35 or 40? And so from our standpoint, the larger study is just going to add more evidence, confirm what we think the science would lead us to believe, what Target-HTN showed us, and see if, in fact, that's confirmed. And then I think that does become a part of the positioning. You know, we talk about a toolkit, about markers, about means to identify where aldosterone is in a dysregulated state. Frankly, for a country physician in the middle of Kansas, which is my home, so I can call that out, having a patient walk in with a BMI above 30 is a lot easier as a marker than doing a blood panel- Right ... Or something more, you know, deeply scientific. And we'll look at those different markers, and that could be a part of the story. But if obesity is the easy tell- Right ... that obesity, dysregulated aldosterone, profound response with lorundrostat, then that's kind of the ideal toolkit for the country doc that's going to be prescribing it. Got it. That completely makes sense. So let's just talk, go back to the trial design differences between CinCor trial and your trial. I'm asking because they had one good trial and one a little bit of hiccup. So how are you making sure that you don't run into anything like that, and how are you making sure in trial designs there? Yeah, it's like I said, as we've thought about our pivotal program, there was so much good learning and even bad learning. I think we learned a lot of good things from our study. We had, you know, our placebo effect was about four millimeters of mercury. Mm-hmm. In the CinCor BrigHTN study, it was nine, which was a positive study, but it was, it's a big placebo response. And then in HALO, it was a 16 mm Hg placebo response. Right. And it was a negative study, we all know that. I think that, that shows the, the challenge. You, you may think hypertension are an easy study to do, put on a cuff and measure blood pressure. I mean, you've got to make sure that your technique's right, that you've trained your sites right, you've selected your sites right, and that you've got good oversight. I think we had an exhibit of that with Target-HTN and how we were able to quiet that background noise. That's something we're going to continue to apply in our pivotal program, not only within the clinic measurements, but using 24-hour ambulatory. HALO, if you're familiar with the story, there were a lot of different reasons for why it didn't work. Was it a Hispanic population? Was it select sites? Was it adherence?... I don't know that I'll ever know the complete truth around it. You know, our standpoint, the Hispanic population, this drug class works just as well in Hispanic as it does non-Hispanic. So I would absolutely set that aside. But I think there, there probably were learnings around site selection that we're applying to our pivotal program. The rigor of what we and our CRO partner are doing to confirm good site selection, good oversight, good management. Compliance adherence is always a challenge. We're not only doing daily diaries and pill counts, but we're using smartphone technology that basically views a patient taking the pill every single day of the study. That data goes to the cloud, it goes to the site, the CRO, and to us, so we can immediately intervene. If a patient missed a dose yesterday, we're calling them today and saying, "Hey, what's going on? How can we help? You need to be compliant." So there are different learnings, again, from our experience, our study, as well as the CinCor studies that we're applying. Got it. That makes sense. Thank you for that. So let's just... like, we have a few more minutes left, so let's just talk about the CKD trial. Sure. I mean, you just recently modified it. When we see the data, what are you looking... This looks like an exploratory kind of trial. Mm-hmm. So what would be... Like, when you see the data, what would you be looking at on this? Yeah, the CKD study really has two parts now. And we announced in July that we had added a proof of concept. So I'll talk about the first part that had always been planned, and that was the safety profiling. In our proof of concept study, we looked at hypertension subjects with eGFR down to 60. In the pivotal program, we're going down to 45 and continuing to use 50mg and 100mg dose, and we think there will be no safety issue. But when you get down to Stage 3B CKD, eGFR 25-44, these patients are more renally compromised. How they handle and manage potassium becomes a really critical point. So we wanted to curate a very specific safety study for them. We're halving the dose of the 50 milligram, and we're starting with 25 milligrams QD for 4 weeks. It's all about safety measures, sodium, potassium, cortisol, eGFR. If the patients continue to have a safe experience at 25, we'll increase to 50. That study is very critical just to inform our thinking for that more renally compromised patient population. But as we were contemplating that program and the IND that we would have to open up because of the CKD, we began looking at, all right, let's look at a proof of concept. Because we know that aldosterone plays a role in chronic kidney disease. We believe that an aldosterone synthase inhibitor is probably a more elegant, specific way to go about affecting aldosterone in CKD than, say, an MRA. We know SGLT2 inhibitors are rapidly becoming standard of care or at least guideline recommended. So we wanted to basically look at what's the benefit of lorundrostat alone, as well as on top of an SGLT2 inhibitor. Our proof of concept study is looking at the combination of an SGLT2 inhibitor, dapagliflozin, with lorundrostat for 12 weeks, and then we pull the SGLT2 inhibitor off for another 12 weeks and look at the benefit of lorundrostat alone. The primary endpoint is urinary albumin-creatinine ratio. The real benefit in CKD is that measurement, UACR, is a great read-through to clinical benefit, so it would de-risk a potential CKD program down the road. If you reduce UACR, you're gonna see a reduction in progression of eGFR. You're gonna see an extension of time to dialysis or death. So it's a really interesting marker for CKD down the road, but it also has a really critical element for hypertension. As we go out and talk to physicians who treat hypertension, their top three attributes are efficacy, so the reduction of blood pressure, doing so safely, and the third one is proteinuria, having a benefit in proteinuria. And so this data set not only helps inform where we may go down the road for CKD, but it also has a real benefit to the profile of lorundrostat in hypertension. Got it. Completely makes sense. And then in terms of opportunity in CKD, obviously, I don't want to put cart before the horse here, but still, like, if you think about longer term, do you see this as a way to enhance the label for hypertension, or could it be an opportunity in itself longer term? Yeah, I think, you know, the. It'll certainly enhance the perception of the molecule. You know, whether this study would be sufficient to get that data into the label or whether we would need to do another phase 2, that remains to be seen. I think, but fundamentally, it will enhance the perspective of lorundrostat. Again, there's such an interplay between all these conditions. You know, hypertension, even diabetes, CKD, heart failure, they're just, they're not these distinct standalone conditions. They're all interrelated. And so, you know, we've clearly shown a benefit in the proof of concept on hypertension. We want to extend that and see what we can see as it relates to kidney function, and then in time, potentially even move down to what can we see as it relates to cardiac health, left ventricular function, heart failure. I just think there's significant opportunity for this molecule now that it's been de-risked to the stage that we've done it. Perfect segue into the next question. So given the opportunity there, how should we think about potential partnerships or licensing opportunities as they present themselves? Yeah, I think from our standpoint, you know, our focus has been over the last 2.5 years to de-risk this program. Let's try to really confirm that, A, this is a selective aldosterone synthase inhibitor, which we have. Let's try to confirm that, all right, is there a clinical benefit? We've now seen that in the proof of concept hypertension study. We're going to continue to be doing that. You know, our view is we think we have the best-in-class molecule based on the selectivity and the half-life. We've got a path that puts this drug at least with a hypertension NDA in the near term. But we also have a molecule that has a lot of functional utility across different conditions. Partnering would be a way for us to really maximize the value of this asset. We obviously have a means to get to a hypertension NDA, I think even pursue CKD. But for all the different benefits this molecule can bring, certainly partnering is going to play a role. That could be in development, that could be in commercialization. But right now, we're just focused on continuing to really show the value this molecule can provide for patients dealing with these conditions. Got it. One last question. I mean, there is a lot of talk about the Roche and Alnylam deal. But since you mentioned about the difference between CinCor asset and your asset, the longer half-life, now we are running into even longer half-life with these kind of agents. I mean, when you talk to clinicians, is this the way to go for hypertension medicines, where you go for longer-acting agents? Yeah, it's, it's a great question. We haven't actually spoken to a lot of physicians about the angiotensinogen- directed therapies. We know compliance and adherence is an issue. The question is just the trade-off from a safety standpoint. Right. I think time will tell. You know, from our standpoint, those angiotensinogen - directed therapies are really interesting, compelling. They're on a different side of the spectrum. Right. You know, that's really the old RAS pathway. That's the vasoconstrictive pathway. We're looking more at the aldosterone-dependent hypertension. So I think from our standpoint, we're thrilled there's more innovation in this space. I mean, I started my career carrying the bag, quote, unquote, "In hypertension." It was a transformative time. ACEs, ARBs, calcium channel blockers, selective beta blockers, and then we went 20-25 years with zero innovation. Right. Now, we've got angiotensinogen - directed vectors, we have endothelin receptor agonists, and we've got what we think are really the transformative class aldosterone synthase inhibitors like lorundrostat. So thrilled to be here, thrilled to see big pharma turn its eye back onto these big chronic conditions, because, again, three out of the top eight global burden of disease is stroke, heart disease, CKD. They're not going away, and we've got to somehow address that. That's kind of what drives us every day. Great. With that, thank you very much, Jon. Really appreciate you providing this time. Sure. No, I appreciate it. Thank you. Thank you.