OK, excellent. Thank you, guys. Our final chat for the day: Mineralys Management. Really excited for the conversation. Huge phase 2 trial coming up for you guys. We want to talk all about it, but I'll let you kick things off and maybe remind us about your prior data and the upcoming trial design. Yeah, so Mineralys is built around really focusing on aldosterone and what it does in cardiorenal metabolic syndrome. We licensed the asset from Mitsubishi Tanabe. It had gone through discovery and development through phase 1. We did the proof of concept study where we did a couple of things. We identified the doses we wanted to move into pivotal development. We showed robust efficacy on blood pressure, double-digit reduction, while having a modest effect on the main on-target adverse event, which is hyperkalemia, potassium. So the study really gave us what we needed as far as proof of concept, doses to move forward, how to think about development from an operational standpoint. We had a really good dialogue with the FDA late in 2022 and began our pivotal program that consists of two hypertension studies. One that is really targeted to specialists called Advance-HTN, where we standardize the background regimen and really eliminate what could be called apparent hypertension, and it's true uncontrolled and resistant hypertension in Advance-HTN study, and then Launch-HTN is really kind of the real-world study where we're just adding lorundrostat to existing background treatment. This is a larger global study. Both, we believe, are going to be sufficient, presuming positive outcome of the trials, for an NDA-enabling package, and then we also have a proof of concept in hypertension and CKD that'll be informative for the NDA filing for hypertension, as well as informative for thinking about future development of lorundrostat and CKD. From our standpoint, at the end of the day, what we're fundamentally doing truly matters because the linkage between reducing BP and improved outcomes is clear and evident as it relates to stroke, heart disease, and kidney disease. So we're excited about the program and a lot of really important data readouts in the first half of 2025. Got it. Thanks, Jon. So just for folks not too familiar with the story, the powering of Advance-HTN, and 90% powered for a placebo-adjusted SBP reduction of 7 millimeters of mercury on 24-hour ABPM. Is that correct? That's correct. OK, OK. Because you mentioned twice, you mentioned two figures, the seven millimeter and the 8-10. The 8-10 refers to AOBP. Yeah, well, and 8-10 is really, when we got the outcomes of Target-HTN, we went out to the marketplace talking to physicians and payers. And the 8-10 is kind of what we put forward as a target product profile. In other words, if we deliver on what we saw in Target-HTN within the pivotal program, then we'll see, I think, a transformative launch with that kind of asset because that's truly meaningful data as far as for physicians, prescribers, and for payers. The 7 millimeters of mercury is what the study was actually built and statistically powered around. OK. So this study is testing two arms versus placebo, 50 milligram and a 50 milligram with the option to titrate up to 100 milligram. Some investors have asked me if we should be looking for a dose response between the patients who are on 50 milligrams q.d. throughout the entire length of the trial versus those who wind up on 100 milligrams q.d. How should we think about a possible, if any, dose response here? Yeah, I think what we saw in the phase 2 study was the 50- and 100-milligram looking fairly similar. I think with the ASIs, the profile that's emerging. We saw it with our low dose, 12.5 q.d., really had no effect at all. The 50 and the 100 had similar effect. If you look at the baxdrostat, the one positive study, 0.5, no effect, one and two fairly similar response. It seems like there's a really tight sigmoidal response curve here. We know that there's variable exposure at the individual level. We saw that within Target-HTN as we looked at individual dose exposure response. The way we think about the 100 is probably less about having a continued reduction in BP, but more for those patients that probably have lower exposure profile, probably don't get as much of a response at 50, but the 100 milligrams may give them that. I think where you may see a difference in the data is less on the amount of millimeters of mercury reduction and more on the number of subjects that are getting to goal in that third arm. In other words, the 50 milligram standalone arm that doesn't have the ability to titrate, we'll see a percent that get to goal. The 100 milligrams, if there's an exposure variability and the 100 milligrams allows them to see that full reduction, there may be a higher percent of patients getting to prespecified goal, which is 125 millimeters of mercury in the 24-hour ambulatory. Got it. And in that 100 milligram option arm, if they're not at goal by week four, then they remain on 50. Yeah, if they don't get to goal. Titrate up, rather. Their electrolytes are still within the normal range. Then they titrate up. Got it. Week four or week six for the updates? Week four for Advance, week six for Launch. I see, I see. Week four for Advance. And I guess, how is that chosen, four versus six week? We worked with Cleveland Clinic on the construct of Advance-HTN. They gave us some insight a little bit on Launch-HTN, but they were mainly our partner on the build-out of the Advance-HTN study. It was really just to give us some additional information to think about how we should direct physicians when to think about titrating up, coupled with the fact that we know Launch-HTN has a little bit more of a heterogeneous population as far as background medication. Got it. It's hyper-homogenized in Advance. Should we go through some of the numbers, Mike, on what we're showing for phase 2 and some of the other sources that we're showing similar trials? Yeah, so Jon, we still get a lot of questions, believe it or not, on Target because people are kind of using Target, that data set to help try to handicap Advance. So I guess one of the main, I guess, areas of questions that we get is on that sensitivity analysis that happened in Target, whereby 28 patients were in the entire 50 milligram cohort, but 14 of those patients were deemed really not to have hypertension because they weren't hypertensive at baseline according to 24-hour ABPM. In those remaining 14 patients, you saw more of a treatment effect, but placebo-adjusted, I think the placebo-adjusted reduction was around 5.5 millimeters of mercury. And people are kind of questioning, well, gee, is that the true effect size here? Any thoughts on that? Yeah, so in Target-HTN, we did the in-office AOBP as the primary endpoint. That was what was used for meeting criteria for randomization. We also did 24-hour ambulatory, but it was not gating to randomization. We got the data from the study and looked at the 25 BID, the 50 q.d., and the 100 milligram q.d. And what we saw were two things. The 25 BID, 50, and 100 on AOBP all had that 8-10 millimeter mercury placebo-adjusted response. We looked at the 24-hour ambulatory. The 25 milligram had that 8-10, the 100 milligram had the 8-10, and the 50 was sitting almost at like no effect. And we said, all right, what's going on? And we went to Luke Laffin, our partner at Cleveland Clinic, said, help us discern what's going on. He said, if you looked at the baseline of the 24-hour ambulatory to see if, in fact, they were hypertensive on 24-hour ambulatory, as you point out, we found that nearly half of those subjects, and it was just random bad luck that they all landed in the 50 milligram, were hypertensive on AOBP but not on ABPM. He said, all right, we'll cut them out and see if you see a response. So we began to see the needle move. And then we looked at, just from a QC standpoint, just some improbable readings that we chose to QC out. And then that's what gave us what we felt was the true drug effect. And at the end of the day, we come back to what was the purpose of Target-HTN. It was to inform our thinking about this molecule within the hypertension space and try to get to the truth of what dose do we want to move into the pivotal study. Very helpful, Jon. I want to drill down on that QC effect because as far as my understanding goes, that QC sensitivity analysis occurred on those remaining 14 patients whereby two of those 14 patients were found to have improbable readings. Correct. That resulted in 12 patients who were truly, and among those 12 patients, that SBP reduction was around 10.5 millimeters of mercury. Right. OK, because that's one of the values that you have in one of your tables in your S-1, and it's really not that clear from the table. But now, kind of. Yeah, so that's the 10 and 1/2. And to a question I think you said before, the nighttime BP, what we showed in the 100 milligrams was about a, because again, these 24-hour ambulatory, they're taking measurements literally for 24 hours through the patient's sleep. And that nighttime BP is really a key metric because that is the one that's been shown most tightly correlated to reducing cardiovascular risk. The 100 milligrams we saw an 8 mm Hg reduction. The 50 we saw about a 4 mm Hg reduction. And so one of the things that we want to interrogate in Advance is, all right, with larger numbers, with absolute rock solid, I mean, people have to be hypertensive on 24-hour ambulatory to randomize in Advance. So we won't have this anomaly in Advance that we had in Target. We'll be able to really see that full effect over the nighttime, not only the reduction overall, but also percent restoration of dipping. But again, from our standpoint, as we dug into exposure response, as we dug into all the data, we got very comfortable that 50 milligram for us and our vantage point is going to be the predominant dose used. But the 100 milligram is going to be there for subjects that need more of the drug based on their exposure profile. I see, I see, and just looking at that, again, the sensitivity analysis in the Target-HTN study, after stripping out those 14 patients out of the 28, when you look at nighttime BP, it was essentially flat. It was like maybe minus 0.01 millimeters of mercury correction, but again, this is before the QC analysis that was done. The QC piece, right? OK. Yeah. OK. Excellent. Omar, any more questions on Advance before we move on? No, no. I think we should move on. Okay, so the larger Launch-HTN trial, Jon, is again more real-world. It kind of mimics or resembles more so Target-HTN because you've got 1,000 patients. And that's the one that's really, I think, 99% powered, if I'm correct. Yeah, I think it's 98% power at the six-week because we get to pool both of the 50 milligram arms, and that's with a 7 millimeter mercury placebo-adjusted change. OK, but unlike Advance and Launch, the background regimen will not be standardized. They won't be standardized. And I agree with you that it, to a large degree, is confirmatory of what Target-HTN is with maybe two exceptions. In Target-HTN, we use plasma renin activity as a bit of an inclusion criteria. That was the low renin aspect of it. And so we're not going to have that renin gate. We're looking at all subjects regardless of low, medium, high renin. And we're also going to be taking the finding from Target-HTN about the synergy with a diuretic. And so while it is the patient's existing background meds, one of them has to be a diuretic. So fundamentally, both Advance-HTN by design of the standardized approach and by protocol with Launch-HTN, they'll both have diuretics required as part of background. In 100% of patients. Yeah. Again, and you touched upon an important point, Jon, that I wanted to drill down on is, and this pertains to both Advance-HTN and Launch-HTN. When you look at the Target-HTN analyses, that stratified patients according to BMI versus those on diuretics, you saw an outsized effect in those subpopulations. And the question I'm thinking of is, is that effect totally teased out from each other? So is the thiazide effect independent of BMI? Yes. OK, because I'm asking that, thinking of Advance, one third of the entire patient cohort per the baseline characteristics that you released is not obese. They have BMI that are below. Below 30. So basically, in that remaining non-obese cohort, granted they're on thiazide diuretics, will they still have an outsized effect just by nature being on thiazide diuretics but not being obese? Yeah, I think when we presented the data first for the obesity and did the categorical analysis and just did the band above 30, below 30, there was maybe a bit of a disservice there because I think there's this perception, if you have a BMI of 28, 29, are you going to be responsive? And so that's why we published subsequently with the active doses the BMI relative to response, and it's more of a continuous variable. So even though we've got a third of the subjects in Advance that have a BMI below 30, I don't think that means they're not going to have a response. Again, the fact that we saw the synergy with the diuretic. We have chosen to develop lorundrostat and the pivotal programs in the background of a diuretic, we're not going to be able to tease that apart. But when we looked at the analysis, we didn't see those as dependent. They were independent predictors of response. And there was not a complete overlap of if you were a diuretic patient, you were also a BMI over 30 patient. Got it, got it. OK, now I want to drill down and say, I apologize, I keep going back and forth between studies, but now hyperkalemia risk in the Advance-HTN trial. How should we think about that? I mean, because in Target-HTN, the 50 milligram, I think, only had maybe one confirmed case of hyperkalemia, whereas more were seen in the 100 milligram. Now, when you think about Advance-HTN, one arm of the study has the option to titrate up to 100 milligrams. I mean, presumably, we could see a lot more cases here. But that may be offset by the different entry criteria in terms of potassium levels. Maybe talk about that for a little bit and how we should think about it. Yeah, so in Target-HTN, we saw there were two subjects that had on 50 milligrams that had an incidence of potassium reading above 5.5. The 100 milligrams, I think, actually had eight subjects in that 5.6 to 6 range. And we think that's related to overexposure. So if we think about what we saw in Target-HTN relative to Advance-HTN, and it's even true with Launch-HTN, a couple of things relative to potassium. Entry criteria was reduced from 5.1 to 4.8 in both studies. Diuretic use 100% per protocol. And the diuretics, particularly HCTZ, actually have a potassium wasting component to it. And only half of the subjects in Target-HTN had that. So if, in fact, there's that positive interplay as it relates to hyperkalemia, that's going to be potentially showing a reduction in the rates of hyperkalemia. So those are the two components. I'm trying to think today. I just lost my other thought. I think those are the two big takeaways, the fact that everybody's on a diuretic. We lowered the threshold on that. Plus titrating should have some sort of. I'm sorry. Thank you. So the titration piece, again, patients only get titrated up if they've not gotten the goal and their electrolytes, both potassium and sodium, are within a normal range. Again, the titration is really driven by what we think is a subject not responding due to their individual exposure. The 100 milligrams, because in Target-HTN, everybody was randomized to a dose, we think we had subjects that just frankly were getting more lorundrostat than they fundamentally needed. The titration will filter that out. If they respond at 50, they'll stay on 50. But if they're not responding, that's likely because they are on that lower exposure profile. The 100 milligram, they'll get a response to, but it should be with less hyperkalemia. But that's why we're doing the study. And that's what we'll be looking at within the data analysis. Got it, got it. Maybe in the remaining minutes we have left, Jon, is kind of just focused on the phase 2 CKD trial. Set to read out, I want to say, second half of next year, no, first half of next year, correct? Yeah, guidance we gave at our November 11th earnings call was Q2. Q2, got it. And maybe I know we're a couple of minutes left too. Could you also remind us some of the trial design changes that were done? Yeah, initially when we kicked off that study, we wanted to look at naive to SGLT2 subjects and then look at the benefit of lorundrostat on both their hypertension and their kidney function with and without an SGLT2. So in working with our KOLs, they thought, great design, let's kick that off. It had good feasibility. The reality was the feasibility wasn't there because the SGLT2s just rapidly became standard of care in these patients with eGFR down to 30. So we made an amendment to the study and basically acknowledged where the world's going and said, all right, per protocol, everybody needs to be on an SGLT2. If somebody's naive to one, which is rare, we'll start them on that. And then if their BP and proteinuria levels meet the inclusion criteria, we'll randomize them in. It's a crossover design study. It's 60 subjects. It's four weeks in duration of lorundrostat relative to placebo on top of background of SGLT2, a four-week washout, then crossover, and then four weeks again. The goal of that study is really twofold. One, the primary endpoint is to show a benefit on blood pressure reduction. The second key objective of the study is with the exploratory endpoint to look at the benefit on UACR. We feel confident that four weeks is sufficient clearly to show the benefit on blood pressure reduction. And based on what we saw with the Boehringer Ingelheim ASI and a hypertension CKD study, we think the benefit on proteinuria is likely to be seen in that four-week window as well. The end result of that study will serve two purposes. One, it will be part of the potential NDA package that we put to the FDA for the hypertension program because it'll give us the exposure of four subjects down to 30 on eGFR. Two, it'll be very informative for us thinking about what do we do next steps for development of the drug. Do we want to pursue a CKD indication, or do we go somewhere else with the molecule? But we'll have that insight with lorundrostat. And maybe just since we have very limited time left, I know ultimately you guys are in the cardiometabolic space, which is very, very resource intense. I do understand that FDA has made the path, at least on your current indication, easier with not requiring outcomes. But could you lay out the scope for us, perhaps, Adam, what the scope of OpEx spend would look like as you head towards the registrational trial? And what are your resources now versus the runway you have? So at the end of last quarter, we had $264 million in cash. That brings us into 2026. And And it'll allow us to get the top line readout of each of the trials that we discussed, which are coming in the first half of 2025. Got it. it. And are these, like this phase 3 program, this is obviously not a CVOT with a $1 billion-dollar type of commitment, but is it still a couple hundred million-dollar type of phase 3 program? For the hypertension program, you're saying? Yeah. I don't know if we've guided what the whole program is called. In broad strokes, just so we understand. Yeah, I mean, so we've raised $500 million roughly to date, and in the phase 2 and phase 3 programs, it will still get through all those and still have runway into 2026. Got it. Everything in the phase 3 program is covered with the cash that we have on hand. Got it. Well, excellent. I think we're at time, unfortunately, but very informative discussion. Thank you guys so much for coming down and spending time with us. Yeah. Wishing best of luck. Yeah, appreciate it. Thanks, guys. Yeah, absolutely. Thank you.