Good morning, ladies and gentlemen, and welcome to the Mineralys First Quarter 2024 Earnings Conference Call. This call is being recorded on Thursday, May 9, 2024, and I would now like to turn the conference over to Garth Russell of Lifesci Advisors. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to our first quarter 2024 conference call. Earlier this morning, we issued a press release providing our first quarter 2024 financial results and business updates. A replay of today's call will be available on the Investors section of our website approximately 1 hour after its completion. After our prepared remarks, we will open up the call for Q&A. Before we begin, I would like to remind everyone that this conference call and webcast will contain certain forward-looking statements about the company. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our annual report on Form 10-K and subsequent filings. Please note that these forward-looking statements reflect our opinions only as of today, May 9. Except as required by law, we specifically disclaim any obligation to update or revise these forward-looking statements in light of new information or future events. I would now like to turn the call over to Jon Congleton, Chief Executive Officer, Mineralys. Jon?

Thank you, Garth. Good morning, everyone. Welcome to our First Quarter 2024 Financial Results and Corporate Update Conference Call. I'm joined today by Adam Levy, our Chief Financial Officer; and Dr. David Rodman, our Chief Medical Officer. Considering the relatively short period of time between this call and our fourth quarter call, we're going to keep our prepared remarks today fairly brief. I'll begin with an overview of the business and recent milestones, followed by Adam, who will review our first quarter financial results before we open up the call for your questions. Let me start by stating that we continue to make great progress with our clinical trials and reaffirm our previously stated guidance on the timing of our top-line data readouts, which I will review in a moment. Before getting into each trial in detail, let me take a moment to touch on our overall strategy and basis for our pipeline, which is focused on targeting dysregulated aldosterone. Aldosterone is known to be a significant driver of cardiorenal metabolic diseases. Thus, we're developing an aldosterone-targeted treatment approach with lorundrostat. We believe lorundrostat has the potential to benefit millions of patients who are impacted by hypertension, kidney disease, and heart disease. For example, dysregulated aldosterone levels are a key factor in driving hypertension in approximately 25% of all hypertension patients. This is a significant population, as there are an estimated 115 million patients in the United States who have hypertension. Of the 60 million treated patients, more than half fail to achieve their blood pressure goal. The outcome can be severe for these patients. According to the World Health Organization, there are 7.5 million deaths attributable to hypertension per year globally. Given the impact of uncontrolled hypertension on cardiorenal outcomes, we made hypertension our lead indication for the development of lorundrostat. In addition to hypertension, we're currently investigating the benefits of lorundrostat in subjects with hypertension in CKD. We entered 2024 with clear goals for our registration program in hypertension, which is comprised of 2 pivotal clinical trials titled Advance-HTN and Launch-HTN, an open-label extension trial called Transform-HTN to capture long-term safety and efficacy data, and the proof-of-concept trial Explore-CKD evaluating lorundrostat in hypertensive CKD subjects. Advance-HTN is the first of the 2 pivotal trials we have initiated, which started enrolling patients 1 year ago. Enrollment in the trial remains ongoing, and we anticipate top-line data to be available in the fourth quarter of this year. This is a state-of-the-art, extremely rigorous hypertension trial which is designed and executed in collaboration with the experienced cardiovascular research team at the Cleveland Clinic. The trial is designed to demonstrate the value of lorundrostat when added to standardized, optimized AHA guideline background treatment in patients with uncontrolled or resistant hypertension as confirmed by 24-hour ambulatory BP measurement. We believe this is the only trial of an aldosterone-directed therapy that is utilizing this rigorous standardized background treatment approach. As such, this trial has the potential to generate high-quality evidence that will be important for potential inclusion in the hypertension guidelines for treating physicians and for creating favorable access via payers. As you may be aware, the targeted treatment of hypertension is a major point of our strategy. Data presented last year from Target-HTN trial laid the foundation for identifying patients who best respond to lorundrostat, such as those patients with an elevated BMI. The planned analysis of the Advance-HTN trial includes a well-powered confirmatory test of the predictive value of obesity on the efficacy of lorundrostat. We believe the inability of an optimized 2 or 3 drug standard anti-hypertensive regimen to reduce BP to goal in the setting of obesity will be a straightforward approach to identifying candidates for treatment with lorundrostat. In addition, we plan to continue to explore other positive and negative predictive tools using an unbiased artificial intelligence model, to expand the repertoire of useful tools for targeting lorundrostat to individuals most likely to derive long-term clinical benefit. Launch-HTN is our second pivotal trial, which we initiated in the fourth quarter of 2023. We continue to anticipate top-line data to be available in the second half of 2025. This Phase III trial, which will enroll up to approximately 1,000 adult subjects, is designed with the objective of evaluating treatment in a real-world setting when added to subjects previously prescribed a background regimen of 2 to 5 antihypertensives. Subjects who fail to achieve blood pressure control on their prescribed background treatment during the run-in period will be randomized 1 to 2:1 to either placebo, once daily 50 milligrams of lorundrostat, or once daily 50 milligrams of lorundrostat with the option to titrate to 100 milligrams once daily as needed at week 6. The primary endpoint for this trial will be change in systolic blood pressure as measured by automated office blood pressure. We believe this endpoint reflects real-world measurements that will be relevant to the primary care provider this trial targets. In addition, subjects from these 2 trials will be offered the opportunity to roll over into the ongoing open-label extension trial called Transform-HTN. In addition to the hypertension pivotal program, we're conducting the Explore-CKD Phase II clinical trial for lorundrostat in patients with hypertension and Stage II to IIIb chronic kidney disease. We continue to anticipate top-line data to be available in Q4 2024 to Q1 2025. Explore-CKD is a within-subject comparison trial designed to demonstrate the benefit of lorundrostat in reducing blood pressure and provide supportive evidence for potential benefit on chronic kidney disease on the background of a stable SGLT2 inhibitor treatment. This proof-of-concept trial will enroll approximately 60 subjects with hypertension in Stage II to IIIb CKD. We are pleased with the steady progress the team has made in strengthening our clinical program for this promising new approach to treating hypertension and the associated complications like chronic kidney disease and heart disease. We look forward to keeping you apprised of the status of the lorundrostat development program. Let me now turn the call over to Adam, who will provide a financial review for the first quarter of 2024. Adam?

Thank you, Jon. Good morning, everyone. Today, I will discuss select portions of our first quarter 2024 financial results. Additional details can be found in our Form 10-Q, which was filed with the SEC earlier today. We ended the quarter with cash, cash equivalents, and investments of $338.6 million compared to $239 million as of December 31, 2023. In February 2024, we completed a private placement financing for net proceeds of approximately $116 million. We believe that our cash, cash equivalents, and investments will be sufficient to allow us to fund our planned clinical trials as well as support corporate operations into 2026. R&D expenses for the quarter ended March 31, 2024, were $30.8 million compared to $12.3 million for the same quarter of 2023. The increase in R&D expenses was primarily due to increases of $16.8 million in preclinical and clinical costs, $3.7 million in clinical supply, manufacturing and regulatory costs, $1.7 million in higher compensation expenses resulting from additions to headcount and stock-based compensation, and $0.3 million in other research and development expenses, partially offset by a decrease of $4 million in license fees. G&A expenses were $4.6 million for the quarter ended March 31, 2024, compared to $2.6 million for the same quarter of the prior year. The increase in G&A expenses was primarily due to $1.3 million in higher compensation expenses resulting from additions to headcount and stock-based compensation, $0.5 million in higher professional fees associated with operating as a public company, and $0.2 million in higher insurance and other administrative expenses. Total other income was $3.9 million for the quarter ended March 31, 2024, compared to $2.3 million for the same quarter of 2023. The increase was primarily attributable to increased interest earned on our investments in money market funds and U.S. treasuries. Net loss was $31.5 million for the quarter ended March 31, 2024, compared to $12.6 million for the same quarter of 2023. The increase was primarily attributable to the factors I described earlier. With that, I'll ask the operator to open the call for questions. Operator?

Your first question comes from Geoff Meacham from Bank of America.

This is John Joy on for Geoff. So with top line data expected in Q4 '24, what would be a positive readout for you in terms of clinical response and safety profile?

Yes, John. Thanks for the question. We've done a fair amount of market research with payers and physicians with the Target-HTN data, where we saw an 8- to 10-millimeter mercury placebo-adjusted drop. We believe if we replicate that, that is a transformative change for subjects using lorundrostat in the third or the fourth line. That's based on the fact that with the currently available treatments, when you go to a third and fourth line agent, you typically see a 5 to 6-millimeter mercury drop at best. And so if we replicate what we've seen in Target-HTN of 8 to 10 millimeters of mercury placebo-adjusted, we believe that will be very resonant within the market and support the opportunity that lorundrostat represents in the hypertension space.

Your next question comes from Annabel Samimy from Stifel.

This is Jack on for Annabel. So could you remind us of the powering for the Advance-HTN trial? And what magnitude of placebo response you might be expecting here, acknowledging that these patients should have truly uncontrolled hypertension? And then with Launch-HTN, because those background treatments are going to be variable, what kind of steps have you taken to help minimize the noise and the variability there when it comes to the top line data generation?

This is David Rodman, CMO. Thank you for the questions. The first inquiry was about the powering for the Advance trial, specifically regarding the placebo expectations. I want to remind you that in Advance, we're using 24-hour ambulatory blood pressure monitoring as the primary measure. With this method, we average measurements throughout the day, which provides more stable averages. In our initial trial, the placebo effect was approximately 2 millimeters of mercury, which is what we anticipate. This is a quite subtle placebo effect. Regarding the powering, we are adequately powered to detect the range that Jon mentioned, which is 8 to 10, and we are actually overpowered for that. You also asked about the Launch trial, which is more reflective of real-world conditions, and what steps we've taken. In the Target-HTN trial for that population, we observed a placebo effect of about 4 millimeters of mercury. All the measures we implemented in that trial to achieve an optimum placebo effect and minimize variability are also integrated into this trial. We have made additional efforts to refine our approach, with the most significant being the use of an app-based AI tool to interpret adherence. As you may know, a major reason patients do not respond to their antihypertensive treatments is often due to poor adherence. A substantial contributor to the placebo effect is patients starting their medication during trials. We address this issue by managing adherence during the run-in phase and utilizing a placebo in that period. This allows us to establish a baseline while eliminating this significant variable. We tested various adherence tools and found that this one performed the best, significantly enhancing our data's quality. There are other considerations, but that's the main point I'd like to highlight.

Got it. And then if I could just sneak in one more, maybe. Now that you mentioned the differences in the placebo effect of maybe 2 millimeters, 4 millimeters, about how much variance is there between the ABPM and AOBP measures. Basically, trying to ask here if you're expecting to see vastly different result ranges in Advance versus Launch?

That's a great question. When Jon mentioned the range of 8 to 10 millimeters of mercury, he was referring to AOBP in the Target-HTN trial, which is also the primary measure in the Launch trial. We anticipate similar findings in both trials, around 8 to 10. In individuals with normal blood pressure control, blood pressure typically decreases during sleep. As a result, when you take a 24-hour average, the blood pressure reading is lower, leading to a proportionately reduced response. The primary measure in the Advance trial is the 24-hour average ABPM, which generally shows a decrease of about 1 to 1.5 millimeters in systolic blood pressure when comparing the two methods. We can also analyze 24-hour daytime readings, which would align more closely with AOBP. Does that address your question?

Your next question comes from Seamus Fernandez from Guggenheim Securities.

Just wanted to clarify, Dave, a couple of those last points. So when we're thinking about the difference between 24-hour ABPM and the AOBP measures, I think that 8- to 10-millimeter threshold. I just wanted to clarify a couple of things. Number one, we do know that the half-life is a bit shorter with lorundrostat. So just trying to get a better characterization of how much you would anticipate that overnight average to change. And how you're actually measuring blood pressure overnight? Is that a continuous monitor that you're using to average over time? And then when you've looked at other studies in terms of that comparison, as you look at comparisons of the design of Advance versus other programs? Just trying to get a more complete understanding of what typically happens during that overnight period. For placebo as well as for a full kind of long-acting once a day versus a program that has a shorter half-life in that regard?

Seamus, I'll start and Dave will add some thoughts. And if we miss any of your points there, let me know. But I want to address the question on the half-life because the point I do want to reiterate from Target-HTN, the primary endpoint was AOBP that was in-office. And those measurements were taken in the morning before that day's dose. So we were looking at patients within the office and we actually saw that 8- to 10-millimeter mercury reduction that was also replicated within the 24-hour ABPM. So we're very confident in the once-daily dose. And we actually think the 10- to 12-hour half-life creates kind of an ideal mix of efficacy and safety, based on what we've seen, and we'll continue to evaluate that. Now to some of your deeper questions on the 24-hour monitoring, I'll have Dave address those.

Thanks, Seamus. We put a lot of thought into what pharmacology would be optimum. And as Jon mentioned, we like this idea of having a time for some release in the sort of the predawn hours, so that aldosterone can do its job in terms of excreting potassium. But if you think about the mechanism of action, this is a diuretic. It lowers your blood volume. And overnight, you don't really take on more volume; you're asleep. In the morning when you get up, you take our drug, and within 1 hour, you've gotten rid of aldosterone. And so essentially, during the period of time when you need the sodium loss, the natural release, you get it from our drug. During the amount of time when you can switch out and lose potassium, you get that window with our drug. And so the other thing that I'll mention is that when we measure aldosterone levels in blood before the dose in the morning, the median value is a 70% reduction from the baseline value that you get without drug. So we still have a substantial reduction even though we have a shorter half-life; it's just not 0. We get complete suppression of aldosterone an hour after a dose and 70% in the morning. So don't think of it as a switch that's on and off. I like to think of it as restoring normal circadian rhythm. This is what you should be doing. You should have a lower aldosterone, which is what we produce, but it should be highest in the morning and then go down during the day, which is exactly what happens.

Seamus, did we get to all of your questions?

I think that covered the majority of it. But just as you look at other clinical studies and the performance of placebo versus an active, whether it be with an ACE or an ARB or mineralocorticoid-targeted agents, what do you typically see during that overnight period?

Yes. So good question. So let me start with the placebo piece. First of all, as I said, in our study, the first study, even with the relatively small numbers of 30 per arm, we saw a 2-millimeter mercury placebo effect. And so that's de minimis. It's not going to change over the course of the day because that's really not a treatment effect; that's just measurement variability. And to answer your question that I completely forgot to answer, people wear a monitoring device and a recorder 24 hours, whether they're awake or asleep. The only difference is we do measurements around every 20 that is during the day, and we space them out a little bit more at night because it can tend to disturb sleep a little bit, which can raise your blood pressure. So that's how we do it. We don't expect to see a difference in placebo effect overnight. We do expect to see a reduction in blood pressure. In fact, we will often see what's called restoration of nighttime dipping. So for you and I, without sleep apnea and without untreated hypertension, our blood pressure will dip at night. It will go down, as I mentioned. Hypertensive patients will first just lose the dipping, then get actually hypertensive overnight. So that's what we expect to see at night.

Great. As I ask my last question, I want to discuss the importance of having a diuretic like HCT. Considering the differences between your two programs, how do you anticipate the role of diuretics? Will these be a standard treatment for all patients, followed by additional therapies in both trials? I’m trying to understand how the use of standard thiazide-based diuretics will be integrated.

Yes. Thanks for letting me clarify that. Everyone in both trials needs to be on a thiazide or a thiazide-like diuretic. I'll mention also that in the United States, at least, the first-line drug now is recommended to be a fixed-dose combination between an ACE or an ARB and a thiazide diuretic. And so this mimics what guidelines would say. You come in on 2 drugs, but they're in the same pill, and there's always a thiazide in that. So we're following to the letter the way we expect patients to show up in the doctor's office. Therefore, when we give them guidelines and say, if they don't respond, if they're on that regimen, if they're obese, you should think about our drug as a next step. Our data are going to exactly support that sort of practice pattern.

And Seamus, as you're well aware, in Target-HTN, we had a little over half of the subjects on a diuretic, a little under half not on a diuretic. And we saw a clear additive benefit of lorundrostat with the diuretic. So when we think about what we hope to see from an effect size in Advance and in Launch of that 8- to 10-millimeter mercury, which is replicating target. That doesn't take into account the potential additivity of the diuretic, which, as Dave said, will be part of the background medication in both Advance and Launch-HTN.

Your next question comes from Michael DiFiore from Evercore.

I have a general question regarding any early thoughts you might have on how Mineralys could approach treatment in cardiac or renal metabolic syndrome if the CKD trial proves successful, especially considering the current trend of looking at cardiovascular issues more comprehensively.

Yes, Mike, thanks for the question. I appreciate it. I think you're right. We're seeing this shift from treating hypertension and CKD and heart failure and OSA as these independent stand-alone conditions, but really looking at the interplay between them and can we find benefits from a single agent across that spectrum? That's really kind of the basis of how we've been advancing forward for us. Hypertension is really kind of the beachhead indication. It's really, in a lot of ways, the genesis of these conditions. So you have hypertension that leads to CKD, heart disease, stroke. From our standpoint, the first step forward into that broader cardio-renal metabolic syndrome is the Explore-CKD study that's going to give us a perspective on not only addressing hypertension, but also the renal insufficiency within those patients. We also believe that that's a white space for us. There are a lot of agents for hypertension. There are a lot of agents for kidney disease, but to have a benefit on both is a little bit unique and distinct, and that's something that we think lorundrostat can point out. As we continue to learn more information about lorundrostat through our development program, we'll continue to contemplate where else can we extend the value of an aldosterone synthase inhibitor that has best-in-class selectivity like lorundrostat. And it could be some of these other areas that begin to get into heart disease, heart failure. There are a variety of places we can go. As we're seeing a renaissance within research and in the pipelines right now, we're seeing more and more focus on aldosterone, which we believe is an important thing to do, given the rising prevalence of dysregulated aldosterone, which Mike, you've heard us say before, we believe at least 25% of all hypertension patients are dealing with this and that probably extends into full cardio-renal metabolic syndrome as well.

Your next question comes from Rami Katkhuda from LifeSci Capital.

I guess first, is there any risk that the 3-week run-in period in advanced HTN is not long enough to have patients get to stable blood pressure on the standardized background regimen?

So good question. Many of the people who come in will already be on most or not all components of that given the type of patients we're screening for and screening out. And so I think the risk is relatively modest. It's taken care of, though, in the design because the placebo group stays on that regimen. So let's just say over 12 weeks in the run-in period, if their blood pressure dropped by 8 millimeters of mercury, it also drops another 3 from the regimen over those 12 weeks. That will then be in the placebo effect, but it will also be in the treatment arms, and it will just get subtracted out. So in the placebo-adjusted, there's no risk.

Got it. That makes a lot of sense. And then I guess with BI's ASI, it was recently shown to have a cell activity of 250:1, but they still saw a number of cases of adrenal insufficiency in their CKD study. I guess, does this change your view at all on the selectivity threshold that's needed to avoid the off-target suppression of cortisol?

Well, it's a really good question. I’m going to point out that when we had LCI 699 at Novartis, when I was there, that's essentially what killed the drug, and that's why it actually is sold now as a treatment for hypercortisolism, not hyperaldosteronism. So the regulators are extremely, if not super sensitive about this issue. When we do those selectivities, what we do is we take recombinant human enzyme and test it. But once you're in a patient, there are other variables, so I don't think I can answer your question and say we know an exact cutoff in vitro. Proof is in humans. We haven't seen this so far, and it hasn't been a close call for us. But we're continuing to look at that. Why BI saw it, I can't say. We're very careful about not including people who've been using high-strength steroid creams or taking inhalers for asthma and things like that and confounding the data. We will look at that in profiling later because the real world is people do that. So it's possible they're taking people who are predisposed and showing that their drug can suppress them. We're going to take that more carefully in our development programs so that when we eventually have guidance for physicians, they know exactly what our drug does and doesn't do.

Your next question comes from Rich Law from Goldman Sachs.

Good to be back and congrats on the progress so far. For Advance-HTN, can you discuss how the patients are enrolled and randomized due to the background standardizing period? Since you're taking patients off to 2 to 5 medications and then putting them on the background of 2 to 3, how do you think that change in treatment from the standardization could affect the results in the study? And then how do you mitigate against that?

Rich, the way Advance is built is really to address the question of whether somebody is truly uncontrolled or truly resistant. We really have 4 main vectors that we address during that run-in period before subjects ever get randomized to either placebo or active. The first is following AHA prescribed guidelines for what subjects should be on. If patients are on 2 medications coming into the trial, we take them off those 2 medications and put them on olmesartan, an ARB, and a diuretic. If they're on 3, 4, or 5 medications, we put them on olmesartan, a diuretic, and amlodipine, a calcium channel blocker. So we're putting them on the right drugs according to the AHA guidelines. Secondly, we ensure that they're on the proper dose of those medications. So in the case of olmesartan, it's 40 milligrams. In the case of the diuretic, it's in-depth mine, it's 2.5 milligrams. If it's HCTZ, it's 25. And amlodipine, 10 milligrams. Now we've got the right drugs at the right dose. The third piece that we do is we ensure compliance. We know compliance is a factor in patients' inability to get to goal. We're working with a firm called AiCure that's done, I think, up to 300 different registrational studies with this technology. It's smartphone technology that captures their consumption of these standardized medications during the run-in and then we use it during the randomization period as well for background meds as well as placebo and active. During that run-in period, this allows us to have daily confirmation that subjects have taken their medications. This is Bluetooth, cloud-enabled. We get daily feedback about whether subjects are being compliant or not. It goes to the site, it goes to our CRO, and it comes to us as far as that information. We can actively reach out to these subjects if they're missing doses and reinforce the importance of taking the study drug. So now we have them on the right drug at the right dose, and we're ensuring they're compliant. At the end of that 3-week period, which, as you heard Dave say, is sufficient to get subjects to peak plasma and probably maximal effect with that background regimen, we do 24-hour ambulatory blood pressure measurement. That's the gold standard measurement. As you heard Dave say earlier, it has a very de minimis placebo response and takes out a lot of noise in what can sometimes be a noisy measurement in the office. If after that measurement they continue to be hypertensive, so they have not achieved goal, then we randomize. If they do achieve goal, we don't randomize them, and they're not included in the study.

Great. And then for patients who are treatment-resistant on 4 or 5 medications coming into the trial and you take them down to 3 background medications and then add lorundrostat. Do you think these patients are more difficult to treat compared to others since they are already resistant on 4 or 5 and then you take them back down to 4?

Yes, this is Dave Rodman. Traditionally, a treatment-resistant patient is one who has not achieved their blood pressure goals with three medications: an ACE inhibitor or an ARB, a thiazide or a similar diuretic, and either a beta-blocker or a calcium channel blocker. They may be taking four or five different drugs. However, when it comes to adding any additional medication after three, the reduction in blood pressure you can expect is usually only about three to five millimeters of mercury at best. The more medications you try, the smaller the benefits tend to be because the root cause of the issue isn't being addressed. This is why guidelines recommend targeting aldosterone as a fourth-line treatment. Unfortunately, the existing medications to tackle this problem are not very effective. For instance, spironolactone cannot be increased to its maximum effective dosage without causing issues. We believe our drug will be significantly beneficial for these patients because we can safely reach the maximum effective dose that aligns with the guideline of attacking aldosterone as a fourth option, leading to substantial blood pressure improvements. Thus, we view reducing their medications to three and providing the needed drug not as a drawback, but rather as a critical advantage that will yield positive results.

I see. And then one more question from me. So looking at the data you guys presented at ASN last year where you show BMI versus the SBP reduction. And we see around like 20% of patients who did not respond to treatment across the BMI spectrum, meaning that the SBP trajectory went up in the study. Have you characterized these patients further on why they did not respond? And was there any difference in nonresponder rate between the 50 mg and 100 mg dose in Target-HTN? And going forward, what do you expect is the nonresponder rate for your pivotal studies?

That's a great question. I hope my answer makes sense. When we analyze the frequency of responses, we find that those who did not respond on a particular day do not typically skew the overall results, as they may respond similarly when considered at another time. This variability is just part of the data noise we see with AOBP measurements. On the other hand, we observe a left skew in the distribution of responders, where some individuals show significant responses, including those with substantial drops in blood pressure. Generally, higher blood pressure correlates with a greater decrease in reading, particularly for those who are aldosterone dependent. This situation is manageable within our placebo-controlled trial design and statistical analysis, and it does not introduce any confounding factors.

And Rich, I'll just add, and you're well aware of this. Our whole intent is to really identify those positive and negative predictors for response to lorundrostat. BMI clearly was a prespecified analysis that we did in Target-HTN. We saw a very tight correlation as far as response magnitude relative to BMI. That's something that we're going to continue to analyze in Advance and Launch-HTN. But as I noted in my opening comments, we're partnering with an AI firm to continue to really identify those predictive values that would say this is the type of patient that's going to respond to lorundrostat very exquisitely. Dave made the point, the data is out there that as you get into that resistant state, we are on 3 or more background meds. There is an enrichment of an aldosterone-dependent form of hypertension in that population because fundamentally, those patients aren't being addressed with an aldosterone-directed therapeutic. All of those, I think, are really going to enable us in this development program to come forward with a really clear toolkit of who should be on lorundrostat and the kind of benefits that they can derive from it.

Got it. And then just following up based on what you guys said. Is there like a certain percentage of patients who are just not aldosterone-driven in that third and fourth line? Have you guys thought about there could be other drivers of hypertension?

I think the literature would say that there are going to be other drivers. Our interest has always been on where aldosterone is driving it. Hypertension is a multifactorial disease. We're not developing lorundrostat as a monotherapy. We actually think an ideal combination would probably be an ARB, a diuretic, and lorundrostat for those patients who have aldosterone-dependent hypertension. There are definitely other factors driving this condition, but that's where frankly, we're taking the vantage point of let's bring a level of precision on the treatment of hypertension and acknowledge those different variables and, in our case very specifically, let's identify those subjects that have dysregulated aldosterone and will benefit extremely well from lorundrostat.

That makes sense. And then just another final follow-up. Are you able to quantify how much of those patients are just not aldosterone-driven at that point and may not respond to an ASI?

So it's a great question. Just to embellish one statement that we've made. If you look at the classical teaching, the most common cause of hypertension beyond what we used to call essential hypertension or primary hypertension is too much aldosterone. Previously, that was called hyperaldosteronism, and it had a very specific and complex way of diagnosing it. We now call it inappropriate aldosterone. The field recognizes that you can have a low aldosterone but be aldosterone dependent. At the end of the day, the gold standard is does your blood pressure go down when you reduce that aldosterone. We'll be looking at that and saying, do we have people who didn't reduce their aldosterone, and is that why they didn't respond? If that's the case, we will see that in the 50 to 100 dose escalation arm of the trials. Or are they truly resistant? Aldosterone does go down, blood pressure doesn't. Then we'll be able to answer your question with data, and we'll have those data.

Your last question comes from Mohit Bansal from Wells Fargo.

Can you hear me?

It was a little bit difficult to hear you. I just wonder if you could reorient the phone.

Can you hear me better now? So I just wanted to ask about the kind of magnitude of benefit you want to see in the CKD proof-of-concept trials here, given the shorter treatment period because I think in the past, you talked about SGLT2 inhibitors could have a 30% to 40% improvement in proteinuria. So can you talk a little bit about that? And how would you compare and contrast when the data come what is out there? And how would you make the decision here?

I think what we would anticipate, Mohit, and thank you for your question. In Target-HTN, again, we saw the 8- to 10-millimeter mercury placebo-adjusted drop in blood pressure with a really nice safety profile. The majority of that response was seen within 2 weeks; we saw the beginning of the drop, and the majority of it was at 4 weeks. So I think we're comfortable that we'll see that level of drop within systolic BP. As far as the renal benefit, I'd hate to extrapolate at this point in time. We know that the kidney benefit, to a large degree, is derisked within aldosterone synthase inhibitors based on what the Beringer Ingelheim data that was presented last fall. We wanted to confirm that we see the same benefit with lorundrostat. We think that the UACR effect is likely driven from the reduction in blood pressure.

Thank you for the question. It's an important one. We focused on blood pressure as our primary target because we have a highly effective blood pressure medication. If we only address the metabolic aspect without treating hypertension, kidney function will still decline. It's essential to manage both, and we believe our drug will be particularly beneficial for this. Regarding your question about proteinuria, which is assessed through UACR, it correlates with a reduction in GFR over one or two years, but this cannot be observed in a short study. You asked if we can expect results in four weeks, and the answer is yes. We've consulted various experts on this. While we may not capture the absolute maximum benefit in that time frame, we should see a significant portion of it. It's worth mentioning that there will be a strong focus on SGLT2 inhibitors, highlighting the added benefit of our drug in comparison. We don't believe a monotherapy trial is necessary since that issue has already been addressed by other companies. We are looking to determine how much additional benefit we can provide above standard care. It's crucial to ensure comparisons are made on an equal basis, specifically ensuring that our addition of lorundrostat is evaluated against a combination product starting from a comparable baseline. The assessment will focus on what benefits are gained over SGLT2 inhibitors, and we anticipate seeing results similar to those from previous trials for that additional benefit.

Got it. This is super helpful. If I may ask one more. I know I understand that you are approaching CKD or chronic kidney disease with a hypertension angle. But there is a lot of activity in the rare kidney disease space as well. I mean the relationship between hypertension and kidney diseases is very much intertwined. Is there an angle where lorundrostat can play in those rare kidney diseases as well? Or am I just making more of a wishful guess right now?

That's a great question. We are excited about the IgA nephropathy data, which often affects children and is a serious condition that now has several treatment options. We believe there is potential for us to contribute in that area, although not specifically targeting IgA. We do have some ideas, but we can't discuss them at this time. However, we do see an opportunity for lorundrostat in this space.

Got it. Helpful. More work for us to do there.

There are no further questions at this time. Mr. Jon Congleton, please proceed with your closing remarks.

Thank you, operator, and thank you to everyone for joining us today. We're very excited about the progress we've made thus far in 2024 in advancing our clinical programs and remain enthusiastic about the upcoming milestones for the rest of the year. We look forward to updating you as our pivotal program for lorundrostat continues to advance. With that, we'll close the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.