Mineralys Therapeutics, Inc. (MLYS) Earnings Call Transcript & Summary

Greetings, and welcome to the Mineralys Advanced-HTN and Launch-HTN Data Review Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Jon Congleton, Chief Executive Officer for Mineralys. Please go ahead, sir.

Good morning, everyone. We'll be making forward-looking statements today, and I would ask you to please note our disclaimer here. We're excited to speak with you this morning after a full weekend at the ACC '25 meeting. With the data presented in the embargo lifted, we look forward to discussing the results today from our pivotal Advance-HTN trial that demonstrated a 15-millimeter mercury reduction in absolute systolic BP and a nearly 8-millimeter mercury placebo-adjusted reduction in the gold standard measure of 24-hour ambulatory blood pressure with a well-characterized safety and tolerability profile of lorundrostat for the treatment of confirmed uncontrolled or resistant hypertension. These data were presented in a late-breaking clinical trial session at the American College of Cardiology's Annual Scientific Session in Expo, which was held in Chicago over the past few days. We're fortunate to be joined today by Dr. Luke Laffin, Lead Author of the Late-Breaking Presentation of the Advance-HTN data. As a leader in the field of hypertension and one of the primary investigators in the Advance-HTN trial, Dr. Laffin will provide you all with a valuable level of insight into the trial data and how he views these data as both an investigator and as a treating physician. Dr. Laffin is from the Preventative Cardiology and Rehabilitation section in the Robert and Susan Tomsick Department of Cardiovascular Medicine, Sydell and Arnold Miller Family Heart Vascular and Thoracic Institute. He maintains patient practice at the Cleveland Clinic Main Campus. He earned his medical degree from Vanderbilt University School of Medicine and served his residency at the University of Chicago Medical Center. He has published dozens of articles and more than a dozen research abstracts and peer-reviewed medical journals, mainly on the diagnosis and management of hypertension. He has made research presentations at regional, national, and international medical meetings and has co-authored several chapters and medical textbooks related to hypertension. Also on the call, we have Dr. David Rodman from Mineralys, our CMO, and Adam Levy, our CFO. Dave will provide a quick review of the Advance-HTN and Launch-HTN trials and a high-level review of the lorundrostat efficacy and safety data. Luke will provide a high-level review of the Advance-HTN data that was presented at ACC '25. Luke will also provide his perspective on the data set from both pivotal trials of lorundrostat and provide a comprehensive view of the efficacy and safety of lorundrostat. Luke will discuss how these data meet the needs of primary care physicians and specialists to address the urgent needs among the roughly 20 million uncontrolled and resistant hypertension patients in the United States alone. I will then discuss a recent physician survey we conducted with over 300 physicians that demonstrates their interest in the clinical profile of lorundrostat from Launch-HTN and Advance-HTN trials. I'll follow these comments up with closing remarks before we open the call for your questions. Let me turn the call over to Dave to review the lorundrostat development program and touch on the high-level efficacy and safety of the Launch-HTN study. Dave?

Thank you, Jon. Good morning, everyone. As many of you are aware, we have completed 3 clinical trials evaluating the efficacy and safety of lorundrostat in these target populations, including Advanced, Launch, and Target-HTN. The overall results from these trials have demonstrated the meaningful and consistent efficacy, safety, and tolerability profile of this highly selective aldosterone synthase inhibitor. Ahead of Luke getting into the additional results from Advance-HTN, I think it's important to note the very deliberate differences between these 2 trial designs for Launch and Advance-HTN in order for you to understand how we are comparing and analyzing the data. The Launch trial with approximately 3x the number of subjects as the Advanced trial is what we describe as our real-world trial in that it utilized automated office blood pressure measurement and allowed participants to stay on their existing hypertension medications. This is compared to the Advanced trial, which we refer to as our specialist trial in that it utilized 24-hour ambulatory systolic blood pressure measurement for the primary endpoint, and subjects who met our highly selective screening criteria had their existing hypertension medicines discontinued and started on an optimized regimen of an R, a diuretic and additionally, a calcium channel blocker previously on 3 to 5 medications. Subjects who remained hypertensive were then randomized into 3 cohorts and treated for 12 weeks. As I have mentioned before, we believe this is one of, if not the most rigorous hypertension trials conducted. The primary efficacy analysis in the Phase 3 Launch-HTN trial was pre-specified at 6 weeks of treatment; an absolute reduction of 16.9 millimeters of mercury and a placebo-adjusted reduction of 9.1 millimeters of mercury in automated office systolic blood pressure were observed with a p-value of 0.0001. At the end of treatment at 12 weeks, the benefit increased with an absolute reduction of 19 millimeters of mercury and a placebo-adjusted reduction of 11.7 millimeters of mercury in the 50-milligram arm with a p-value less than 0.001. The results out to 12 weeks add confidence that the treatment response is robust and likely to persist and confirm that 50 milligrams once daily is an efficacious starting dose. An analysis of key secondary outcome measures in both trials was done prior to up-titration at week 6 for Launch-HTN and week 4 for Advance-HTN when all subjects in the active arms were being treated with the 50-milligram dose and could be pooled, providing more statistical power for the smaller subsets. Lorundrostat worked equally well in those taking 2 baseline medicines and those taking 3 or more. Lorundrostat worked equally well in both men and women as well as in white and black subjects. The clinical safety and tolerability findings from Launch-HTN showed a low incidence of serious adverse events and changes in serum potassium, estimated GFR, and serum cortisol. There were 13 subjects, or 2.4%, with treatment-emergent SAEs in the 50-milligram arm compared with 9 subjects, or 3.3%, in the placebo arm. There was only 1 subject, or 0.1%, in the trial with a treatment-related SAE that occurred in the 50-milligram arm. The incidence of hyperkalemia over 6 millimoles per liter in the Launch-HTN trial during study visits in the 50-milligram arm was 1.1% and in the placebo arm was 0.7%. In the Advanced-HTN trial, in the 50-milligram arm, the incidence of observed potassium greater than 6.0 millimole per liter was 5.3%. In trials of this nature, the confounding incidence of falsely elevated potassium due to sample hemolysis can be as high as 5% to 10%. Per protocol, all values above 6.0 were required to be repeated within 72 hours while the subject was maintained on study medication. Using these criteria, the incidence was 2.1%, with only 2 of 5 observed episodes being confirmed as having potassium over 6. Two repeat values were less than 5.5 millimoles per liter and the third was 5.6 millimoles per liter. The observed incidents and individual listings are required by the FDA, and a review of our correction for factitious hyperkalemia will be considered. After consultation with a senior ex-FDA regulatory consultant, we believe the label will likely reflect the lower incidence in this trial. Now, we're going to hear more about the Advanced-HTN trial, which was designed in close collaboration with Dr. Laffin and his very experienced team at the Cleveland Clinic. With that, I'd like to turn it over to Luke to discuss the results and put them into context. Luke?

Great. Thank you, Dave. Good morning, everyone on the line today. Yes, so it was an exciting weekend for presenting and getting this Advanced-HTN data out there. So what I want to first really address is the trial design because, as was alluded to earlier, this was designed as a specialist trial. And another way to sort of think of it almost is like a skeptic's trial. If someone is coming to me on a low-dose ARB, maybe a low-dose diuretic, or medium-dose calcium channel blocker, what I'm going to do first, and many of my colleagues and hypertension specialists, is we are going to adjust their medicines in those 3 classes to maximize their potential and potency. And that's exactly what this trial did, with a maximum dose of olmesartan, which is one of the most potent ARBs, and a large percentage of patients on indapamide, which is actually recommended to switch to in the resistant hypertension guidelines. And then, obviously, amlodipine is very commonly used as a good calcium channel blocker. So that was really important. Patients got this for 3 weeks, then they were randomized equally to placebo, lorundrostat 50-milligram daily or a dose titration strategy of lorundrostat where it could be increased to 100 milligrams. So, it's really important data. And it's interesting even at the ACC this week, just the number of comments about how rigorous and well done this was when we think about maximizing the standard anti-hypertensive therapy and then using 24-hour ABPM. Next slide, please. Baseline patient characteristics. I really highlight here on this slide that it is a real representative population. 40% women, very nice representation there. 53% black or African-American, which is not surprising. That group has a higher burden of resistant hypertension. And so given the rigor of the trial in terms of different inclusion and exclusion criteria and different cut points, it's not surprising that we saw that. A couple of other points I want to make about this. The GFR randomization is very important to note. When you look across studies of patients with resistant hypertension, typically, the GFR has been higher. When you look at PATHWAY 2, for example, the starting GFR there was 91. And that impacts any type of AEs you see, hyperkalemia, which Dave alluded to. And so lower GFR, so it just suggests a higher risk population that was studied. Also, it is really important to note that the starting blood pressure in this trial at the time of randomization was 141 systolic. And as many of you on the call may know, the higher your blood pressure starts, the more blood pressure lowering you see. It's still uncontrolled, but this is not starting out at 155. I'll refer to the PATHWAY 2 trial again. The blood pressure there starting out was 155. So it's a lot easier to show significant blood pressure lowering when you're starting up in the 150s rather than right around 141. Next slide, please. When we look at the primary endpoint, highly statistically significant, both lorundrostat groups were compared separately to placebo. I think over 15 millimeters of mercury of reduction in that 50-milligram daily arm is very impressive. And then 8 millimeters of mercury placebo adjusted is also very impressive when we think about 24-hour ABPM. What we also know is that ABPM values are typically lower in terms of blood pressure reduction than office. And we're talking in about the 3 to even 6 millimeter mercury range. And that was pointed out by a discussant yesterday when we did the deep dive into the trial as well and confirmed. So, very highly statistically significant and not only statistically but clinically meaningful reductions in blood pressure in a high-risk group that was already well treated on standardized therapy. Next slide, please. Dave went through a lot of these and the hyperkalemia issue in terms of how it was calculated and how it was looked at in different ways. The other thing to point out is hyponatremia. So most of the hyponatremia, as you can see, since 6% in the placebo group had it, was due to the use of the potent thiazide-type diuretic due to indapamide. But really, these adverse events were keeping with something that you would see with a drug that lowers blood pressure and impacts the renin angiotensin aldosterone system, and it was essentially very well tolerated. Next slide, please. So these are the final thoughts that I left the audience with, and I'll say, at least in terms of Advance-HTN, we need new therapies for hypertension. We're doing a horrible job at controlling blood pressure, even though there's a bunch of generic options out there, we're doing a horrible job. We need new strategies, and we know aldosterone and dysregulated aldosterone really drive a lot of this uncontrolled treatment-resistant hypertension. Drugs that target aldosterone production have been clearly shown they reduce blood pressure. But ultimately, they're going to reduce cardiovascular risk. I mean, there's a real good push and a lot of data that suggests that they will do that. And then, importantly, clinical trials of blood pressure drugs need to test therapies in populations that are at the highest risk and will drive the most benefit. And I really believe Advanced-HTN did that as well as any hypertension trial recently. So, that's an overview of the Advanced data. How do we put this in context with Launch? How do we put it in context in the clinical realm? So now there are 3 trials: Target, Advanced, and Launch. And I'm not involved with Launch, just to be clear, but I know the public data. When you think about it, the data is remarkably similar amongst the 3. I don't think there are any surprises with Lorundrostat. We know that it lowers blood pressure very well. When we look at Target and Advanced and the increase to the 100-milligram dose, not having more effective blood pressure lowering than the 50, I think that, that's just really good drug development. We know that 50 is the dose where you're going to get the maximum efficacy and really not necessarily go beyond that. We know that this drug is safe. I mean, I think that this is something where when we look at this, the rigor of advance contributed to a much higher risk population. As I alluded to earlier, the starting GFR at the time of randomization was in the low 70s. And if you do it by cystatin C, it was right at 70. So that's important to note as well. This is a drug that has great potential, and it's really checking a lot of boxes in terms of convincing the subspecialists that we have to be aggressive and that we have good 24-hour ABPM data. And then when we translate it to the wider community of primary care doctors, nurse practitioners, PAs, we can turn to the launch data and say, look, at 12 weeks, you're getting a little bit more blood pressure lowering than you are at 6 weeks, but you're getting double digits placebo lowering, which is quite a great feat when you look at this class of drugs. Other things to really think about this is when we think about GFR data and thinking about how that's actually assessed and measured, we want to see at least a little bit of a decrease in the GFR, and we definitely will because you're lowering intraglomerular pressures. One thing to keep in mind is that lorundrostat interacts with the MATE1 receptor, which impacts creatinine in terms of its secretion. And so cystatin C measurements of GFR are going to be more appropriate to really assess what the impact is on kidney function. And so that was done. And so these trials ultimately really differentiate themselves. Launch is 3x bigger. So we have to take that and say that's going to be more representative than the smaller numbers, particularly when we come down to AEs, hyperkalemia, hyponatremia; those are small numbers in Advanced. So you're going to get a much better perspective from Launch when you look across, obviously, a 3 to 4x bigger study. And so that's really important. The question that comes up is this potassium issue. If you're not seeing a little bit of increase in potassium, then I would question if the drug is actually doing its job in terms of impacting aldosterone. So you're going to expect that. One thing that's really important to note, and we show this nicely ultimately in the publication, is you're going to see this increase in potassium, and it's not a huge increase by any means. You're going to see that about 2 weeks later after starting it. So it doesn't change the clinical workflow at all. As you know, if we start a patient in the clinic on a thiazide, on an ARB, or on an MRA, we're checking basic metabolic panel 2 weeks later. That's what the guidelines say, and that's what we do. And so this just fits perfectly into the workflow that we would normally see. And then when you look at the difference between a single value for over 6 versus confirmed, the clinically relevant is confirmed. It's not a single isolated value that's hemalized. I mean, I think that's very clear as well. So I don't see the potassium as being any issue. All right. I'm going to turn the call back over to Jon Congleton. Jon, I'll turn it over to you.

Thanks, Luke. Sorry about that. As I noted at the beginning of this call, we believe the clinical data represented in these 2 successful trials provide promise for the 20 million patients failing to achieve their blood pressure goal on 2 or more medications. While our initial launch target may be the resistant hypertension population, the one with the greatest cardiovascular risk, we believe the profile of lorundrostat will be quite competitive in the third-line usage sooner, frankly, rather than later. The reason for my optimism is based on a recently conducted Sermo survey that was fielded from March 18 to March 25, that tested the recently announced pivotal data from the Launch-HTN and Advanced-HTN trials, including efficacy, key secondary endpoints, adverse events tables and potassium listings similar to what we have on our website in the corporate deck. The results from this survey showed that a vast majority of primary care physicians and cardiologists are likely to prescribe lorundrostat broadly in the uncontrolled population and in the resistant hypertension population. This intent to prescribe is based on health care professionals' interpretation of the efficacy data relative to what they currently have available for uncontrolled and resistant hypertension as well as the safety and tolerability profile they reviewed. These are excellent ratings of the profile of lorundrostat. They speak to the interest in our data set, and I believe speak to the desire for innovative solutions that physicians want in their treatment armamentarium to address uncontrolled and resistant hypertension. These survey data speak directly to the market opportunities for this novel innovation in the treatment of hypertension. Before I open the call for your questions, I want to leave you with my final thoughts regarding the results from our pivotal trials and how these data could position lorundrostat in the market. With approximately 30% of all hypertension patients having elevated or dysregulated aldosterone, we believe the clinical profile of lorundrostat as an aldosterone synthase inhibitor could have the potential to extend and improve the lives of millions of patients, if approved. The data from Launch-HTN and Advanced-HTN, when compared to other agents, new or old in uncontrolled or resistant hypertension, are at a minimum competitive and in many ways, superior to what is currently available. We believe that lorundrostat is clinically differentiated as a fourth-line therapy for resistant hypertension. If approved, we believe it could help address the needs of roughly 10 million resistant hypertension patients in the United States. In our trials, lorundrostat also demonstrated a clear benefit in patients on 2 background hypertension medications. These data could support broader third-line usage for the approximate 10 million subjects with uncontrolled hypertension if approved. In terms of the next steps for Mineralys, additional data from the pivotal Launch-HTN trial will be presented at an upcoming medical conference and in a peer-reviewed publication. We look forward to augmenting the profile of lorundrostat with the Explore-CKD data in the second quarter of this year. We initiated the Explore-OSA study last quarter, and we'll provide guidance for the top line once we have a clear view of the enrollment rate. We're also evaluating potential commercial and partnering activities to ensure that we can maximize the value of this novel, best-in-class, and potential first-to-market aldosterone synthase inhibitor, lorundrostat. With that, I'll ask the operator to open the call for questions.

[Operator Instructions] Our first question comes from Michael DiFiore with Evercore ISI.

Congrats on a great data set. Two questions for me. Number one, just given the confusion surrounding hyperkalemia with unconfirmed values versus confirmed values, what will the New England Journal of Medicine publication reflect? And what is the sense of urgency to get this publication out? I'm asking because if the publication will only reflect unconfirmed values, is there any possible way the draft manuscript could be pulled to incorporate the confirmed values? Again, I'm asking because every hypertension specialist and cardiologist in the country will likely read it. And I have a follow-up.

Yes. Michael, I'll address that real quick. The journal publication will have the incident, so the 5.3% figure. As you're aware, we announced the top-line data on March 10, shortly after the database lock, and had ourselves on a fairly aggressive time line. Again, I think it's important to put the 5.3 into context as far as the given uniqueness of this population. We think it represents an acceptable safety profile given the risk profile of these patients, as Luke alluded to, being maximally treated and yet still not a goal. So the journal article itself will have the any incident rate, but I think it was important that as we did our analysis, we had that information within Luke's ACC presentation as well as within the corporate deck.

And my final question is, I know you said before you've done your own due diligence with hypertension specialists who accept or who consider the hyperkalemia rates to be within acceptable range. But will primary care doctors be willing to treat through hyperkalemia levels between 5.6 and 6?

I think I'll have Luke opine on that. Luke, do you mind addressing Mike's question about how primary care docs will be the potassium profile of lorundrostat?

Yes. I think this is a very much overblown issue, to be perfectly honest with you. When you look at the study that's 3x as large, we're talking like 1% from launch from a hyperkalemia perspective. They're going to do exactly what is recommended in the guidelines right now in terms of checking electrolytes. And it's not something that's going to dissuade people from prescribing or using this medication.

Yes. And Mike, I'll add just a quick thought. The exercise that we went through, which is pretty exhaustive to confirm the hyperkalemia rates, as Dave described, is work that's underway right now with Launch-HTN, which, as Luke said, is very low right now, and we know is going to be the maximum number that's there. We anticipate even those, I think, 6 subjects that were above 6; some of those were probably haemolysed samples, and we'll be getting those confirmed numbers out shortly, either in the corporate deck or in a future communication. So, again, I agree with Luke. I think it's supported by what we saw within the Sermo survey, Mike. We put those numbers for both Launch and Advanced in that survey at 5.5 to 6 and above 6. And clearly, there's significant interest in lorundrostat within that treating population.

Our next question comes from Tim Anderson with Bank of America.

This is Alice on for Tim. My questions are directed to Dr. Laffin. So, given you're at ACC and speaking with a lot of KOLs, I'm curious: What is your current view on the potential value proposition and positioning of lorundrostat now? And what feedback have you been hearing over the weekend from speaking with other KOLs?

People love this drug. They love the study design. As I alluded to earlier, the consistency of the data amongst obviously targeted Advanced and then Launch as well, which many had seen that top line data because it was a pretty extensive press release. The consistency. There's not going to be any surprises with lorundrostat. It's a very effective drug with a new mechanism and less potential side effects than spironolactone. And so that makes it very interesting. And there's a whole narrative around aldosterone now that was really prominent, interestingly at the ACC as well. And so people are starting to get it, and there's a lot of excitement.

Our next question comes from the line of Richard Law with Goldman Sachs.

Congrats on the data. I have a couple of questions for me for Dr. Laffin. So, looking at the patient disposition for Advance where 89% of patients were not qualified for randomization, does it mean that most of the resistant uncontrolled patients could be treated by just optimizing their existing background therapies? And does that lower the unmet need for lorundrostat? And then I have a couple more questions.

The first answer is no. I mean, 926 participants. And I don't really like to look at that 617 that were screened. I mean, there are all kinds of reasons why they could screen out. I think the most important number to look at is the 926 turning into 285. I mean, that's just under 30%. And that's very consistent with the incidents that we talk about is about resistant hypertension, depending on the cohort that you look at, is anywhere between about 15% and 30%, particularly if you're doing really true out-of-office blood pressures and all that. So we have aggressive treatment targets in terms of hypertension now because we know we need those to reduce strokes, heart attacks, and heart failure. And so yes, so I don't think that's an issue. What's your next question?

Based on the safety and then the efficacy profile, how do you think the CV guidelines could list lorundrostat in the third and fourth-line setting relative to CCBs and spiron? Do you think these guidelines could continue to favor generic medications over novel drugs such as lorundrostat?

I think that based on some of the 24-hour ABPM data, which there's some with spironolactone, but it looks a little bit better in advance, if you look at the comparison between the ASPIRANT trial. I think that they could put them probably equivalently and say these are all options for the treatment of resistant hypertension. And then it just comes down to what the guideline writers ultimately what their bias is in terms of generic versus more potentially more efficacious therapy. I think a lot of guideline writers are practical in that sense. And what they're going to say also is, look, spironolactone has been around for 60 years. There's a reason why treating physicians are not using it for hypertension. It's a dirty drug, and there are problems with it. And that's why they don't do it. It's not a lack of knowing what the drug is. So, I think it's well-positioned for guideline iterations.

And then just one more question. The cystatin C is not widely used or available compared to creatinine in measuring eGFR, and it's also more expensive as a test. How much of a barrier or deterrent do you think cystatin C is for lorundrostat in the commercial setting? Also, just curious, is there a way that you can characterize inhibition of the MATE-1 receptor and the effect on creatinine in such a way that you can compensate or adjust the level of creatinine to better or more accurately measure eGFR without getting effect just reading?

Yes, yes. So I don't know about that second question. I don't believe there is, but I'm not certain. The only way that the cystatin C would really have to be drawn is if someone saw an outsized decrease in GFR based on serum creatinine. And then some of the education would be, okay, then check a cystatin C. But I see no means does everyone need to follow GFR based on cystatin C. It's just something where if you see an outsized decrease, then it's important to check it and confirm that, no, guess what, the GFR actually isn't that low, it's just a component of the MATE-1 issue.

Our next question comes from the line of Seamus Fernandez with Guggenheim Partners.

So, this is a little bit more of a question for the commercial team and Jon. Jon, just hoping to get a better sense of your evaluation of the utilization of spironolactone and its frequency of drop-off in patients that could be characterized as resistant hypertension. So where is it actually used potentially as a fourth-line drug such that you could relatively easily target a patient population? And then sort of adjacent to that for Dr. Laffin, is there a way, or have you in the past evaluated your patient population in terms of resistant hypertension in a backward look at your existing patients to determine if they would relatively easily qualify from a resistant hypertension perspective? Just trying to get a better sense of what the Launch of an asset like this might look like. And then just my last question is the importance of outcomes, whether it be CKD-related outcomes, the ability to use this in the CKD population or perhaps even an event-based clinical trial, its requirement to really drive meaningful uptake of the ASI class.

Yes. Luke, let me take the first question, and I'll let you address Seamus's last 2. So Seamus, last summer, June of '24, we did about a $1.6 billion claim pull with IQVIA data and found that the, to Luke's point, the underutilization was evident within the prescribing. If you look broadly across all antihypertensives, it's about 2% of the market share. If you dig into both commercial and Medicare population data, which represents about 85% of all the prescribing, it's really not even evident market share data even at the fourth line. It's really when you get into the fifth line, it's largely in more of the Medicare population that you see maybe about 10% usage at fifth line. So to Luke's point, this drug is characterized in the eyes of the prescribers, and it's just not being chosen because of the issues that surround that molecule, which is a shame because clearly, the efficacy of an aldosterone-directed treatment, which spironolactone is the main one available now, has been demonstrated, but it's just not used because of the issues around hyperkalemia off-target usage. So I don't think spironolactone usage itself is a good surrogate for the opportunity in this class. I think it's actually probably closer to that 15% to 30% that Luke characterized. But I'll let him talk about the backward look he may have done in this practice and the relevance of outcomes data. Luke?

Yes. So we haven't specifically looked at our practice in terms of background look, although I think that with this new class, there's going to be multiple people looking at that when we look across the nation. So that's point number one. There are a couple of different analogies that I think about with the ASI class. One is SGLT2 inhibitors. Remember when those were just drugs that lowered glucose? And then you have CKD outcomes. Obviously, you have cardiovascular outcomes. Something like this, an ASI actually has the potential to take that path is that it lowers blood pressure, which is a much better surrogate outcome, let's be very clear, than lowering blood glucose, but then can be expanded to CKD, heart failure, even just overall cardiovascular risk. So I think there's great potential there. I don't think that's needed at this point. Remember, when you get a label for hypertension, it very clearly states that you reduce the risk of strokes, nonfatal MIs, and cardiovascular death. So if you compare it to like the label for aprocitentan and any other hypertension label. So I think the class is very promising for that, but I don't necessarily think it needs that because blood pressure is such a good surrogate marker.

Our next question comes from the line of Annabel Samimy with Stifel.

And this is directed to Dr. Laffin; you've touched on this a little bit before. But I know this hyperkalemia issue has been a big focus for the investor community. But when we step back and look at the bigger picture, how do you think primary care will approach treatment with ASIs? Do they see this as a good option that are uncontrolled and even though they need to maybe manage them a little bit more, follow their metrics, passing levels, will they be willing or these incidences that you see don't really give them cause and they'll just see it this is definitely a better option and now we can get these patients' blood pressure under control and not really need to monitor them that closely as far as some of these other side effects that you'll see? Like, how do you think they'll sort of approach ASIs as a class? That's my first question.

Yes. Thanks for the question. As I alluded to earlier, this is not going to change the standard workflow for monitoring for potassium levels, sodium, and GFR. You're supposed to do that when you start a diuretic or when you start an ARB or when you start an MRA. It's very clearly in the guidelines. So this doesn't change the workflow at all. And I think that's a very clear message that will be demonstrated by the data. So I think they're going to be really happy about that. We also know that from a primary care perspective, the reason they don't do it is because the patients that are coming in there, then they're coming back in a month or 2 and saying, my breath hurt or they're larger or I have sexual side effects associated with it. They see all this. I mean, we see it obviously in our clinic, but they see it. And so I think having an option that is once a day is effective at lowering blood pressure without side effects that just fits into the normal workflow, they're going to be really happy to have something. Also, this increasing aldosterone story is where the most seminal data for that is not published in cardiology journals. It's in internal medicine journals. Jennifer Brown's seminal paper of aldosterone in the annals of internal medicine. So they're starting to get it as well, and I think they're going to be really excited.

And Jon, just what are the further requirements for filing at this point? What are the rate-limiting steps here?

Yes. The main thing, Annabel, is the open-label extension. Obviously, with the potential of lorundrostat and the size of this marketplace, the FDA wants to make sure that the long-term safety is well-characterized. I think Luke made a point earlier that really needs to be repeated: the consistency of the profile of lorundrostat from the proof-of-concept Target HTN into Advanced-HTN with, frankly, the most challenging uncontrolled subjects and the broader real-world study of Launch-HTN. I think we've got a really good picture of the efficacy profile, the safety profile, and the tolerability profile short-term now through 12 weeks. It's that open-label longer-term safety extension out to 48 weeks and making sure that we accumulate enough data that goes into the submission. We have the 120-day safety update where we can augment that. But the majority of the safety data really needs to go into the initial filing. So I would say that's the main next clinical step for submission.

Our next question comes from the line of Mohit Bansal with Wells Fargo.

This is Sadia Rahman on for Mohit. So first, just wanted to understand, given Launch was a global trial and much larger in size, were the protocols for launch in advance the same with regard to testing for hyperkalemia as far as the frequency and time points for testing? Were there any differences there? Just trying to understand if that could be a factor in the difference, at least in unconfirmed rates.

Dave, do you want to address Sadia's question?

Sure. There were no major differences. When you look for hyperkalemia from these mechanisms, it occurs within 2 weeks. So the important thing is just bringing the subject back or the patient back in 2 to 4 weeks and checking a value. As Dr. Laffin said, that's the standard of care for any of these agents in that pathway. Other than that, it was exactly the same.

And then you addressed this with regard to guidelines, but just with regard to the comparison to MRAs, especially lower doses of spironolactone, do you think payers might put into place step-throughs with MRAs for lorundrostat in the commercial setting? Or do you think there are good arguments against this based on all of this data?

Yes. Thanks, Sadia. Based on the market research we've done with payers in the United States, which we've done 4 separate projects. The most recent one was Q4 of 2024. We don't believe step edit through spironolactone or MRA is how lorundrostat would be treated from a market access standpoint. The main feedback we get on step edits are typically through ACE inhibitors or ARBs and diuretics, which are typically the first and second line, which make up 85% in the case of ACE and ARB prescribing and 60% for diuretics, and that's where the payers are focused more on. I think they'd be more concerned if we were trying to push lorundrostat into the first-line setting, just given the size of that market. But when we position this drug third and fourth line with the payers, in the past, we've used a target product profile that I would safely say with the full data from Advance and Launch, we've exceeded in many ways, both on efficacy and safety. We see access as a very manageable element for this. I think pharmacy directors and medical directors know the issues with spironolactone that I think Luke has articulated very well. I think the payers are also aware that from a quality scoring standpoint, the percentage of their population under management getting to goal is a key criterion for their incentives for their quality scores. And so I think we feel very comfortable that with the proper pricing and rebate strategy, coupled with the clinical value proposition that's now emerged with lorundrostat, we're going to be able to create access for that third and fourth line usage.

Our next question comes from the line of Rami Katkhuda with LifeSci Capital.

Congrats on the update. I guess, can you touch on the difference in eGFR change and discontinuation rates between Launch and Advance?

Dave, do you want to touch on that?

Yes, absolutely. Thanks for the question, Rami. So, at a technical level, when we started the trials, we started with the Advance trial. And when we started the Advance trial, as you heard from Dr. Laffin, in part because the subjects were on such a potent combination of ARB and diuretic, their initial GFRs went down from being on such an intense regimen. So when they were started on our drug, we did observe more drops in eGFR because of that. And early in the trial, when we hadn't worked out the cystatin C was the right way to do it, we did have a number of additional treatment cessations related to that AE. Once we got a handle on that earlier enough in that trial and for the complete Launch trial, that became reflective of the real incidence, which was really pretty low. So I hope that answers your question. Basically, both trials look pretty similar once we take care of that cystatin C as a follow-up test for people who have anything over, say, a 15% or a 20% or 30% fall. But we eventually saw in that trial a 14% mean fall in eGFR, which is really not just an acceptable range, but it's actually a positive predictor of outcomes.

But just to confirm, I guess, in the Launch, we saw a negative 4.1% change in eGFR with cystatin C, a negative 12.8% reduction in advance. I guess, is the delta between those 2 studies is just based on the background regimen.

Yes. Dave, let me hit that real quick. Rami, yes, the delta because in the launch, it went up about 3% and placebo went down about 40%, as you alluded to, on the active delta of 7% in Advance, eGFR went down about 3%, went down about 12.8% with lorundrostat, a delta of about 9%. So I think we're seeing a really similar profile when you factor in the placebo-adjusted difference and the distinction between the studies. In advance, as Luke alluded to, everybody is really maximized on optimal treatment. And we know in the real-world study, as Luke again alluded to earlier, you're seeing subjects maybe not on the right drugs or certainly not pushed to the max dose. And yet you're seeing a really pretty similar profile as it relates to eGFR that is related largely to the beneficial reduction of intraglomerular pressure that has been shown to have long-term benefits on kidney health. So I think they're looking fairly similar across the 2 trials in that regard. When we look at it with cystatin C, it reflects what's truly going on with the kidney.

Our final question this morning comes from the line of Matthew Caufield with H.C. Wainwright.

For Dr. Laffin, you touched on the ASI mechanism relevance in CKD, but can you elaborate a bit on your expectations for read-through to benefit in CKD patients? Should we anticipate a comparable profile there? Or are there important nuances to consider?

I mean, I don't think there's any additional nuance, necessarily. If you lower intraglomerular pressure, you're going to have a beneficial impact on kidney disease, particularly in a high-risk population with diabetes and uncontrolled or treatment-resistant hypertension. So I think that mechanism has been very well established with multiple preceding classes of medicines, and ASLIs are built upon that.

Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Congleton for any final comments.

Yes. Thank you, operator. First and foremost, I'd like to thank Luke. As you can all imagine, he's had quite a busy not just weekend but the lead-up to this weekend. We're thrilled with the partnership with both he and Dr. Steve Nissen and the Cleveland Clinic and their C5 team and really conducting, again, as Dave said, probably what we think is one of the most rigorous studies done that really showcase the benefit that lorundrostat can provide to patients with uncontrolled and resistant hypertension. So, Luke, thank you very much. We're obviously excited about this pivotal data that we've announced over the past several weeks and the progress that we've made in advancing our clinical programs. We certainly look forward to keeping you apprised of future progress in subsequent calls. And with that said, we will close this call today. Thanks, everybody. Have a great day.

Thank you. This concludes today's conference call. You may disconnect your lines at this time. Thank you for your participation.