Greetings and welcome to the Mineralys Advance-HTN and Launch-HTN Data Review Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad. 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 data presented and the embargo lifted, we look forward to discussing the results today from our pivotal Advance-HTN trial that demonstrated the 15 mmHg reduction in absolute systolic BP and the nearly 8 mmHg 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 the late-breaking clinical trial session at the American College of Cardiology's annual scientific session and expo, which was held in Chicago over the past few days. We're fortunate to be joined today by Dr.
Luke Laffin, the 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 Preventive Cardiology and Rehabilitation Section in the Robert and Suzanne Tomsich 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 in 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 co-authored several chapters in medical textbooks related to hypertension. Also on the call, we have from Mineralys Dr. David Rodman, 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 the 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 three clinical trials evaluating the efficacy and safety of lorundrostat in these target populations, including Advance-HTN, Launch-HTN, 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 two trial designs for Launch-HTN and Advance-HTN in order for you to understand how we are comparing and analyzing the data. The Launch-HTN trial, with approximately three times the number of subjects as the Advance-HTN 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 Advance-HTN 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 medications discontinued and started on an optimized regimen of an ARB, a diuretic, and additionally a calcium channel blocker if previously on three to five medications. Subjects who remained hypertensive were then randomized into three 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 III Launch-HTN trial was pre-specified at six weeks of treatment. An absolute reduction of 16.9 mmHg and a placebo-adjusted reduction of 9.1 mmHg 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 mmHg and a placebo-adjusted reduction of 11.7 mmHg in the 50-milligram arm with a p-value less than 0.0001. 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 six for Launch-HTN and week four 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 two baseline medicines and those taking three 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 nine subjects, or 3.3%, in the placebo arm. There was only one 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 millimole per liter in the Launch-HTN trial during study visits in the 50-milligram arm was 1.1%, and in placebo was 0.7%. In the Advance-HTN trial, 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%-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 two of five observed episodes being confirmed as having potassium over 6. Two repeat values were less than 5.5 millimole per liter, and the third was 5.6 millimole per liter. The observed incidence 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 Advance-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. Yeah, it was an exciting weekend for presenting and getting this Launch-HTN, or excuse me, Advance-HTN data out there. What I want to first really address is the trial design because, as was alluded to earlier, this was designed as a specialist trial. Another way to sort of think of it almost is like a skeptic's trial, okay? If someone's coming to me on a low-dose ARB, maybe a low-dose diuretic, medium-dose calcium channel blocker, what I'm going to do first, and many of my colleagues and hypertension specialists, is we're going to adjust their medicines in those three classes to maximize their potential and potency. That's exactly what this trial did.
Maximum dose of olmesartan, which is one of the most potent ARBs, a large percentage of patients on indapamide, which is actually recommended to switch to in the resistant hypertension guidelines. That was really, and then obviously amlodipine is very commonly used in a good calcium channel blocker. That was really important. The patients got this for three weeks. 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. Really important data. 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 antihypertensive therapy and then using 24-hour ABPM. Next slide, please. Baseline patient characteristics I really highlight here on this slide. It was a real representative population, right?
40% women, very nice representation there. 53% Black or African American, not surprising, right? That group has a higher burden of resistant hypertension. 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. That impacts sort of any type of AEs you see, hyperkalemia, which Dave alluded to, and lower GFR. It just suggests a higher risk population that was studied. Also really important to note, starting blood pressure in this trial at the time of randomization was 141 systolic.
As many of you on the call may know, the higher your blood pressure starts, the more blood pressure lowering you see. This is not, 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. It is 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 mmHg of reduction in that 50- milligram daily arm is very impressive. And then 8 mmHg 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. We're talking about the three to even six mmHg range. That was pointed out by discussion yesterday when we did the deep dive into the trial as well and confirmed. Very highly statistically significant. Not only statistically, but clinically meaningful reductions in blood pressure in a high-risk group that was already well treated on sort of 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. 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.
These adverse events were really keeping with something that you would see with a drug that lowers blood pressure and impacts the renin-angiotensin-aldosterone system. It was essentially very well tolerated. Next slide, please. These are the final thoughts that I left the audience with. 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. We know aldosterone and dysregulated aldosterone really drives a lot of this uncontrolled treatment-resistant hypertension. Drugs that target aldosterone production, we've clearly shown that 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 to suggest that they will do that.
Then importantly, clinical trials of blood pressure drugs need to test therapies in populations that are at highest risk and will derive the most benefit, okay? I really believe Advance-HTN did that as well as any hypertension trial recently. That is an overview of the Advance-HTN data. How do we put this in context with Launch-HTN? How do we put it in context in the clinical realm? Now there are three trials: Target-HTN, Advance-HTN, and Launch-HTN. I am not involved with Launch-HTN, just to be clear, but I know the public data. When you think about it, the data is remarkably similar amongst the three. I do not think there are any surprises with lorundrostat. We know that it lowers blood pressure very well.
When we look at the Target-HTN and Advance-HTN 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, right? 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, when we look at this, the rigor of Advance-HTN contributed to much higher risk population. As I alluded to earlier, the starting GFR at the time of randomization was in the low 70s. If you do it by cystatin C, it was right at 70. That is 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 got to be aggressive and that we have good 24-hour ABPM data. When we translate it to the wider community of primary care doctors, nurse practitioners, PAs, we can turn to the Launch-HTN 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 sort of 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 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-HTN is three times bigger, right? 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 Advance-HTN.
You're going to get a much better perspective from Launch-HTN when you look across, obviously, three to four times bigger study. That's really important. The question that comes up is this potassium issue. When we think about potassium, 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, right? 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 two weeks later, right, after starting it. It doesn't change clinical workflow at all.
As you know, if we start a patient in the clinic on a thiazide, on an ARB, on an MRA, we're checking basic metabolic panel two weeks later. That's what guidelines say, and that's what we do. This just fits perfectly into the workflow that we would normally see. When you look at the difference between a single value for over 6 versus confirmed, the clinically relevant is confirmed, right? It's not a single isolated value that's hemolyzed. I mean, I think that's very clear as well. 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 two successful trials provide promise for the 20 million patients failing to achieve their blood pressure goal on two or more medications. While our initial Launch-HTN Target-HTN 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 18th to March 25th. The test of the recently announced pivotal data from the Launch- HTN and Advance- HTN trials, including efficacy, key secondary endpoints, adverse events tables, and potassium listing 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 healthcare 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 Advance- 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 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 two 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 next steps for Mineralys, additional data from the pivotal Launch- HTN trial will be presented at an upcoming medical conference 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 will provide guidance for top line once we have a clear view of enrollment rate. We are 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.
Thank you. If you'd like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions. Thank you. Our first question comes from the line of Michael Di Fiore with Evercore ISI. Please proceed with your question.
Hey, guys. Thanks for taking my question and 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 that 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 have a follow-up.
Yeah, 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 date of March 10th shortly after database lock and had ourselves on a fairly aggressive timeline. Again, I think it's important to put the 5.3% into context as far as given the uniqueness of this population. We think it represents an acceptable safety profile given the risk profile of these patients that, as Luke alluded to, being maximally treated and yet still not at goal. 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.
Got it. Thanks for that, Jon. My final question is, I know you said before you've done your own due diligence with hypertension specialists who accept the 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?
Mike, I'll have Luke opine on that. Luke, do you mind addressing Mike's question about how primary care docs will view the potassium profile of lorundrostat?
Yeah. I think this is a very much overblown issue, to be perfectly honest with you. When you look at the study that's three times as large, we're talking like 1%, right, from Launch-HTN 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 going to it's not something that's going to dissuade people from prescribing or using this medication.
Yeah. Michael, 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, six subjects that were above 6, some of those were probably hemolyzed samples, and we'll be getting those confirmed numbers out shortly, either in the corporate deck or in a future communication. 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-HTN and Advance-HTN in that survey at 5.5-6, above 6, and clearly there's significant interest in lorundrostat within that treating population.
Got it. Thanks so much.
Thank you. Our next question comes from the line of Tim Anderson with Bank of America. Please proceed with your question.
Hi. Thank you so much. This is Alison for Tim. My questions are directed to Dr. Laffin. Given you're at ACC 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? Thank you so much.
People love this drug. They love the study design. As I alluded to earlier, the consistency of the data amongst, obviously, Target-HTN, Advance-HTN, and then Launch-HTN as well, which many had sort of 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, and it's a very effective drug, new mechanism, less potential side effects than spironolactone, right? That makes it very, very interesting. There's a whole narrative around aldosterone now that was really prominent, interestingly, at the ACC as well. People are starting to get it, and there's a lot of excitement.
Thank you. Our next question comes from the line of Richard Law with Goldman Sachs. Please proceed with your question.
Hey, guys. Congrats on the data. I have a couple of questions for Dr. Laffin. Looking at the patient disposition for Advance-HTN 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? Does that lower the unmet need for lorundrostat? I have a couple more questions.
First answer, no. I mean, 926 participants. And I don't really like to look at that 2,617 that were screened. I mean, there's all kinds of reasons why they could screen out, right? I think the most important number to look at is the 926 turning into 285. I mean, that's just under 30%, right? And that's very consistent with the incidents that we talk about, right? It's about resistant hypertension. Depending on the cohort that you look at, it's anywhere between about 15%-30%, particularly if you're doing really true out-of-office blood pressures and all that. We have aggressive treatment targets in terms of hypertension now because we know we need those to reduce strokes, heart attacks, and heart failure. No, I don't think that that is yeah, 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 spironolactone? 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-HTN if you look at the comparison between the ASPIRANT trial. I think that they could put them probably equivalently, right, and say these are all options for the treatment of resistant hypertension. It just comes down to what the guideline writers ultimately, what their bias is in terms of generic versus sort of a potentially more efficacious therapy. I think a lot of guideline writers are practical in that sense. What they're going to say also is, "Look, spironolactone has been around for 60 years, and there's a reason why treating physicians are not using it for hypertension. It's a dirty drug, and there's problems with it.
That is why they do not do it. It is not a lack of knowing what the drug is. I think it is well-positioned for guideline iterations.
Got it. And then just one more question. Does the cystatin C not want to use 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 the cystatin C is for lorundrostat in the commercial setting? And also, just curious, is there a way that you can characterize inhibition of MATE1 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 a factitious reading?
Yeah, yeah, yeah. 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 serum creatinine or, excuse me, in GFR based on serum creatinine. Some of the education would be, "Okay, then check a cystatin C." By 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 MATE1 issue.
Great. Thank you so much.
Thank you. Our next question comes from the line of Seamus Fernandez with Guggenheim Partners. Please proceed with your question.
Oh, thanks for the question. 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, where it actually is used potentially as a fourth-line drug such that you could relatively easily target a patient population. 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-HTN of an asset like this might look like.
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. Thanks.
Yeah. Luke, let me take the first question. I'll let you address Seamus' last two. Seamus, last summer, June of 2024, we did about a 1.6 billion data, 1.6 billion claim poll with IQVIA data and found that, 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 fourth line. It's really when you get into the fifth line, it's largely in more the Medicare population that you see maybe about 10% usage at fifth line.
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 and off-target usage. 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%-30% that Luke characterized. I'll let him talk about kind of the backward look he may have done in his practice and the relevance of outcomes data. Luke?
Yeah. We haven't specifically looked at our practice in terms of background look, although I think that there's probably going to be with this new class, there's going to be multiple people looking at that when we look across the nation. That's point number one. I make this, there's a couple of different analogies that I sort of think about with the ASI class. One is to SGLT2 inhibitors, right? Remember when those were just drugs that lowered glucose, right? Then you have CKD outcomes. Obviously, you have cardiovascular outcomes. Something like this in ASI actually has the potential to sort of take that path, right? 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. 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, non-fatal MIs, and cardiovascular death. If you compare it to the label for aprocitentan and any other hypertension label. 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.
Thanks, guys. Congrats again.
You bet. Thank you.
Thank you. Our next question comes from the line of Annabel Samimy with Stifel. Please proceed with your question.
Hi. Thanks for taking my question. 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. 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 for those that are uncontrolled? Even though they need to maybe manage them a little bit more, follow their metrics, potassium levels, will they be willing, or are these incidences that you see not really giving them pause and they'll just see that this is definitely a better option? 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.
How do you think they'll sort of approach ASIs as a class?
I think as a class.
That's my first question.
Yeah, yeah. I think that, as I said, sort of thanks for the question. As I said, I alluded to earlier, this is not going to change the standard workflow for monitoring for potassium levels, sodium, GFR. That's already 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. This doesn't change the workflow at all. I think that's a very clear message that will be demonstrated by the data. 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 two and saying, "My breasts 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. 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, Jenifer Brown's seminal paper of aldosterone in Annals of Internal Medicine.
They're starting to get it as well, and I think they're going to be really excited.
Okay. Great. Thanks for the context. Jon, just what are the further requirements for filing at this point? What are the rate-limiting steps here?
Yeah. 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 Advance-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, the tolerability profile, short-term now through 12 weeks. It is that open label longer-term safety extension up to 48 weeks. 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. I would say that's the main next clinical step for submission.
Okay. Great. Thank you.
Thank you.
Thank you. Our next question comes from the line of Mohit Bansal with Wells Fargo. Please proceed with your question.
Hi. This is Sadia Rahman on for Mohit. Thanks for taking our questions. First, just wanted to understand, given Launch-HTN was a global trial and much larger in size, were the protocols for Launch-HTN and Advance-HTN 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. Thanks.
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 two weeks. The important thing is just bringing the subject back or the patient back in two to four weeks and checking a value, as Dr. Laffin said. That's standard of care for any of these agents in that pathway. Other than that, it was exactly the same.
Okay. Got it. Thanks. You addressed this with regard to guidelines, but just with regard to the comparison to MRAs, especially lower dose 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?
Yeah. Thanks, Sadia. Based on the market research we've done with payers in the United States, which we've done four 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 inhibitor or ARB and diuretic, which are typically first and second line, which make up 85% in the case of ACE and ARB prescribing and 60% for diuretic. 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.
When we position the drug third and fourth line with the payers, in the past, we'd use the target product profile that I would safely say with the full data from Advance-HTN and Launch-HTN, 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 payers are also aware that from a quality scoring standpoint, the percent of their population under management getting to goal is a key criteria for their incentives for their quality scores. 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.
Great. Thanks so much.
Thank you.
Thank you. Our next question comes from the line of Rami Katkhuda with LifeSci Capital. Please proceed with your question.
Hey, guys. Thanks for taking my questions as well and congrats on the update. I guess, can you touch on the difference in eGFR change and discontinuation rates between Launch-HTN and Advance-HTN?
Dave, do you want to touch on that?
Yeah. Absolutely. Thanks for the question, Rami. At a technical level, when we started the trials, we started with the Advance-HTN trial. When we started the Advance-HTN trial, as you heard from Dr. Laffin, in part because the patients were on such a—the subjects were on such a potent combination of ARB and diuretic, their initial eGFRs went down from being on such an intense regimen. When they were started on our drug, we did observe more drops in eGFR because of that. Early in the trial, when we had not worked out that 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 early enough in that trial and for the complete Launch-HTN trial, that became reflective of the real incidence, which was really pretty low.
I hope that answers your question. Basically, both trials looked pretty similar once we took care of that cystatin C as a follow-up test for people who have anything over, say, a 15% or, well, a 20% or 30% fall. 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.
Got it. Just to confirm, I guess in Launch-HTN, we saw a negative 4.1% change in eGFR with cystatin C, negative 12.8% reduction in Advance-HTN. I guess, is the delta between those two studies just based on the background regimen?
Yeah. Dave, let me hit that real quick. Rami, yeah, the delta, because in Launch-HTN, it went up about 3%, and placebo went down about 4%, as you alluded to, on active delta of 7%. In Advance-HTN, eGFR went down about 3%, went down about 12.8%, with lorundrostat at delta of about 9%. I think we're seeing a really similar profile when you factor in the placebo-adjusted difference and the distinction between the studies, right? In Advance-HTN, as Luke alluded to, everybody's really maximized on optimal treatment. 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 max dose.
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 benefit on kidney health. I think they're looking fairly similar across the two trials in that regard when we look at it with cystatin C that reflects what's truly going on with the kidney.
Got it. Thanks so much, and congrats again.
Thanks, Rami.
Thank you. Our final question this morning comes from the line of Matthew Caufield with H.C. Wainwright. Please proceed with your question.
Hi. Thank you. Good morning, guys. For Dr. Laffin, you kind of 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? Thanks again.
I mean, I don't think there's any additional nuance necessarily, right? 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. I think that mechanism has been very well established with multiple preceding classes of medicines, and ASIs build upon that.
Excellent. Thank you.
Thanks, Matt.
Thank you. Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Mr. Congleton for any final comments.
Yeah. 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 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 in 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. 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 Advance-HTN in our clinical programs. We certainly look forward to keeping you apprised of future progress in subsequent calls. 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.