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

Greetings. Welcome to the Mineralys Top Line Data Conference Call, Launch-HTN and Advance-HTN Pivotal Trials. [Operator Instructions] As a reminder today's conference is being recorded. It is now my pleasure to introduce Jon Congleton, Chief Executive Officer of Mineralys. Thank you. You may now begin.

Thank you, operator. Good morning, everybody. Before I get to my prepared remarks, I just -- I want to say I'm thrilled with the news that we shared with you today. We had high confidence in the studies and the designs that we put together and frankly, the near flawless execution of our team. And certainly, what we believe is the transformative nature of lorundrostat. But to finally see the results I just -- I can tell you, the team is excited, I'm thrilled with the results that we've seen. We're going to go through a great deal of data today. But just fundamentally, we're thrilled to be at the stage we are from where we were with Target-HTN to now 2 pivotal studies, really announce so robustly as we've done. So I just want to let you know the team is thrilled to be able to bring this news to you today and we'll be walking through a great deal of details within the slides that we have. The remarks made during this conference call and webcast will contain forward-looking statements regarding our financial outlook, regulatory, product development and commercialization plans as well as research activities. The statements are subject to risks and uncertainties that could cause actual results to materially differ from those forecasted. A description of these risks can be found in our most recent 10-K on file with the SEC. Okay, joining me today on the call are Dr. David Rodman, our CMO; and Adam Levy, our CFO. As I said, I'm very pleased to speak with you this morning to discuss the positive top line data for both of our hypertension pivotal trials, Launch-HTN and Advance-HTN. We have now executed and successfully completed 3 positive trials of lorundrostat in uncontrolled and resistant hypertension patients with all 3 trials demonstrating a meaningful and consistent efficacy, safety and tolerability profile of this novel, highly selective aldosterone synthase inhibitor. This is a significant outcome for the 15 million to 20 million uncontrolled hypertension patients in the United States alone that we believe could benefit from a targeted aldosterone directed treatment. The Launch-HTN trial is the largest aldosterone synthase inhibitor trial to ever readout. This global trial enrolled 1,083 subjects who had failed to achieve their blood pressure goal while compliant on their existing regimen. In this real-world trial, the 50-milligram once-daily lorundrostat arm demonstrated an absolute reduction of 16.9 mmHg and a 9.1 mmHg placebo-adjusted reduction in their systolic blood pressure at week 6. The benefit was sustained with potential further reduction through week 12, with a 19 mmHg absolute reduction and an 11.7 mmHg placebo-adjusted reduction. Reductions in blood pressure of this magnitude have been linked to significant reduction in overall cardiovascular risk. Lorundrostat continued to demonstrate a modest impact on potassium and a safe and well-tolerated profile. Advance-HTN is our highly rigorous pivotal trial evaluating lorundrostat in confirmed uncontrolled or resistant hypertension patients despite on optimized background treatment. The study was conducted in partnership with the team at the Cleveland Clinic. The results from Advance-HTN in the 50-milligram once-daily lorundrostat arm were highly statistically significant on the primary endpoint with a 7.9 mmHg placebo-adjusted reduction in systolic blood pressure as measured by the gold standard 24-hour ambulatory blood pressure measurement at week 12. The safety and tolerability of lorundrostat was consistent with what was demonstrated in our Target-HTN proof-of-concept trial and in Launch-HTN. We're also excited to share that Advance-HTN has been accepted for a late-breaking presentation at the ACC.25 on March 29. Due to the embargo restrictions, we will be limiting the information that we shared today on this trial beyond the top line efficacy and safety data. Based on currently available and in development treatment options for hypertension, we believe the results of both of these pivotal trials may position lorundrostat as a transformative option for patients with uncontrolled and resistant hypertension. Since our inception, it's been our mission to bring what we believe to be the best-in-class aldosterone synthase inhibitor to the market with the potential of helping the millions of patients dealing with uncontrolled or resistant hypertension. This clinical challenge remains a leading inadequately addressed global cause of death and loss of quality of life. With today's positive top line announcement, we've made substantial progress towards meeting this significant unmet medical need. I'd be remiss if I didn't acknowledge and say I'm grateful to the participating trial investigators and subjects for their enthusiasm and commitment to the development program for lorundrostat. I'm especially grateful of the Mineralys team for completing and reading out 2 pivotal hypertension trials today. Their dedication and hard work has allowed us to get to this significant milestone for Mineralys for our shareholders and most importantly, the patients in need of transformative innovations. Our Chief Medical Officer, Dr. David Rodman, will now take some time to review the top line data from the Launch-HTN and Advance-HTN trials. David?

Thanks, Jon, and good morning. I'm going to share some more detail about the top line results from our 2 successful trials Launch-HTN and Advance-HTN, which are intended to provide the core data set for our anticipated new drug application. The primary efficacy analysis in the Phase III Launch-HTN trial was prespecified at 6 weeks of treatment. This trial was intended to evaluate the efficacy and safety of lorundrostat when added to existing background medication over a 12-week period. The traditional threshold for determining clinically meaningful change for the purpose of new drug registration has been approximately 5 mmHg, placebo adjusted reduction in blood pressure. The observed treatment effect far exceeded that threshold. Absolute reduction of 16.9 mmHg and placebo-adjusted reduction of 9.1 mmHg in automated office systolic blood pressure were observed with a p-value of 0.001. At the end of treatment at 12 weeks, the benefit was sustained and potentially 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 of less than 0.001. In the lorundrostat dose escalation arm, the week 12 reductions in systolic blood pressure were absolute 15.7 mmHg and placebo adjusted 8.4 mmHg with a p-value of 0.0016. There was an appearance that the effect size in the lorundrostat dose escalation cohort was lower than in the 50-milligram dose arm. However, this was not confirmed at the individual subject level in those whose dose was increased, and there was overlap in the group confidence intervals in the 50-milligram lorundrostat and the -- with the 50 to 100-milligram dose escalated arm. Therefore, we did not see a benefit to increasing the lorundrostat dose in individuals who failed to achieve their target blood pressure goal with the 50-milligram dose. This confirms that 50 milligrams is the optimum and maximum efficacious dose level. A finding in Launch-HTN observed also in Advance-HTN, the reduction in systolic blood pressure was sustained with potential further reduction at the end of treatment at 12 weeks compared to the earlier time point. This adds confidence that the treatment response is robust and likely to persist and confirms again that the 50-milligram once daily dose is an efficacious starting dose. Analysis of key secondary outcome measures in both trials was done at the earlier time point when all subjects in the active arms were being treated with the 50-milligram dose, providing more statistical power for their smaller subsets. In Launch-HTN, 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. We are pleased that approximately 1/4 of study subjects in Launch-HTN were black, a population with particularly high incidence of poorly controlled hypertension and a high incidence of major adverse cardiovascular events. With respect to analysis of the effect of obesity, we treated BMI as a continuous variable and no statistically significant effect was seen. It is important to note that lorundrostat worked equally well in overweight subjects and obese subjects, confirming the utility in a broad range of patients. We look forward to reviewing results of additional prespecified supplementary analysis using more direct measures of abdominal obesity, namely waist circumference and waist-to-hip ratio as well as serum biomarkers, including Leptin, Adiponectin, Aldosterone and Renin. We anticipate there will be a future presentation and publication reporting on these analyses. Equally important to developing a drug for difficult-to-treat hypertension is having an acceptable safety profile and good tolerability. We believe the clinical safety and tolerability findings from both pivotal trials, including the low incidence of serious adverse events and the low incidence of changes in serum potassium, eGFR and serum cortisol support a favorable benefit risk profile in both the real-world use case studied in the Launch-HTN trial and in the Advance-HTN trial in established uncontrolled or resistant hypertension. Regarding safety in the Launch-HTN trial, there were 9 subjects or 3.3% with serious adverse events, 8 of which were treatment emergent in the placebo arm. In the 50-milligram and in the 50- to 100-milligram arms, there were 13 subjects or 2.4%, 12 of which were treatment emergent and 2 subjects or 0.7%, all of which were treatment emergent, respectively. There were 5 subjects or 1.9% with treatment emergent adverse events requiring dose discontinuation in the placebo arm and 14 subjects or 2.6% and 4 subjects or 1.5%, respectively, in the 50-milligram and 50-milligram to 100-milligram arms. The incidence of elevations in serum potassium of greater than 6 millimole per liter was 0.7% in the placebo arm 1.1% in the 50-milligram once-daily arm and 1.5% in the 50-milligram to 100-milligram arm and reserved soon after discontinuation of lorundrostat. The primary efficacy analysis in the Phase III advanced hypertension trial was at 12 weeks of treatment -- sorry, this rigorous trial in confirmed uncontrolled and resistant hypertension was designed to evaluate the efficacy and safety of lorundrostat when added to optimized background medication over 12 weeks. As Jon mentioned, we're excited that the Phase II Advance-HTN trial will be featured in the late-breaking clinical research session at ACC.25 later this month and additional trial results will be presented there as well as in an upcoming publication. In subjects treated with lorundrostat, we observed a clinically meaningful reduction in systolic blood pressure at week 4 and at the week 12 prespecified time point for the primary analysis of efficacy, a highly statistically significant 7.9 mmHg, placebo adjusted reduction in systolic blood pressure in the 50-milligram once daily arm. The incidence of elevations in serum potassium of greater than 6 millimole per liter was approximately 5.3% in the 50-milligram arm, and 7.4% in the 50-milligram to 100-milligram arm. As in the Launch-HTN trial, potassium elevation resolved soon after discontinuation of lorundrostat. There was one death in a subject receiving 50 milligrams of lorundrostat that was deemed not related to study medication by the site investigator and the medical monitor. We believe the efficacy and safety findings in this especially rigorous hypertension trial support a favorable benefit risk profile for lorundrostat in patients with confirmed uncontrolled or resistant hypertension. I'm now going to turn the call back over to Jon Congleton.

Dave, thanks. The lorundrostat development program, as you see here is really achieved 2 significant milestones today. The completion of what you just heard Dave talk about the highly rigorous Advance-HTN trial with the 7.9 mmHg placebo-adjusted change and the real-world study Launch-HTN, which is now completed with the 19 mmHg absolute change in that 11.7 mmHg placebo-adjusted change with the 50-milligram for both. We're obviously thrilled with the success, the completion, but certainly the outcome. As I said at the beginning, there's a lot of work behind these clinical trials. We felt we had the right plan, the right team and are thrilled now with the results we're able to report with this program. But we have additional studies that are ongoing and underway. We have the Explore-CKD trial looking at hypertension and CKD for patients with an eGFR down to 30. We're still on track for top line data in Q2 of this year. Earlier this year, we announced the OSA in hypertension study. That study has initiated at this point. We're still waiting for the early role of patients coming into the trial and once we get a sense for the feasibility and the timing, we will update on guidance for that. As we progressed the clinical development program for lorundrostat, we maintained a focus on the market opportunity the physician interest and the payer needs for novel innovations in the treatment of hypertension. In our market research, and as we shared with you, a clinical profile of 8- to 10-mmHg reduction in systolic blood pressure with a modest impact on potassium in a well-tolerated profile resonated with payers and physicians as an ideal option certainly in fourth line and potentially with a targeted approach in the third-line treatment. Now with the data that Dave just shared with you today, lorundrostat clearly provides clinically differentiated value in that fourth line position for those resistant hypertension patients. And as we've done the analysis, that breaks down to about 10 million patients in the United States. The benefit demonstrated in patients on 2 background hypertension medications in our clinical program potentially support broader third-line usage for the approximately 10 million subjects with uncontrolled hypertension than we had originally planned. As we continue to analyze the data, we will continue to evaluate predictors of an enhanced response to guide access and demand for the patients looking to address their unmet need, particularly when their condition is driven by dysregulated aldosterone. In September of 2023, we saw the initial signs of promise with lorundrostat when the Target-HTN proof-of-concept trial results demonstrated a meaningful clinical benefit that was safe and well tolerated once daily with the 50-milligram lorundrostat. The top line data today from our 2 pivotal clinical trials provides further evidence of the consistent clinical benefit that lorundrostat has in uncontrolled and resistant hypertension patients. With approximately 30% of all hypertension patients dealing with the ramifications of elevated or dysregulated aldosterone, we believe the clinical profile of lorundrostat as a best-in-class aldosterone synthase inhibitor could have the potential to extend and improve the lives of millions of patients. We will continue to advance our commercial and partnering activities to ensure that we maximize the value of this novel, best-in-class and potential first-to-market aldosterone synthase inhibitor, lorundrostat. We're clearly excited about the new clinical data that we've shared with you today. We've given you a lot of information. We look forward to your questions. And with that, I'll ask the operator to open up the call for questions.

[Operator Instructions] Our first question today comes from the line of Umer Raffat with Evercore ISI.

Congrats on the data. I have a few today, if I may. Perhaps first, just wanted to understand your broader thought process around. Is this an asset you think you can take to commercialization yourself? I know there's a lot of commercial background for much of the management team, but just curious if you think you do or don't need a partner. Second, I know the BIGGER trial had AOBP as a primary endpoint. Curious if ABPM was tracked as well and if you could speak to the consistency? And speaking of consistency, could you remind us resistant versus uncontrolled patients and obese, what you saw there? And finally, any thoughts on hyperkalemia with a definition on 5.5 threshold.

Yes, Umer, thanks for the questions. Make sure that I capture them all, if I miss one, please let me know. Your question, can we go commercial or partner? I think the answer is there's -- with the kind of data that we're seeing here, the profile that's emerged. And the profile to me is not just the robust reduction in blood pressure that we saw of 19 mmHg, absolute and 11.7 mmHg adjusted, but it's the hyperkalemia as well. We're looking at 1% in the level that is probably concerning for physicians. So it's really a great profile and a nice balance of efficacy and safety for patients and well tolerated. So taking that forward into the fourth line, certainly, third line, yes, I could see a path where Mineralys can do that because as you saw on the slide, about 47,000 physicians in the United States control about half of that third and fourth line prescription volume. That said, and it's why I acknowledge the partnering to really maximize the value of an asset like lorundrostat, we would be looking for a partner to do that in the United States, certainly, and we've said this before, ex-U.S., I don't envision Mineralys being the commercial driver in Europe, in the Asian markets. And so that will be a key part of our strategy. But when you have an asset like lorundrostat, yes, there's clearly a path for Mineralys to tap into that value. If I go to your next question, in Launch-HTN because that was our real-world study, in other words, how lorundrostat would be used in the marketplace, we did not do ABPM. Launch-HTN was about 4x bigger than Advance-HTN doing the kind of rigor that we put on Advance-HTN with the 24-hour ambulatory just would have been a bit challenging in that trial. But as we saw in target, we've seen really nice concordance between ABPM and AOBP. And so I think for Launch-HTN with that real-world measurement, we're in good shape. Umer, you had a question about resistant versus uncontrolled as it related to obesity. I would say at this point in time with the analysis we've done at a broad level, as Dave said, the BMI was not predictive in -- relative to response and Launch-HTN, David built out some additional endpoints that frankly, are probably using better metrics for measuring visceral adiposity, and that's waist circumference and waist-to-hip ratio. We're going to be doing further analysis on that and sharing that data likely in future publications. I think the overall good news that Dave made was whether overweight or obese, you're clearly seeing a robust response in helping patients get to their goal ideally and reducing their overall cardiovascular risk.

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

A couple of questions for me. So given that Advance was designed with the state of the art feature that you mentioned, why do you think we're seeing the efficacy and safety differences between the study where the largest results look better and has lower hyperkalemia rate? And then I'll save those -- the other questions for later.

Yes, Rich, thanks for the question. Let me address the efficacy question, I may have Dave talk about the potassium profile, which is still well within the -- from our standpoint, acceptance from a market standpoint to 5%. From an efficacy standpoint, over the last year, 2 years, I've been asked to kind of hedge what -- for these 2 studies, where I think the efficacy will be. We have consistently guided to 8 to 10 as a win. And hitting that target with Advance-HTN and exceeding it with launch I think it's a very positive outcome. In the case of advance, there were 2 factors working there. On the one hand, we had truly confirmed uncontrolled and resistant patients based on the fact that we were putting them on a high dose optimized AHA approved background treatment, tracking them for 3 weeks using the gold standard measurement. And so we were really with that study, weeding out potential apparent hypertension patients and getting the very difficult, truly confirmed hypertension population. And so we are putting lorundrostat to the test with those very difficult to treat patients. On the other hand, we said maybe we're enriching for aldosterone because you've hit a lot of different pathways that are driving their hypertensive condition and yet there's still not a goal. I think the answer, Rich, is that it was probably a little bit of both. If you think about comparative studies of Advance's rigor, think about renal denervation with The RADIANCE trial, think about aprocitentan with the PRECISION trial, where I think there was 5 and 4 mmHg placebo-adjusted change. And with Advance-HTN, we're effectively seeing an 8 mmHg placebo-adjusted change. And so I actually look at Advance as an equally robust outcome in a really difficult-to-treat patient population that likely has aldosterone as a part of their condition. As far as the potassium, maybe a difference between Launch and Advance, let me have Dave talk to that a bit.

So it's a good question, and we expected this, as did our advisers. The main difference is the background medication in the Launch-HTN trial, the subjects came in on whatever they were on as long as there was a thiazide diuretic in the regimen. In the Advance trial, we stipulated they needed to be on really, the highest dose of the most long-acting and potent angiotensin receptor blocker or ARB olmesartan. Now I'll remind you that these ARBs increased potassium and they decrease your ability to clear potassium. And so you would expect a bit more increase in potassium. In particular, this is what we refer to as a double RAS therapy, upstream and downstream, angiotensin and aldosterone. This combination was tested 20 years ago, combining ARBs and angiotensin converting enzyme inhibitors, and it was abandoned because there wasn't much benefit over just the ARB and the potassiums were unacceptable. Here, we seem to have achieved that goal without much of a potassium liability. Now I'll finalize by saying, we spoke to a number of experts because this regimen is going to be particularly useful for them and what their response was -- we're not too concerned about high potassium. We will use potassium binders, which we're very comfortable with, these patients need blood pressure reduction.

I see. Got it. And then another question on how should we think about the lower efficacy for the 50 to 100 mg arm compared to 50 mg arm. Do you think the uptitration provided any benefit?

Yes, Rich, I think if we think about the entire program for lorundrostat going back to Target-HTN, we really didn't see a difference from an efficacy standpoint between 50 and 100 milligrams. These results with Advance and Launch really confirm the 50-milligram as Dave said, as the dose. And we went into this program with that in mind. What we wanted to test was would the opportunity to titrate to 100 provide any additional benefit. As Dave said, there is overlap within the confidence intervals between these 2. But if we think about the design of Launch, and it's important to point this out, the design of Launch was to randomize 1 to 2:1. We had twice as many patients in that 50-milligram alone arm without the complications of 50 to 100 titrated and that gave us really strong assurance of that 11.7 mmHg placebo-adjusted change as really the most accurate assessment.

Okay. Got it. And then just I'm going to squeeze in one more. Do you plan to present the detailed results for both trials in one conference? Or would these be spread out over multiple conferences?

Yes. Thanks, Rich. The -- as we said, we're really thrilled with the acceptance of Advance-HTN as a late breaker at ACC. I would anticipate seeing more detail about Launch-HTN at a future medical conference as well as peer-reviewed publication.

Our next questions are from the line of Seamus Fernandez with Guggenheim Partners.

So congrats on the data. And a couple of quick questions. So just as you look at the sort of pooled overall 50-milligram dose performance, can you just remind us what we're seeing in terms of the maybe you can't talk about Advance, but in Launch-HTN, if the data basically came in above a sort of 10-millimeter threshold. I just want to ensure that when we're looking at the primary endpoint, which, again, I know in that study was at 6 weeks, but at 12 weeks, what are we seeing for -- in terms of the overall pooled data set when -- if you were to pull the 50-milligram dose without inclusion of the 100-milligram dose across the 2 arms. We're just getting a lot of questions from investors on that front and what that would have showed. Second question is just the path to filing from here. What are the gating factors? What additional data do you need 6-month safety follow-up, et cetera? Prior to potential filing with FDA. Have you satisfied from your perspective, other than the 6-month follow-up, the ability to file and any kind of timelines you can offer along those lines would be helpful. And then just the last question. In terms of the 50-milligram dose being kind of the core dose, is that much different from other hypertension drugs. Do you feel that there's any need at all to request a 100-milligram dose as part of the label? Or will you only pursue 50 milligrams?

Yes, Seamus, thank you. Let me have Dave start off with the question on the 50-milligram pool, and then I'll give you some color on the path to filing and how we're thinking about the doses that would likely be in the label. Dave?

Thanks for the questions, Seamus. So we haven't reported on the pool data, and that will be part of a subsequent report in the publication, but I can guide you that remember, there's twice as many subjects in that 50-milligram arm than the 100-milligram arm. And you can get a rough idea from just doing a weighted average. So 2/3 at that 11.7 and then 1/3 at the lower number, and it's above 10.

And Seamus, to your question on the path to filing, obviously, we're thrilled with the data that we have for Advance and Launch in the active control. Even the target data will be part of the overall safety package that we put forward. Obviously, the open-label, long-term safety, it's actually out to about 48 weeks or 12 months is what will make up the safety package that we'll put forward. We're continuing to collect that. I think everything else is on track as far as for the program. We haven't provided guidance at this stage. There's the ability to do an update of safety data once you've made the filing, but we want to make sure we have the proper balance and the majority of that safety data within the initial filing for the package. So as we continue to progress the program, we'll provide guidance as we have clarity on that. Lastly, as far as the dose that we anticipate having in the label, I would say at this point, the evidence is pretty clear from Target from Advance and from Launch. The 50 milligrams is really delivering the kind of efficacy that's going to make a big difference in patients' lives and do so with a really nice safety and tolerability profile. But I would remind people, we also have the 25-milligram dose. That's something that's been available as a down titration through the pivotal program. It's the key dose that we're focused on in our Explorer-CKD study. And it is anticipated that the label will have both 25 and 50 milligrams within it. And at this point in time, I would say it's unlikely that the 100 milligrams would be a dose that we feel would be even necessary for prescribers and patients.

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

Congratulations on some great data. Just I guess broad question. Given that lorundrostat is working so well across all the different populations, obese as well as overweight, do you expect physicians -- how do you expect physicians to really be identifying those patients who are specifically have hyperaldosteronism? Does it complicate their diagnosis? Or does it make it easier for them. They don't have to consider that anymore? And is this going to be, I guess, more difficult for the general practitioner or the primary care practitioner or are you keeping this still in the specialist cardiovascular -- cardiologist population who are really treating the third, fourth line patients? And then I guess that also speaks to the question of hyperkalemia rates. Will this be something that I guess, the general practitioner will be concerned about? Or is it still, again, in the cardiologist office and they know how to manage this very well. And then I guess last question is, can you discuss the AEs of special interest, can you characterize this at all? Is there anything there that we need to be thinking about?

Yes. Thanks, Annabel. Let me make sure I touch on all these. So identifying the patients with aldosterone, is it easier or harder? Is it a GP? Is it a cardiology? I'll maybe step back a little bit more broadly from that. If you see what's going on in the medical community now progressively, there is more and more interest and attention being paid to aldosterone and frankly, the medical community acknowledging that they're under diagnosing that. You're seeing more inclusion in guidelines speaking to aldosterone about how to test it, how to evaluate it. And so the medical community, I think, is rapidly becoming attuned to the prevalence that we've discussed with you in the past is likely around 30% of all hypertension patients having some form of either dysregulated or elevated aldosterone. And so if I think about how does that awareness in the market match up with the data that we're seeing today, I think it's becoming really evident that in that resistant population, I'll talk to that one first. So fourth line that lorundrostat said is going to become, I think, a pretty rapid clear choice for those patients. We've seen in published literature before as you move from various earlier stages of hypertension resistance, that prevalence grows higher. I think the, again, lorundrostat is going to be a clear choice in that space. For third line, I actually think, as I said in my remarks, that overweight and obese population is going to continue to be a really informative group, even at the GP level. And we're not giving up on the obese. I think the again, was informative in Target-HTN. It did not show the signal in the pivotal program, but we're going to continue to look at other more sensitive measures of visceral adiposity that could inform that. But given the data that we saw in both uncontrolled and resistant in the pivotal program, I think there's a clear place to use lorundrostat even at the third line position. And I think what makes it even easier for a general practitioner or primary care population to not only use lorundrostat fourth line, but third line is that 1% hyperkalemia rate that we saw in Launch-HTN. And that's the real-world setting, right? That's where patients are coming in. They're on their existing background meds. In the primary care, they tend not to be pushed on background dose nearly as high as what we saw in Advance-HTN, which is where your specialist, your cardiologists are going to be going. And so for a primary care doc, to see that 1%. We didn't even test that level of hyperkalemia because we didn't anticipate it being that low. And so we feel very confident that the efficacy that we've seen, coupled with that safety is going to really open up the possibility for primary care prescribers to work with the drug. Again, I think the -- for the specialists who are dealing with those very difficult-to-treat certainly resistant hypertension patients, that's why we did Advance-HTN. We wanted to make sure that we did or had within the clinical data set of lorundrostat, a truly rigorous confirmed hypertension trial to address the needs of those specialists and to basically show them what lorundrostat can do in the populations they're treating. We've also discussed this in the past, Advance-HTNs rigor was by design to hopefully enable us to get lorundrostat into the hypertension guidelines. I can't speak to how that's going to be interpreted or the placement of treatment. But certainly, the rigor of that study, I think, will be recognized by those guideline positions. As far as the AEs of special interest, Dave walked through that I would characterize them as really the -- more of the on target. And so we're talking a hyperkalemia, hyponatremia and maybe changes in eGFR, but all within the acceptable range.

Next questions are from the line of Mohit Bansal with Wells Fargo.

Congrats on the data. I have a question regarding the real-world implications of these hyperkalemia rates. So David, if you could help us understand how physicians manage something like Spiro, what time frame point after the first dosing this get tested for hyperkalemia? And do you expect the management of lorundrostat being any different from what we see with other MRAs or other agents like that?

Thanks Mohit. So the first question was what are the implications in general of these rates? Well, compared to spironolactone, these rates are dramatically lower. And spironolactone has had a really hard problem getting used as fourth line where it's supposed to be used. So I think in that space, this is going to be seen as a really useful new tool. The question was how do physicians manage this. Within 2 weeks of starting the drug, you'll see the maximum change in potassium. So typically, you write the prescription for 50 milligrams, 2 weeks later, they come in just for a lab test. A quick one. It can be at their neighborhood blood draw, a physician looks at it. In general, if it's a grade 1 increase, in other words, above normal, but certainly below 6, then for the most part, you would observe and follow and get another measurement. As Jon mentioned, though, we are carefully studying the 25-milligram dose as well from the data that we had in the Target study, we are confident it will be effective, and it will give physicians another tool, which is to decrease the dose and then bring them back in. It should still be effective. Was there another part of your question?

Yes. Let me add to it. And Mohit, I think it -- I agree with everything Dave said. I think if you think of the practice of a primary care doc, they're attuned to doing this, what Dave just described, and they're attuned to that, even with ACEs and ARBs. We know that ACE inhibitors, the angiotensin receptor blockers have kind of a similar profile. A couple of weeks after initiation, a slight rise in potassium that then stabilizes over time. And so what we're asking physicians to do is nothing different than they're currently doing with our hypertension patients right now with the existing treatments they have.

Got it. And then if I could ask one more. So what would be the -- as you just said that high -- they were higher -- there was a high dose of olmesartan or ARB in this trial. So what would you see or what do we expect in terms of higher potassium levels on this kind of dose in clinical settings?

Yes, I don't know that you're asking what do we typically see for almost aren't alone as it relates to...

Yes at the highest dose. Yes.

Yes, I don't know that I have specific data on that, Mohit, but I can tell.

Okay. I can find out.

But I can tell you real quick that for Advance-HTN, that 3-week titration period before subjects could be randomized, they needed to be stable on their electrolyte measures. So -- but we haven't investigated that as far as what was the rise within Advance.

Our next question is from the line of Tim Anderson with Bank of America.

This is Alice on for Tim. Congrats on the data. Following up on your comments on the obesity signal. When do you plan to share those additional analyses on waist conference and other metrics? And I know you just touched on it in your -- one of your previous responses. But how important is it commercially for you to demonstrate a signal there? And then I have a follow-up.

Yes. I think the -- we'll obviously be doing the analysis and plan on sharing it at a future congress and peer-reviewed publications. So I can't guide as far as the specific timing, but it's obviously something we're going to continue to analyze. It was a part of our -- from a commercial standpoint, I don't know that it was a part of the resistant population. We've always viewed lorundrostat and a safe, well-tolerated aldosterone-directed treatment being a difference maker for resistant hypertension population writ large. In the third line population where I would say, typically, you see ACE or ARB first-line diuretic second and calcium channel blocker like amlodipine third line we felt that obesity could be a way to guide to subjects that are going to get a better response with lorundrostat than amlodipine. And we're going to continue to evaluate that. As you heard Dave say, we have different measures of -- and maybe more sensitive ones for visceral adiposity, we're going to look at other markers such as leptin, certainly looking at aldosterone and renin. But I would say with the data that we have shown now with Launch-HTN, this is a very competitive profile writ large for third line. And so I think it basically enables for both not only the obese, but also the overweight potential benefit for a safe and well-tolerated means of getting to their goal.

And on the hypertension guidelines, assuming approval, when do you think could be the next opportunity to get lorundrostat into the hypertension guidelines? And then finally, now that we have your top line data, how should investors think about the upcoming AstraZeneca baxdrostat readout? Any differences that you would like to flag for investors?

Yes. I -- on the guidelines, it's hard to opine on the timing of that. We're obviously thrilled that we've got a clinical package that I think will meet the rigorous criteria of those guideline committees. I know historically, as new innovations and new data has come forward. They've tried to reflect that within the guidelines, but it's difficult for me to opine on the timing of that. As to the AstraZeneca data, I don't know that I'm here to opine on that. We're just thrilled with frankly, the consistency of the profile that we've seen now in 3 clinical studies with lorundrostat, the magnitude of response, the kind of safety and tolerability profile that's emerged. And again, we've been very bullish on lorundrostat. We think the half-life of this molecule, the selectivity makes it a best-in-class ASI and having these 2 data readouts as part of our pivotal package now certainly gives us an opportunity to move rapidly forward to introduce it to patients.

The next question is from the line of Rami Katkhuda with LifeSci Capital.

Congrats on the data. Two quick ones for me. I guess, first, do physicians utilize the high olmesartan dose that was used as the -- as part of the standardized background regimen in Advance as part of the real-world setting? Or do they just generally add another treatment? And then secondly, I know you can't probably go into details, but were there meaningful differences when comparing systolic blood pressure reductions with ABPM versus AOBP in Advance? Or could you remind us of differences in those measurements in historic studies?

Yes. Rami, to your first question, the high dose. I think that's what makes Advance somewhat distinct from Launch. I think the real-world setting, it's rare that physicians push to max dose. And it's not just ARBs. I think it's across the board. And part of that reason is to avoid adverse events or side effects. So it becomes a tolerability question. And so that's why I think the Launch-HTN is such a critical part of the data story for lorundrostat. Because, again, that's how the drug will be used with a variety of background treatments. I'm not saying that there weren't subjects in Launch that weren't more maximally treated. But it's that a variety of background meds that we've now seen lorundrostat have that 19 mmHg absolute reduction and the 12 mmHg -- 11.7 mmHg placebo-adjusted change. So I think that's really the benefit that lorundrostat that can provide there. As far as the 24-hour in the AOBP, I really can't opine on what is going to be presented at ACC at this point. We're obviously thrilled with the partnership with the Cleveland Clinic, and Luke will be sharing information about Advance-HTN that we think will be really informative to the medical community. We're at large about the profile that we're seeing there. As far as distinctions between 24-hour measurement and AOBP writ large. As you recall, in Target-HTN we saw a pretty tight concordance as far as response to lorundrostat between those 2 measures. In some historical constructs, there's a view that the change on a drug in AOBP, maybe a couple of millimeters of mercury higher than in ABPM, but I think that's a little bit of a misnomer or an artifact, if you will. I don't know that there's always a great deal of separation between the 2. I think the key is having well controlled design of study and measurement. And Rami, you know the links that we go to, to make sure that our in-office measurement is reflective of reality as we can. So I think the concordance like we saw in Target-HTN is maybe reflective of what we've seen in the past.

The next question is from the line of Matthew Caufield with H.C. Wainwright.

And great to see this data. Congratulations. You just mentioned evaluating the additional obesity criteria for going forward. But I was thinking from a mechanism standpoint, is there any sense of what could have impacted not observing superior benefit among the high BMI patients at least at this stage?

This is Dave again. It's a good question. We did have a poster at ASN last year that showed what it looked like in the Target-HTN when we did this treating the BMI as a continuous variable. In other words, a regression line instead of a cut at 30. And we did see a trend from all the way at BMIs of 23 and up that the drug worked and it worked progressively better. And so it may be technique wise, I do think the consensus now is this is about fat around your belly, men have that more than women. And you really need to measure the circumference of the abdomen or the ratio with the hips, we have that plan. That's going to give us a better index on that. And I really don't think I should speculate any more than that about the differences.

Thank you. At this time, I'll turn the floor back to Jon Congleton for closing remarks.

Yes. Thank you, operator, and thanks, everyone, for joining us today. Obviously, we're very excited about the data that we've announced today. A lot of work went into this we're just -- we're thrilled with the outcome. The overall progress that we've made over the last 4 years moving for the proof-of-concept Target-HTN, now with the readouts of Advance and Launch-HTN and really the concordance of data that we continue to see with lorundrostat, the meaningful difference it's making on systolic blood pressure and with the safety and tolerability profile, we think there's significant opportunity with this potentially transformative agents. So thanks. We look forward to keeping you apprised on our future progress. And with that, we'll close the call. Thanks, everybody.

Thank you. This will conclude today's conference. We thank you for your participation. You may now disconnect your lines at this time.