Mineralys Therapeutics - Earnings Call - Q1 2025

Executive Summary

• Mineralys reported Q1 2025 net loss of $42.2M and diluted EPS of $-0.79, improving sequentially from Q4 2024 ($-0.98), and reflecting higher R&D to advance pivotal programs; cash, cash equivalents and investments totaled $343.0M after a March equity raise, extending runway “into 2027”.
• Both pivotal hypertension trials for lorundrostat hit primary endpoints: Launch-HTN showed a 9.1 mmHg placebo-adjusted AOBP reduction at week 6, sustained to 11.7 mmHg at week 12; Advance-HTN showed a 7.9 mmHg placebo-adjusted 24-hr ABPM reduction at week 12 with favorable safety, including low confirmed hyperkalemia incidence.
• Management plans a pre-NDA meeting with FDA in Q4 2025, while Explore-CKD topline remains targeted for Q2 2025; Explore-OSA Phase 2 was initiated in Q1 2025, broadening the cardiorenal-metabolic footprint.
• EPS beat Wall Street consensus in Q1 2025 (actual $-0.79 vs. consensus $-0.982), following an earlier Q4 beat (actual $-0.98 vs. consensus $-1.077); the company remains pre-revenue as expected (consensus $0).
• Stock catalysts over the near term include Explore-CKD topline (Q2 2025), ESH presentation for Launch-HTN in May 2025, and partnering/commercial strategy evolution under newly appointed CCO Eric Warren.

What Went Well and What Went Wrong

What Went Well

• Pivotal efficacy success in two distinct hypertension settings: “The Advance-HTN late-breaking presentation… and the recent publication in the New England Journal of Medicine underscore the strength of our clinical data… With the success of our two pivotal trials, we are working toward submitting our new drug application… anticipated in the fourth quarter of 2025.” — CEO Jon Congleton.
• Durable safety profile with low confirmed hyperkalemia: Launch-HTN confirmed hyperkalemia 0.6%–1.1%; Advance-HTN 2.1%–3.2%, with modest electrolyte changes and low discontinuations.
• Strengthened balance sheet and commercial readiness: “On March 18, 2025, the Company completed a public equity financing for gross proceeds of approximately $201.2 million… reported $343.0 million of cash, cash equivalents and investments… Appointed Eric Warren as Chief Commercial Officer.”.

What Went Wrong

• Operating losses widened YoY on elevated development costs: Q1 2025 net loss increased to $42.2M vs. $31.5M in Q1 2024, primarily from higher preclinical/clinical and compensation expenses.
• Other income declined YoY on lower interest earnings (money market/treasuries): $2.2M in Q1 2025 vs. $3.9M in Q1 2024.
• Macro/tariff/inflation risks persist (supply chain/materials/capital markets), potentially affecting manufacturing and financing flexibility as noted in 10-Q risk factors.

Transcript

Operator (participant)

Good afternoon, ladies and gentlemen, and welcome to the Mineralys first Quarter 2025 earnings conference call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question and answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Monday, May 12, 2025. I would now like to turn the conference over to Dan Ferry. Please go ahead.

Dan Ferry (Head of Investor Relations)

Thank you, Aubrey. I would like to welcome everyone joining us today for our first quarter 2025 conference call. Earlier this afternoon, we issued a press release providing our first quarter 2025 financial results and business updates. A replay of today's call will be available on the investors' section of our website approximately one hour after its completion. After our prepared remarks, we will open the call for Q&A. Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements about the company. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our annual report on Form 10-K and subsequent filings.

Please note that these forward-looking statements reflect our opinions only as of today, May 12, 2025, and as except as required by law, we specifically disclaim any obligation to update or revise these forward-looking statements in light of new information or future events. I would now like to turn the call over to Jon Congleton, Chief Executive Officer of Mineralys Therapeutics.

Jon Congleton (CEO)

Thank you, Dan. Good afternoon, everyone, and welcome to our first quarter 2025 financial results and corporate update conference call. I'm joined today by Adam Levy, our Chief Financial Officer, and Dr. David Rodman, our Chief Medical Officer. I'll begin with an overview of the business. Then Dave will discuss our clinical programs and recent milestones, followed by Adam to review our first quarter financial results before we open up the call for your questions. This has been an exciting past few months for Mineralys as our team delivered on several clinical milestones to make significant progress across our entire development pipeline. The most highly anticipated of these accomplishments was the simultaneous announcement of positive top-line data from the pivotal trials Launch-HTN and Advance-HTN, which evaluated lorundrostat in uncontrolled and resistant hypertension subjects.

We were pleased to announce in March that both trials successfully achieved statistical significance and were clinically meaningful in their primary efficacy endpoints and demonstrated a favorable safety and tolerability profile. Detailed results from the Advance-HTN trial were also published in the New England Journal of Medicine and presented in a late-breaking presentation at the American College of Cardiology's ACC 25 meeting. The Launch-HTN data has been accepted for a late-breaking presentation at the European Society of Hypertension meeting on May 24, with a planned future publication. Each of these exciting outcomes helps to underscore the strength of these clinical data and the potentially transformative nature of lorundrostat to help people achieve their blood pressure goal and potentially reduce their cardiovascular risk.

The positive efficacy, safety, and tolerability data from these two pivotal trials, along with the data from our Target-HTN phase II trial of lorundrostat, are key elements of our planned New Drug Application to the FDA. We continue to believe that dysregulated aldosterone is not adequately addressed with the currently available RAS-directed therapeutics, including mineralocorticoid receptor antagonists. These results we have seen with lorundrostat reinforce the need for a new aldosterone-directed therapeutic approach. The Transform-HTN open-label extension trial is evaluating the safety and efficacy of lorundrostat long-term use, which will be an important aspect of lorundrostat's profile and a critical component of our New Drug Application.

We anticipate discussing the results from the Advance-HTN, Launch-HTN, Target-HTN, and Transform-HTN trials, as well as the ExploreCKD trial with the FDA at a pre-NDA meeting in the fourth quarter of 2025, during which we expect to define the path forward for an NDA submission and potential approval of lorundrostat. We look forward to providing updates on this program throughout the remainder of 2025. We're very optimistic about the interest physicians have in lorundrostat's overall clinical profile based on the pivotal data, especially given the double-digit absolute reduction in systolic blood pressure. Supporting our excitement around the market opportunity for lorundrostat are the data we collected in a [CIRMO] survey fielded in March, which evaluated the data from the Launch-HTN and Advance-HTN trials with cardiologists and primary care physicians.

The results from that survey showed if lorundrostat is approved, 95% of the physicians are likely to prescribe lorundrostat broadly for hypertension and specifically in the third and fourth-line position. This intent to prescribe is based on the healthcare professional's interpretation of the efficacy data relative to what they currently have available for uncontrolled and resistant hypertension, as well as lorundrostat's safety and tolerability profile. The overall results speak to the desire for innovative solutions that physicians want in their treatment armamentarium to address uncontrolled and resistant hypertension. Our two ongoing proof-of-concept trials address advanced chronic kidney disease, specifically those with uncontrolled hypertension, as well as obstructive sleep apnea with nocturnal hypertension. These trials are designed to enhance and extend the lorundrostat profile in hypertension subjects with comorbid conditions largely driven by inadequately controlled blood pressure and dysregulated aldosterone.

We've made steady progress with both trials since the beginning of 2025 and anticipate announcing top-line data from ExploreCKD trial later this quarter. We're also pleased to announce the appointment of Eric Warren as Chief Commercial Officer. Eric brings approximately 30 years of experience in the pharmaceutical industry, during which he has developed a breadth of commercial and partnering expertise, focusing primarily on cardiometabolic and acute care medicine. He started his career as a pharmacist and then joined Merck & Company, where he went on to hold commercial positions of increasing responsibility for almost two decades. In addition, Eric has held commercial leadership roles at Sanofi and Aspireon and was most recently the Chief Commercial Officer at Aspireon Therapeutics. As the Chief Commercial Officer at Mineralys, he'll lead our commercial strategy as we prepare for the potential FDA approval of lorundrostat and support our partnering ambitions in the U.S.

and ex-U.S. markets. In March, we completed a public equity financing that raised gross proceeds of approximately $201.2 million before deducting fees and expenses. This financing contributed meaningfully to the strength of our balance sheet. Now, to provide more color on our clinical pipeline and recent milestones, I'll turn the call over to Dave.

David Rodman (CMO)

Thank you, Jon, and good afternoon, everybody. As Jon mentioned, our team has had an exciting few months with the advancement of our clinical programs. I'll start by summarizing the top-line results of the pivotal phase III Launch-HTN trial, which randomized 1,083 subjects in North America and Europe who had failed to achieve the U.S. guidelines-specified blood pressure targets despite having been prescribed a multi-drug antihypertensive regimen. The trial, which tested lorundrostat in a real-world clinical context, met its primary and secondary endpoints with highly statistically significant and clinically meaningful placebo-adjusted reduction in systolic blood pressure, as well as in the observed change in blood pressure that is conventionally used by prescribing physicians to assess response to antihypertensive therapy.

At week six, the primary endpoint, the 50 mg once-daily lorundrostat arm demonstrated a 9.1 millimeter of mercury placebo-adjusted reduction in systolic blood pressure and a 16.9 millimeter of mercury reduction in observed systolic blood pressure. At week 12, the reduction in systolic BP was maintained, with the point estimate being greater than that observed at week six, 11.7 millimeters of mercury and 19 millimeters of mercury for placebo-adjusted and observed changes respectively. Reductions in blood pressure of this magnitude have been linked to significant reduction in overall cardiovascular risk and the incidence of major adverse cardiovascular events. The Launch-HTN trial confirmed the expected modest on-target increase in serum potassium that accompanies the therapeutic benefit in individuals with inadequately controlled hypertension, as well as an overall safe and well-tolerated profile.

The incidence of any potassium measurement over 6 millimoles per liter in the Launch-HTN trial in the 50 mg arm was 1.1% in placebo inactive and 0.7% in placebo. The pre-specified rate, excluding falsely elevated or factitious hyperkalemia, was comparable to placebo, with the demonstrated incidences being 0.6% and 0.4% respectively. While quantitative comparisons between different clinical trials are difficult, the incidence of moderate or severe hyperkalemia of approximately one-half of 1% compares quite favorably with most prior reports of mineralocorticoid receptor antagonists tested in a similar clinical context. The Launch-HTN global pivotal trial is the largest aldosterone synthase inhibitor trial reported to date, and the benefit-risk profile compares quite favorably with previously reported smaller trials of the three other aldosterone synthase inhibitors that have been tested in hypertensive individuals.

Now, turning to the Advance-HTN trial, here we tested the effect of lorundrostat in the clinical context of hypertensive individuals who are the most refractory to current standard of care and often referred to hypertension specialists. The trial used highly rigorous criteria for enrollment and randomization designed to mirror best practice care provided in the most advanced hypertension referral centers. Maximization of conventional best practice two and three drug treatment regimens, along with active monitoring of compliance, were used to document and confirm the existence of uncontrolled or resistant hypertension. The results from the trial in the 50 mg once-daily lorundrostat arm were highly statistically significant. The 7.9 mmHg reduction in placebo-adjusted systolic blood pressure and 15.4 mmHg reduction in observed systolic blood pressure measured by 24-hour ambulatory blood pressure were observed at the pre-specified 12-week visit.

Lorundrostat demonstrated a favorable safety and tolerability profile with modest on-target changes in serum potassium, sodium, and eGFR, and a low discontinuation rate. This trial was designed and conducted in partnership with the Comprehensive Hypertension Center at the Cleveland Clinic and their C5Research team. Results were presented by the Co-Director of the Cleveland Clinic Hypertension Clinic, Dr. Luke Latham, in a late-breaking session at the American College of Cardiology's ACC 25 meeting and published in the New England Journal of Medicine on May 8. As was reported in the New England Journal of Medicine paper, the Advance-HTN trial per protocol confirmed incidence of hyperkalemia over 6 millimoles per liter in the 50-milligram arm was 2.1%.

Given the high dose of olmesartan, a potent long-acting arm, which also elevates serum potassium, we feel that this incidence of serum potassium greater than 6 millimoles per liter has an acceptable benefit-risk profile appropriate for the use in these patients. Okay, now turning to our other programs, ExploreCKD and Explore-OSA phase II proof-of-concept trials. Both of these trials are designed to provide data that augments the antihypertensive protocol of lorundrostat by profiling the safety and efficacy of lorundrostat in these two special populations of hypertensive individuals. During the first quarter, we announced the completion of enrollment in the ExploreCKD phase II trial.

This trial evaluates the safety and efficacy of lorundrostat for treatment of hypertension in subjects with an eGFR from 30 to 90 and at least 200 milligrams of uACR, despite receiving stable treatment with an ACE inhibitor or an ARB, as well as an SGLT2 inhibitor. Hypertension and associated hypertensive nephropathy is a leading cause of kidney damage alone and in combination with other obesity-associated comorbidities. This is another area with great unmet medical need where aldosterone synthase inhibition with lorundrostat has the potential for transformative benefit to patients. In this trial, the primary outcome measure is change in systolic blood pressure during a four-week treatment period relative to that seen in a four-week placebo treatment period in the same individuals.

The key mechanism of kidney damage in hypertensive nephropathy is elevated blood pressure-induced glomerular hyperperfusion, scarring, and reduction of the number of glomeruli available to filter the blood. Change in proteinuria is being assessed in this trial as well. In contrast to CKD due to diabetes and metabolic syndrome, where proteinuria is a useful surrogate endpoint, individuals with predominant hypertensive nephropathy tend to have modest levels of proteinuria. Change in blood pressure, along with acute physiological reduction in eGFR, rather than change in proteinuria, may be a more useful outcome measure for a phase II trial in this population. In the first quarter of 2025, we announced initiation of the Explore-OSA phase II trial to evaluate the effect of lorundrostat in the treatment of moderate to severe obstructive sleep apnea. Blood pressure increases significantly as arterial oxygenation falls during upper airway obstruction at night.

By dosing lorundrostat at bedtime, we believe we will suppress the majority of aldosterone produced during sleep while maintaining 24-hour blood pressure control. Episodes of nocturnal hypertension are underdiagnosed and lack a demonstrated highly effective treatment. The current treatment armamentarium is limited to weight loss and the use of positive airway pressure. We believe that neither is sufficiently effective at minimizing the impact of OSA on major adverse clinical outcomes. In summary, we have now demonstrated the clinically meaningful benefit-risk profile of lorundrostat in individuals with aldosterone-mediated hypertension. We are focused both on moving lorundrostat towards an NDA submission, as well as exploring its use in prevalent comorbidities such as OSA and hypertensive nephropathy, for which normalizing aldosterone production may result in meaningful clinical benefit. I'll now turn the call over to Adam to review our financial results for the first quarter of 2025.

Adam Levy (CFO)

Thank you, Dave. Good afternoon, everyone. Today, I will discuss select portions of our first quarter of 2025 financial results. Additional details can be found in our Form 10-Q, which will be filed with the SEC today, May 12. We ended the quarter with cash, cash equivalents, and investments of $343 million as of March 31, 2025, compared to $198.2 million as of December 31, 2024. We believe that our current cash, cash equivalents, and investments will be sufficient to fund our planned clinical trials and regulatory activities, as well as support corporate operations into 2027. R&D expenses for the quarter ended March 31, 2025, were $37.9 million, compared to $30.8 million for the quarter ended March 31, 2024.

The increase in R&D expenses was primarily due to increases of $4.8 million in preclinical and clinical costs and $2.8 million in compensation expense resulting from additions to head count, increases in salaries and accrued bonuses, and increased stock-based compensation, partially offset by $0.5 million in lower clinical supply, manufacturing, and regulatory costs. G&A expenses were $6.6 million for the quarter ended March 31, 2025, compared to $4.6 million for the quarter ended March 31, 2024. The increase in G&A expenses was primarily due to $1.2 million in higher compensation expense resulting from additions to head count, increases in salaries and accrued bonuses, and increased stock-based compensation, and $0.7 million in higher professional fees. Total other income net was $2.2 million for the quarter ended March 31, 2025, compared to $3.9 million for the quarter ended March 31, 2024.

The decrease was primarily attributable to decreased interest earned on our investments in money market funds and U.S. Treasuries. Net loss was $42.2 million for the quarter ended March 31, 2025, compared to $31.5 million for the quarter ended March 31, 2024. The increase was primarily attributable to the factors impacting the company's expenses described above. With that, I'll ask the operator to open the call for questions. Operator?

Operator (participant)

Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star one on your touch-tone phone. You will hear a prompt that your hand has been raised. Should you wish to decline from the polling process, please press star two. If you are using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. Your first question comes from Michael DiFiore of Evercore. Your line is already open.

Michael DiFiore (Analyst)

Hey, guys. Thanks for taking my question and congrats on all the progress. Just two from me. With regards to the CKD trial, in the past, you said that these patients are so sick that physicians will readily accept some level of hyperkalemia if it means that lorundrostat will improve their blood pressure. I guess my question is, what would be the max level of grade 2 hyperkalemia that would be acceptable if lorundrostat were to yield a high single-digit placebo-adjusted SBP reduction? I have a follow-up.

Jon Congleton (CEO)

Yeah, Mike. Just a quick response. I don't know that we've categorized what would be an acceptable level. I think what's key and critical is we talk to specialists and our advisors who are treating these patients with hypertension and more advanced kidney disease. They're really looking at providing a benefit to the BP as well as relieving or improving the kidney function overall. I think these specialists, which tend to be predominantly nephrologists, are more comfortable with a higher level of potassium readings within these patients. They have a means to manage that. They've got tools to use that. They're also more likely to modulate other background treatments. In other words, if they're getting the BP reduction with lorundrostat, they may reduce the dose of ACE or ARB.

I think the key takeaway for us is with an ExploreCKD, get a clear sense of the safety, characterize the efficacy with this drug, and knowing full well that providing a benefit on both BP as well as kidney function in these subjects is what the specialists who are treating these patients predominantly are looking for.

Michael DiFiore (Analyst)

Got it. That's helpful. My final question is, despite Baxdrostat's shorter half-life and lesser selectivity for aldosterone synthase inhibition relative to lorundrostat, it still showed a high single-digit percent SBP reduction over 14 weeks in their phase II CKD trial. I guess, should we expect similar efficacy and safety with lorundrostat?

Jon Congleton (CEO)

Yeah, Mike, I think it's too hard to hedge what we expect to see. I think we would anticipate seeing a clinically meaningful reduction in BP. I think the profile for lorundrostat has been well characterized now with three successful studies from Target-HTN, Advance-HTN, and Launch-HTN. It's too early to hedge what we'd anticipate seeing. I would anticipate certainly a clinically meaningful reduction, and then we'll see how the data unfolds as far as for those other hemodynamic characteristics.

Michael DiFiore (Analyst)

I see. Thank you.

Jon Congleton (CEO)

Yeah.

Operator (participant)

Your next question comes from Richard Law of Goldman Sachs. Your line is already open.

Richard Law (Analyst)

Great. Thank you so much, and congrats on the progress from me as well. A couple of questions for me. Can you discuss how the overall ExploreCKD study fit into the strategy for regulatory submission with Launch and Advance? My understanding is that this study is important to provide clinical support for patients below eGFR 45, and it would be great to hear your latest thinking on this and if that has evolved. I have a follow-up.

Jon Congleton (CEO)

Yeah, Rich, thanks for the question. We're certainly excited about the benefit-risk profile that's emerged now with lorundrostat with the successful completion of the Advance study and the Launch study seeing double-digit reduction in BP with a really acceptable safety tolerability profile. The submission of the lorundrostat NDA will be inclusive of all three of those studies, as I noted, as well as the Transform open-label extension, and ExploreCKD will be a component of that. Really, the biggest driver of ExploreCKD was really to inform the blood pressure response in subjects with an eGFR down to 30, as well as going with a lower dose of 25 milligrams qd. And so it will be a component. I think it's going to be part of the totality of evidence of lorundrostat that will go into the NDA.

I don't know if I could opine at this point as far as the specific language that will be included in the label from Explore, but it's certainly a part of the total package we'll be having the dialogue with the agency on.

Richard Law (Analyst)

Great. Fantastic. And then we saw in the New England Journal publication that the patients who have the potassium levels greater than 6 have a much lower average eGFR compared to the rest of the population. I mean, in your view, what is the typical eGFR delta between such study population in the ExploreCKD study and those in a general hypertension study, like the one in your pivotal study program? I guess, beyond the CKD study, is that a good benchmark in terms of patient population, or is it a different population from that?

Jon Congleton (CEO)

Rich, and I'm sorry to do this. Can you rephrase your question? I just want to make sure I'm answering what you're looking for.

Richard Law (Analyst)

Yeah. In your New England Journal publication, the patients who have the higher potassium levels greater than 6 millimole, they all have lower than average eGFR compared to the rest of the population. The question here is that how do we think about sort of the differences between the eGFR in your ExploreCKD study compared to the Advance and Launch? What would be a good benchmark in terms of the type of patient that would, in terms of the eGFR level for your ExploreCKD study?

Jon Congleton (CEO)

All right. Thanks, Rich. I appreciate that. Yeah, I think it's why we're doing the ExploreCKD study. We know the eGFR, mean eGFR on Launch was higher than that in Advance. Advance was obviously a more high-risk population, truly uncontrolled, truly confirmed, resistant hypertension. They had lower eGFR. I think you're alluding to what Luke shared at the ACC about the subjects above 6 had a mean of about a 58. As far as how tight is the correlation between eGFR and risk of hyperkalemia, I think we need more data and more evidence, but it's part of why we're doing the ExploreCKD trial. Looking at subjects going down to an eGFR of 30, we know they have the risk of potential more challenges in managing electrolytes. That's why we're testing the 25 milligram qd. that we believe is an effective dose of lorundrostat.

As far as the correlation, I think that's something that will continue to unfold. Dave, if you've got some additional thoughts, please.

David Rodman (CMO)

Hey, Rich, good question. How are you doing? When you talk about studies like this, the outliers are in some ways more important than the means, right? The mean was above 60, say, for the people who did not have any of an incidence. It was a little bit lower, and they had it. In this trial, what we are really looking for are those individuals who are in that 30-45 range, maybe on the lower side, and saying, "What happens to them?" None of this is an issue other than giving guidance to clinicians for who to keep an eye on and probably who to give a potassium binder if needed. As Jon said, back off on the ARB and see if you can maintain the same blood pressure. It is a guidance.

It's what we call a special population profiling study, and we anticipate looking just as much at outliers as we do about means in that trial.

Richard Law (Analyst)

Got it. Very helpful. Just one last question. Similar to ExploreCKD, do you expect to include data from the Explore-OSA in your filing package?

Jon Congleton (CEO)

I think, Rich, it's a fair question. I think it's too early to opine on that. We haven't guided on top-line data. We're excited about that study to address a significant unmet need within that resistant hypertension OSA population, but it's too early to comment whether or not that would be included in the discussions with the FDA.

Richard Law (Analyst)

Great. Thank you.

Jon Congleton (CEO)

Thanks, Rich.

Operator (participant)

Your next question comes from Seamus Fernandez of Guggenheim. Your line is already open.

Seamus Fernandez (Analyst)

Great. Thank you for the questions, guys. John, I think on the last discussion call, you mentioned that as many as 47,000 physicians could actually be appropriate for promotion in the uncontrolled and resistant hypertension opportunity. I think you also at ACC emphasized that the opportunity may sit a little bit more initially in the sort of fourth-line hypertension opportunity. Can you just help us understand how does the sort of intersection of that broad physician base intersect with your view of the needs of a partner in that context? What are you really looking for in the context of either a partner or something perhaps more strategic or an opportunity to actually start advancing the opportunity to promote on your own? Thanks.

Jon Congleton (CEO)

Yeah. The 47,000, Rich, for those that maybe hadn't heard before, so we did a significant project about a year ago with IQVIA with about 1.6 billion prescription claims within that. When you basically narrow down where does 50% of the prescribing come from for third-line or later prescribing, there's about 47,000 doctors that account for about half of that prescribing and a significant portion of the influence on the other 50%. From our standpoint, there's a very efficient commercial model, particularly with kind of clinical profile that lorundrostat has now demonstrated, to go out and target those 47,000 prescribers and generate significant value. As we've talked about in the past, partnering for us is inclusive of U.S., but certainly global.

Looking for partners that could help maximize the opportunity of lorundrostat ex-U.S. because we have no intentions of creating Mineralys commercial entities standalone outside of the United States. Finding partners that could help maximize that opportunity ex-U.S., but then really fully tap into the opportunity in the United States as well. That would basically mean some level of overlap maybe with the targeted physicians that we've talked about, but certainly coverage of those outside of those 47,000 that we target. In fact, that target may be a little bit smaller as we think about an initial launch of lorundrostat. Fourth-line is probably going to be the ideal place to go. That's where there's minimal benefit with existing treatments beyond aldosterone-directed therapeutics. We know spironolactone is thought to be valuable there, but it's greatly underutilized.

I think our clinical program to date where we've targeted those subjects failing to get to goal on two or more meds shows the value of an aldosterone-directed treatment that physicians are going to want to work with, that patients are going to want to take and persist with. We think there's significant opportunity there. We think we could tap into a significant portion of those prescribers, but having a partner clearly is going to help us maximize the value of the asset in the United States.

Seamus Fernandez (Analyst)

Great. Maybe just one follow-up. Can you just remind us what the gating factors are to sort of finalizing and filing the NDA specifically? Thanks.

Jon Congleton (CEO)

Yeah. Happy to do that. First and foremost, we're obviously very pleased with the benefit-risk profile that we continue to see with this molecule. Now with the two active portions of the pivotal program completed, as we've stated before, the open label extension is a critical aspect of that. If you think about when the last subjects enrolled in Launch and Advance, that was at the end of October last year, we would anticipate all subjects completing the 52-week open label by Q1 of next year. Now, we don't need to have all of those subjects to enable a filing, but we need certainly a majority of those subjects through 52 weeks before we'd be comfortable with the NDA. That is part of what we'll have a dialogue with the FDA in Q4, as we've discussed in the pre-NDA meeting.

It'll be both the pivotal programs for Advance and Launch. It'll be part of the target data, the ExploreCKD data, and then a portion of that open label extension will be informative for that pre-NDA meeting that will then have better guidance for timing of an NDA submission.

Seamus Fernandez (Analyst)

All right. Great. Thanks, guys, and congrats.

Jon Congleton (CEO)

Thanks, Seamus.

Operator (participant)

Your next question comes from Tim Anderson of Bank of America. Your line is already open.

Hi, this is Alice from Tim. Thank you for taking our questions. I just want to check. Can you hear me okay?

Jon Congleton (CEO)

Yes, we can.

Okay. Perfect. Just following on from Seamus's questions on partnering, could you talk about any early discussions you may have had so far, and what are the limiting factors that a partner may be looking for? We're going to have the full data from Launch and the top-line from the CKD study very soon, but do potential partners need to wait for the outcome of the pre-NDA meeting, for example, as well as the AstraZeneca/Baxdrostat full data? I have a follow-up.

Sure. To date, we haven't given updates on our partnering discussions, but we do continue to believe that a partner or multiple partners will be a part of our story and will keep you updated as appropriate.

Okay. Thank you. AstraZeneca commonly references a $5 billion peak sales for Baxdrostat. I'm curious, how are you thinking that you can best leverage a partner in order to realize this sort of potential with lorundrostat? For example, does it involve developing fixed dose combinations or other indications and things like that? Thank you.

Yeah. Thanks, Alice. There's clearly a great deal of unmet need in this space. We're focused exquisitely right now on hypertension, but we know there's utility for an ideal aldosterone-directed treatment beyond that. It's why we're looking at the adjacencies, because there's such an overlap in all of these cardiorenal metabolic syndromes that have either hypertension or diabetes kind of at the central point. For us, we think there is significant unmet need. There's significant value to provide to patients to help reduce their BP, which is the leading modifiable risk factor for cardiovascular risk. Moving from hypertension into adjacencies such as obstructive sleep apnea, hypertensive nephropathy, as you heard Dave speak about, we think basically generates significant value for us.

As we have partnering dialogues, as I've spoken about in the past, part of that is partnering from a commercial perspective, but for those that have a shared vision, it also could be development partnerships as well, looking at some of these adjacent areas such as heart failure or CKD. Again, we know that aldosterone plays a role across the spectrum, and having what we believe to be a leading ASI gives us significant opportunity to tap into that value.

Thank you very much.

Thank you.

Operator (participant)

Your next question comes from Annabel Samimy of Stifel. Your line is already open.

Hey, guys. This is Jayed on for Annabel. Thanks for taking our questions. I have two questions. First is, at what point do you think that guidelines, hypertension guidelines, would start including Launch and Advance-HTN data? Is there any possibility that it could be updated before you guys would theoretically launch?

Jon Congleton (CEO)

Yeah. I appreciate the question. I don't know that we can opine on when the timing will be specifically. I think we can only look at historical precedents, and I think the various guideline committees, when faced with new valued innovations, have been responsive to try to guide their constituents on how they should think about and integrate these new innovations into their treatment paradigm. It is too early to opine, but it's a fair question. It's why we went to the effort we did in Advance-HTN, because I think it fundamentally addresses the kind of questions these guideline committees wish to have, and that is not only in maybe an existing background treatment, but when you get to truly high-risk patients like we tested in Advance, what is the profile physicians could expect, and how would guideline committees inform their communication to their constituents?

Got it. Thank you for that. My other question is related to ExploreCKD. What do you think is the primary thing that you're looking for here? Are you looking for safety in the CKD population with concomitant drugs like SGLT2 inhibitors and ARBs? Do you expect efficacy to generally be in the line of what you saw in Launch and Advance, or are there some nuances with that patient population that we should know of?

Yeah. I'll just reiterate what Dave had said with a profiling study like this. Safety is a key element of the analysis, and what we expect from a clinical benefit standpoint would be clinically meaningful reduction in blood pressure. I think that's been well characterized in the three studies to date. That's what we would anticipate to see in this population. Then providing additional information about the 25-milligram qd dose.

Great. Thank you. That's all I had.

Thank you.

Operator (participant)

Your next question comes from Mohit Bansal of Wells Fargo. Your line is already open.

Sadia Rahman (Analyst)

Hi. This is Sadia Rahman on for Mohit. Thanks for taking the questions, and congrats on all the recent progress. On the hypertension readouts, you previously mentioned plans for subgroup analyses. Can you elaborate on those plans for which subgroups you're focused on and the timeline for presentation of that data? Can you talk about how it could potentially help physicians select patients for lorundrostat, and if it could also influence placement of lorundrostat into treatment guidelines?

Jon Congleton (CEO)

Yeah. Sadia, thank you for the question. As you know, we've efforted to pre-specify analysis of populations that may be unique responders to lorundrostat. You saw some of that data within the Advance-HTN ACC as well as NEJM presentation and publications respectively. I would anticipate seeing something similar with Launch-HTN. I think to date, what we've seen, and it's frankly beneficial for a prescriber, is whether failing to achieve goal on two meds or three meds, so uncontrolled or resistant hypertension, you're seeing a pretty profound reduction in BP regardless of gender, age, race, number of background medications. It creates a predictable response that physicians can anticipate when using lorundrostat. We're going to continue to investigate and dive into the data.

I mean, what we've shared to date has been very informative about the value from a clinical reduction and safety standpoint, but there's a great deal of data we're going to continue to dig into within Launch and Advance and eventually ExploreCKD to really continue to further inform, all right, what is the ideal population to respond to this drug? To date, we've seen great responses across a multitude of subsets of patients.

Sadia Rahman (Analyst)

Great. Thanks. Then on the OSA trial, how are you thinking about this four-week endpoint, how it aligns with expected timelines for improvements in the apnea-hypopnea index and in nocturnal blood pressure? What magnitude of HI reduction would you consider to be clinically meaningful and also competitive in the context of the data reported with GLP-1s, for example?

David Rodman (CMO)

Really good questions. Let me try to take those one at a time. The first question was four weeks. What might we see? As far as apnea-hypopnea index, the primary mechanism through which our drug will work is the diuretic effect and reducing the amount of salt and water overload, because when you lay down at night, the excess salt and water, the fluid, shifts up. It is called rostrocaudal redistribution into your upper body and neck. That benefit is accrued within a few weeks. By four weeks, we would expect to see the benefit on apnea-hypopnea index. As you know, around a 50% reduction has been seen with the Lilly study, similar with the Apnimed of a different mechanism, where power down to about 30%. These are small trials. We would ultimately be observing where we are in that range.

Let me just say something. Treating the apnea-hypopnea index is important, but the main risk for adverse outcomes is these extreme bursts of hypertension, these spikes that you see at night when those things happen. We're going to be doing the first trial using sub-one-second measurements, beat-to-beat blood pressure over the course of an entire night. We'll be able to look at how well does this drug actually reduce the risk for adverse clinical outcomes. In many ways, that's a more important endpoint. However, apnea-hypopnea index and patient-reported performance metrics are the current guidance from the agency for approval. We're going down both of those paths. This is an anti-hypertensive drug, and it's a sodium depleter. We expect to see benefits on both, but both are going to be meaningful.

I can't tell you for sure if apnea-hypopnea index is 30, but we see a terrific impact on nighttime blood pressure, maybe restoration nighttime dipping. We'll be the only ones with those data at that point, and we'll be reporting them, and I think that will be really an important milestone in studying this disease.

Sadia Rahman (Analyst)

Great. Appreciate the context. Thank you.

Jon Congleton (CEO)

Thanks, Saadia.

Operator (participant)

Your next question comes from Rami Katkhuda of LifeSci Capital. Your line is already open.

Rami Katkhuda (Analyst)

Hey, guys. Thank you for taking our questions as well. I guess I just wanted to confirm a statement that Dr. Rodman made that patients with hypertensive nephropathy may have more modest levels of proteinuria. I guess, is the patient population in ExploreCKD similar to that of the Boehringer study, or are there other key differences in enrollment criteria? I guess, is that 37% placebo-adjusted uACR reduction with monotherapy of Baxdrostat a fair bar here?

David Rodman (CMO)

Okay. Those are good questions. If we think about this, and this has happened in other diseases, chronic kidney disease is a syndrome, right? It can be autoimmune, and you want to use an anti-IgA, which has been very effective. If it is in the context of obesity and diabetes, it is from metabolic syndrome, and that is the one that is associated with a fair amount of proteinuria, even nephrotic syndrome, which is an extreme of that. What we are looking at, some of these patients may have high levels of proteinuria, but we anticipate that that will not be the majority in this trial. It will be a different subset, and it is actually a different subset of CKD. These people have scarring of their external part of their cortex of their kidney, loss of these glomeruli from this water hammer effect of the pounding of blood pressure.

For these people, getting their blood pressure down to 125 or 130 is not all they need. They need lower blood pressures than those to truly protect the glomeruli that are left. We are going to be looking at that and continuing to explore the possibility of differentiating on that basis as we get into this chronic kidney disease space. It is not our primary objective per se, because we are going after hypertension broadly. We are now, since we have proven that it is a highly safe and effective drug for uncontrolled and resistant hypertension, starting to go to the very high unmet need subpopulations, which right now we consider to be hypertensive form of nephropathy and OSA.

Jon Congleton (CEO)

Rami, just to add to that, the distinctions between the studies, I think the baseline systolic BP in that study was below what is our inclusion criteria. To Dave's point, we really are recruiting those subjects with low eGFR and hypertension. I think that does create a distinct population between the two studies.

Rami Katkhuda (Analyst)

Got it. That makes a lot of sense. Thank you.

Operator (participant)

There are no further questions at this time. I would hand over the call to Jon Congleton for closing remarks. Please go ahead.

Jon Congleton (CEO)

Yeah. Thank you, operator. Mineralys Therapeutics, we're committed to improving the lives of patients with cardiorenal metabolic diseases. Uncontrolled and resistant hypertension are significant unmet medical needs impacting more than 20 million patients in the U.S. alone. Our Launch-HTN and Advance-HTN studies reinforce the differentiated clinical profile of lorundrostat versus agents that are typically used in the third and fourth-line treatment positions, and the quantitative research that we've done supports the commercial potential. We're excited for key upcoming milestones and look forward to sharing updates with you in the coming quarters. Thank you all. Thank you for joining us today. With that, we'll close the call. Have a good day, everyone.

Operator (participant)

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