Q4 2024 Mineralys Therapeutics Inc Earnings Call
Thank you. Thank you.
Speaker Change: Good morning, ladies and gentlemen, and welcome to the Mineralis fourth quarter and fourth year 2024 earnings conference call. At this time, all lines are in a listen-only mode.
Speaker Change: Following the presentation, we will conduct a question and answer session, and if at any time during this call you require immediate assistance, please press star 0 for the operator. Also note that this call is being recorded on Wednesday, February 12, 2025.
Speaker Change: and I would like to turn the conference over to Dan Ferry of Lifesci Advisors. Please go ahead, sir.
Thank you, Operator.
Speaker Change: I would like to welcome everyone joining us today for our fourth quarter and full year 2024 conference call.
Speaker Change: Earlier this morning we issued a press release providing our fourth quarter and full year 2024 financial results and business updates.
Speaker Change: A replay of today's call will be available on the Investor section of our website approximately one hour after its completion.
Speaker Change: After our prepared remarks, we will open up the call for Q&A.
Speaker Change: Before we begin I would like to remind everyone that this conference call and webcast will contain forward-looking statements about the company.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: Please note that these forward-looking statements reflect our opinions only as of today, February 12.
2025, except as required by law.
Speaker Change: We specifically disclaim any obligation to update or revise these forward-looking statements in light of new information or future events.
Speaker Change: I would now like to turn the call over to Jon Congleton, Chief Executive Officer of Mineralis Therapeutics.
Thank you, Dan.
Speaker Change: Good morning everyone and welcome to our fourth quarter in full year 2024 financial results and corporate update conference call
Speaker Change: I'm joined today by Adam Levy, our Chief Financial Officer, and Dr. David Rodman, our Chief Medical Officer.
Speaker Change: I'll begin with an overview of the business, then Dave will discuss our clinical programs and recent milestones.
Speaker Change: Then Adam will review our fourth quarter financial results before we open up the call for your questions.
Speaker Change: And looking back over the past year, it was a tremendous period for the company. I'm very proud of the work our team has done in executing and supporting our clinical strategy of targeting dysregulated or elevated aldosterone in patients with uncontrolled and resistant hypertension.
Speaker Change: The data for ADVANCE-HTN will be available this coming March, and LAUNCH-HTN will be available mid-first half of this year.
Speaker Change: We also have our exploratory programs evaluating laryngostatin, hypertension and chronic kidney disease, as well as hypertension and obstructive sleep apnea.
Speaker Change: Our purpose at Mineralis is to create more healthy days for people dealing with cardiorenal metabolic disorders. And the trial readouts we have this year will evaluate the potential of Lorander's SAT to deliver on that promise.
Speaker Change: The first of the two ongoing pivotal trials is the ADVANCE-HTN trial that is evaluating the efficacy and safety of lorandastat for the treatment of uncontrolled or resistant hypertension when used as an add-on therapy to a standardized background treatment of two or three antihypertensive medications.
Speaker Change: The trial enrolled 285 subjects and the rigor of the standardized American Heart Association recommended background regimen was designed to ensure only subjects who were enrolled had confirmed uncontrolled or confirmed resistant hypertension.
Speaker Change: As noted, we anticipate announcing the top-line data for this trial next month.
Speaker Change: The second pivotal trial is LAUNCH-HTN, with 1,083 subjects enrolled, and is designed to be confirmatory to our TARGET-HTN proof-of-concept trial.
Speaker Change: The objective is to evaluate the benefit-risk of larundrostat in a real-world setting when added to a subject's previously prescribed regimen of two to five antihypertensive medications, one of which must be a diuretic.
Speaker Change: As previously guided, we anticipate top-line data in the mid-first half of this year.
Speaker Change: Upon completion of the treatment phase in the ADVANCE-HTN and LAUNCH-HTN trials, participating subjects were offered the opportunity to enter the TRANSFORM-HTN Open Label Extension Trial.
Speaker Change: As we await the announcement of these pivotal top-line data, I invite everyone to revisit the KOL event we held last quarter. An archived webcast is available on the Investor Relations section of our website.
Speaker Change: This discussion focused on the unmet medical need and uncontrolled and resistant hypertension.
Speaker Change: The long-term impact of uncontrolled blood pressure and insights into the treatment of hypertension from these leaders in cardiovascular medicine.
Speaker Change: In addition, during the event, the KOLs gave their perspectives on our highly selective aldosterone synthase inhibitor, lorandristat, as a new therapy and its potential to change the current treatment paradigm.
Speaker Change: To provide more color on our clinical pipeline and recent milestones, I will now turn the
Speaker Change: Thank you, Jon, and good morning, everybody. Picking up from where Jon just left off, discussing the KOL event we just had last quarter, I agree that there were a lot of great topics discussed.
Speaker Change: The clinicians did an excellent job of highlighting the need for innovation. And there was agreement that targeting aldosterone would address an important gap in the current antihypertensive armamentarium.
Speaker Change: They also agreed that a confirmation of the favorable safety and blood pressure reduction of eight to 10 millimeters of mercury we saw in the TARGET-HTN trial would be transformative for patients.
Speaker Change: Over the next few months, we look forward to sharing the data with you for Laryngostat from both the Advanced HTN Trial and Launch HTN Trials. We are excited about the potential of Laryngostat to demonstrate a meaningful benefit
in patients with uncontrolled or resistant hypertension.
Speaker Change: I would like to echo Jon's appreciation for the work of the Mineralis team, as well as the investigators and patients in both trials, to advance the hypertension development plan.
and Adam Levy. Thank you. Thank you.
Speaker Change: We recently had some exciting news around the rest of our clinical program, including the EXPLORE-CKD and EXPLORE-OSA Phase II proof-of-concept trials.
Speaker Change: Both of these trials are designed to provide data that augments the antihypertensive profile of laryngostat while also providing insight into the potential benefit in reducing overall cardiovascular risk.
Speaker Change: Last week we announced that enrollment was completed in the EXPLORE-CKD Phase 2 trial.
Speaker Change: This trial is evaluating the efficacy and safety of lorander stat.
Speaker Change: for the treatment of hypertension in subjects with an EGFR as low as 30 and albuminuria, despite having received stable treatment with an ACE inhibitor or an ARB, as well as an SGLT2 inhibitor.
Speaker Change: Hypertension and associated hypertensive nephropathy is a leading cause of kidney damage alone and in combination with other obesity-associated comorbidities.
Speaker Change: This is another area with great unmet medical need, where aldosterone synthase inhibition with lorandastat has the potential for transformative benefit to patients.
Speaker Change: We look forward to announcing top-line data from the trial in the second quarter of 2025.
Speaker Change: During the night, blood pressure increases significantly during each hypoxic episode.
Speaker Change: This leads to resistant nocturnal hypertension that is underdiagnosed and lacks a specific therapy. We are using a novel approach in this trial to measure blood pressure continuously with each heartbeat during sleep.
Speaker Change: In addition, we anticipate that dosing laryngostatic bedtime will maximize aldosterone suppression during the period that it is being driven by hypoxia.
Speaker Change: while still providing daytime blood pressure control and the favorable safety profile achieved with once-daily dosing of lorandastat.
Speaker Change: It is estimated that 60-85% of patients with OSA have resistant hypertension.
Speaker Change: Establishing the benefit-risk of lorandristat in treating these patients could lead to the development of lorandristat as a unique small molecule treatment for the adverse respiratory and cardiovascular manifestations of obstructive sleep apnea.
Speaker Change: We are very excited about our programs that are designed to evaluate the value of the Runderskat and the associated milestones expected in the first half of this year.
Speaker Change: I will now turn the call over to Adam to review our financial results for the quarter and the full year.
Adam Levy: Thank you, Dave. Good morning, everyone. Today I will discuss select portions of our fourth quarter 2024 financial results.
Adam Levy: Additional details can be found in our Form 10-K, which will be filed with the SEC today, February 12th.
Adam Levy: We ended the quarter with cash, cash equivalents, and investments of $198.2 million dollars as of December 31st, 2024, compared to $239 million dollars as of December 31st, 2024.
Adam Levy: We believe that our current cash, cash equivalents, and investments will be sufficient to fund our planned clinical studies, as well as support corporate operations through the first quarter of 2026.
Adam Levy: R&D expenses for the year ended December 31st, 2024 were $168.6 million compared to $70.4 million for the year ended December 31st, 2023.
Adam Levy: R&D expenses for the quarter ended December 31st, 2024 were $44.6 million compared to $23.7 million for the quarter ended December 31st, 2023.
Adam Levy: The annual increase in R&D expenses was primarily due to increases of $88.7 million in preclinical and clinical costs.
Adam Levy: Driven by the initiation of the Runderstad Pivotal Program in the second quarter of 2023, $10.6 million in clinical supply, manufacturing, and regulatory costs.
Adam Levy: $7 million in higher compensation expense resulting from additions to headcount, increases in salaries and accrued bonuses, and increased stack-based compensation, and $0.9 million in other research and development expenses.
Adam Levy: Partially offset by a decrease of $9 million in licensing fees associated with development milestone payments in 2023 that did not recur in 2024.
Adam Levy: G&A expenses were $23.8 million for the year ended December 31st, 2024, compared to $14.3 million for the year ended December 31st, 2023.
Adam Levy: G&A expenses were $7.2 million for the quarter-end of December 31, 2024, compared to $4 million for the quarter-end of December 31, 2023.
Adam Levy: The annual increase in G&A expenses was primarily due to $6.6 million in higher compensation expense resulting from additions to headcount.
increases in salaries and accrued bonuses and increased stock-based compensation
Adam Levy: $2.6 million in higher professional fees and $0.3 million in higher other administrative expenses.
Adam Levy: Total other income net was $14.6 million for the year ended December 31st, 2024, compared to $12.8 million for the year ended December 31st, 2023.
Adam Levy: Total other income net was $2.8 million for the quarter end of December 31st, 2024 compared to $3.3 million for the quarter end of December 31st, 2023.
Adam Levy: The annual increase was primarily attributable to increased interest earned on the company's investments in money market funds in U.S. Treasuries.
Adam Levy: Net loss was $177.8 million for the year ended December 31, 2024, compared to $71.9 million for the year ended December 31, 2020.
Adam Levy: Net loss was $48.9 million for the quarter ended December 31, 2020.
Adam Levy: compared to $24.4 million for the quarter ended December 31, 2023. The increase was primarily attributable to the factors I described earlier. With that, I will ask the operator to open the call for questions. Operator?
Thank you, sir.
Speaker Change: Ladies and gentlemen, if you do have any questions at this time, please press star followed by one on your touchtone phone. You should then hear a prompt that your hand has been raised.
Speaker Change: And should you wish to decline from the polling process, please press star followed by 2. If you are using a microphone, you will need to lift a handset first before pressing any keys. Please go ahead and press star 1 now if you do have any questions.
Speaker Change: First, we will hear from Michael DeFiori at Abicor ISI. Please go ahead, Michael.
Michael DeFiori: Hey guys, thanks so much for taking my questions and congrats on all the products, the progress. A couple from me, I guess a hypertension question. In the phase 2 target trial, when the QC analysis was performed on the 50 mg QD group,
Michael DeFiori: You know, you took out two additional patients that had improbable readings.
Michael DeFiori: leaving 12 valuable patients that were truly hypertension's. This seems like a very small N to extrapolate to the larger pivotal study. So I guess my question, my first question is what gives you confidence that the SVP reduction seen in this
Michael DeFiori: 12 patients and these 12 patients can be extrapolated to phase 3 and then I have two follow-ups.
Yeah, Mike, thanks for the call. I appreciate it.
Speaker Change: From our standpoint as we looked at both the in-office measurement as well as the 24-hour ambulatory and as you noted
Speaker Change: When we looked at the 24-hour ambulatory, we had some subjects that actually had baseline blood pressure below goal, and so that confounded the findings a bit, but as we looked at...
Speaker Change: The totality of the evidence for the 50 QD, the 100 QD, even the 25 BID.
Speaker Change: We looked at the individual exposure response. We got very comfortable that the 50 mg QD
Speaker Change: provided what we believe is the ideal benefit-risk as far as reduction of blood pressure, as well as benefit from a safety-tolerability standpoint. So, obviously, as we moved the 50 milligram into the pivotal program, it showed our confidence in that dose to provide 24-hour blood pressure control.
Speaker Change: Got it, very helpful. And then just two follows from me, one on the OSA trial, one on the CKD trial. For the OSA trial, will improvement in the apnea hypopnea index after four weeks be
Speaker Change: primarily due to fluid volume reduction or would non-genomic anti-fibrotic effects equally contribute over that time period.
Speaker Change: And my final question is for the CKD trial, for the SGLT2 naive patients who start their SGLT2 for the first time in the trial, to what extent may that confound SBP and or EGFR changes? Thank you.
and Adam Levy.
Dave Rodman: Okay, why don't I take that one. This is Dave Rodman. Thanks for the call, for the questions. And so I'm gonna take the...
Dave Rodman: Your first of those two questions, which was an OSA question.
Dave Rodman: And, oh wait a minute, did you want me to do, yeah, so the OSA question.
Dave Rodman: and your question there was about the apnea-hypopnea index and what the mechanism is.
Dave Rodman: As you know, first of all, in two small trials with both spironolactone and a plurinone,
Dave Rodman: The apnea hypopnea index was reduced on a pretty short-term study like
Dave Rodman: We anticipate being at least as good as that with our mechanism and it may be mediated by both.
The decrease in MR activation...
Dave Rodman: and non-genomic effects. But when we look at the mechanism with MR,
Dave Rodman: It's volume shifts. In other words, there's something called rostrocodal redistribution of fluid. These patients will have edema in their legs.
Dave Rodman: When they lay down, that fluid will redistribute horizontally and caudally towards the head. And their neck, which is already obstructed usually with fat tissue, will then become even more obstructed.
Dave Rodman: So, you're right. That mechanism's volume and the combination of a diuretic...
plus larunderstat should dramatically decrease that effect.
Now, you asked about non-genomic effects.
Thank you. Thank you.
Dave Rodman: The answer there is yes, but not fibrosis, it's inflammation most likely. So if there is a contribution, it will be related to the genomic effects on inflammation but also the effects on oxygen radical production in small vessels, which is non-genomic.
Does that answer that question?
Yes, it does. Thank you.
Now, SGLT2 inhibitor.
Dave Rodman: We know that SGLT2 inhibitors in combination with an ASI do have some theoretical and practical advantages.
Dave Rodman: I would say one of them is those are modest antihypertensive drugs and it's possible that there will be some additivity between the two mechanisms.
Dave Rodman: In addition, there is some loss of potassium that you have with the SGLT2 inhibitor.
Dave Rodman: The three-week, the run-in period in this trial is sufficiently long for most of those effects to already be manifest by the time that we start the drug. In addition, it's a crossover study where the...
Dave Rodman: In the first period, the placebo people will have that same effect. So it's built in that we can assess exactly the effect that you are discussing, know what it is, and have a sensitivity analysis to address that possibility.
Very helpful. Thank you
Rich Law: Thanks, bye. Thank you. Next question will be from Rich Law at Goldman Sachs. Please go ahead, Rich.
Rich Law: Hey guys, good morning. A couple of questions for me. Given your guidance for advance and launch readout timelines overlap with each other, is there more refined guidance now on your base case of when each of those will be presented first? Can we assume that advance will go first before launch, or is there a chance that both can go together? And then I'll follow up with that.
Rich Law: Yeah, Rich, thanks for the question. As we noted in our opening remarks, we're continuing to guide Advanced HTN for March and Launch HTN for mid-first half of this year.
Rich Law: Okay, got it. And then for advanced, I know you potentially could present at twice, one for like a top-line webinar, and one at ACC. Do you see something similar for launch?
Rich Law: Yeah, we're certainly excited about the acceptance of the late-breaking abstract for Runderstad and the advanced HTN trial at the upcoming ACC meeting.
Rich Law: Depending upon when we get the top line results, we'll either do a corporate announcement in conjunction with that, or if we have the results sooner than that, we would anticipate doing a corporate top line announcement.
Rich Law: As to launch, I think it's too early to opine on what the communications would look like with that trial.
Speaker Change: And then one final question. So the advanced trial actively tracks and enforces adherence of the treatment.
Speaker Change: and then are patients required not to do certain activities while wearing the device, like exercise or stuff like that.
Yeah, Rick, yeah, thanks. We...
Dave Rodman: how to use that device, how to teach and train sites and subjects on proper technique with that. We do allow subjects when they either exercise or bathe to have breaks from that. There are compliance...
or QC requirements with the 24-hour ambulatory
Dave Rodman: You know, I think it's roughly 70 measurements over a 24-hour period. So, we're very confident that we have sites and subjects well-trained for that and the experience that our team has in working with that device.
Thank you. Thank you.
Dave Rodman: gives us high comfort in the data and the quality of the data that we're going to get from that. And that's why we chose 24-hour ambulatory, which, as you know, is the gold standard.
Dave Rodman: And in a trial as rigorous as ADVANCE H-10 where we
Dave Rodman: are optimizing treatment, optimizing dose, optimizing compliance, using the gold standard, really gives us, I think, a high quality data set, particularly relative to what's been done with new innovations in this space and what's being done with other ASIs.
Dave
Rich Law: Hey Rich, that's a great question. It's key to have as much good data from the primary as you can.
You'll never have it perfect with ABPM.
Rich Law: But we went through the QC and the procedures as a root cause for losing data in the first trial and we identified several ways to improve retention of informative data from those studies.
Rich Law: We did lots of work on statistics, and we're confident that we're going to have more than adequate, good quality data to have the power that we imputed when we designed the size of the trial.
Thank you.
Speaker Change: Great and then just to follow up on that is there any what's a plan for like any missing data if patients take off the device and then for like say a couple hours and then what's a plan for that?
Speaker Change: Rich, that was part of the root cause analysis. We've got that built into the algorithms. We went over it with the FDA. They approve it.
Okay, thank you so much.
Thanks, Rich.
Speaker Change: Next question will be from Charlie Yang at Bank of America. Please go ahead, Charlie.
Speaker Change: Hi, this is Alice. I'm for Charlie. Thank you for taking our question.
Speaker Change: So just on the upcoming Pivotal readouts, what are your latest expectations around safety and tolerability? Where do you hope to differentiate most versus typical MRAs?
Speaker Change: and even if efficacy were to be slightly less than MRAs for example, wouldn't a cleaner drug still be a commercial winner? Thank you.
Speaker Change: Yeah, thanks for the question. I think it's important to continue to distinguish the aldosterone synthase inhibitor class from the mineralocorticoid receptor antagonist.
Speaker Change: The MRAs block the effect of aldosterone at one of the biological pathways that aldosterone affects, and that's the mineral corticoid receptor. Aldosterone synthase inhibitors, however, go to the root cause of the problem and actually reduce the amount of plasma aldosterone.
The benefit of that is not only
Speaker Change: how aldosterone can be, its effects mitigated at the mineral corticoid receptor, but also at other pathways such as GPR30 that affects fibrosis, inflammation, and oxidative stress. So, as such, the adverse events that are attributable, particularly for spironolactone,
Speaker Change: on blockade of BMR such as the androgenic effects such as gynecomastia and fertility issues with women are something we don't see with this class of drugs.
I think it's also...
Speaker Change: It's fairly well accepted that the mineralocorticoid receptor antagonists seem to have a compromised tradeoff that as you push dose to get to efficacy, you invariably see a push in hyperkalemia.
Speaker Change: From our perspective, we think there's a more modest impact on potassium with an aldosterone synthase inhibitor. It's something that was exhibited in Target HTN. And so we'll continue to evaluate that in the PIDL program, but we believe that is the key distinguishing factor relative to the.
I'll have Dave at a thought as well.
Dave Rodman: Yeah, so obviously everyone thinks about this a lot. I want to point out something about just the trial designs. When you say, how are we going to compare to, say, MRA?
Dave Rodman: As far as I know, no one's ever done a trial like our ADVANCE trial as rigorously to deliver the data we're going to have with ADVANCE. In other words, we're looking at confirmed you failed on two or three drugs at maximum doses.
Dave Rodman: You took the drug, and then we used 24-hour ambulatory to prove it.
So, there is no benchmark.
Dave Rodman: The launch trial is the closest thing to a benchmark. And so what I encourage you to do is look at these trials as they stand alone. These will be, especially the advanced trial, but also launch, definitive.
Dave Rodman: establishment of the point estimate for how good these drugs are.
Thank you.
Thank you.
Next will be Annabelle Sammy at CIFO. Please go ahead.
Annabelle Sammy: Hi all, thanks for taking my questions. Just to put things in perspective, again, can you remind us
Annabelle Sammy: what coverage payers could give you if you hit in specific ranges like
Annabelle Sammy: you know, 7 to 9, 8 to 10, over 10, you know, as you did, you know, just in various subpopulations. So, can you help us frame how payers are going to look at the different responses and where they can position you within the treatment paradigm? And then I have a follow-up.
Speaker Change: Yeah, Annabelle, thanks for the call. We have, to date, completed four
Speaker Change: separate payer research projects in the United States and feel very bullish about our ability to get access for LaRunderstat.
Speaker Change: and particularly in our targeted approach. We have basically put forward a base case of an 8-10 mm mercury improvement.
Speaker Change: that's well-tolerated, and typically, fourth line, we think that's a space we can own. So in that resistant population, particularly as Dave highlighted with the prior answer, with advanced HTN, frankly, being one of the most rigorous, if not most rigorous study ever done.
Speaker Change: That kind of data set, we believe, based on the research gives us an opportunity to really own the resistant hypertension space.
Speaker Change: And then as we look at third line, and this is what we put in front of payers as well, when we bring forward a patient type or an endopheno type of responder, such as those with a BMI over 30.
Speaker Change: So that more targeted approach, that is viewed favorably by payers as well, with that 8-10mm mercury improvement. Now all of this, obviously, Annabelle is going to be based on.
Speaker Change: Also, the pricing and the rebate strategy within that, but just that clinical profile has resonated with the payers in that resistant population and targeted third line.
Speaker Change: Okay and then I guess can you remind us the proportion of the population that are you know truly
the third, fourth line population, how does...
Each of those different
Speaker Change: I guess, how does that positioning change your opportunity within the different populations that you have? Yeah, it's, I think the resistant population, so those failing on three or more with the diuretic is a little bit more easy to...
Speaker Change: quantify. It's typically seen as about 10 to 15 percent of the treated population, so roughly seven and a half to ten million subjects are in that resistant hypertension category.
Speaker Change: Those that would be third line so failing on two or more is a little bit difficult to triangulate to with the data But ballpark we view that population is about 10 million as well. So collectively
Speaker Change: between those that are failing on two or those are failing on three or more. It's roughly, you know, 15 to 20 million, I would say, as an addressable market.
Annabelle Sammy: Okay, great. All right. Thank you. That was great. Helpful. Thanks, Annabelle.
Thank you for joining us.
Speaker Change: Next question will be from Seamus Fernandez at Guggenheim. Please go ahead.
Speaker Change: Hi, it's Colleen on for Seamus. Thanks for taking our question. Could you just talk a little bit of where you view the threshold for hyperkalemia rates in advance and launch and what needs to be shown there to be differentiated in the clinic? And then just how would you expect the addition of diuretics required in every patient to impact the rates versus what we saw on target?
Yeah, thanks Colleen. We've done a, as I said a
and Adam Levy. Thank you for joining us.
Speaker Change: A significant amount of payer research. We've also done a significant amount of physician research over the last several years. 5% or less is what we've always tested as a rate of hyperkalemia as part of a base case. And I think that's viewed as favorable by the physicians that we've done the research with.
Speaker Change: As you may recall, we saw about a 3.6% rate in target HTN.
Speaker Change: To your point, there is a belief that the use of a diuretic can be potassium-wasting, so could offset the modest rise that we know we see with aldosterone synthase inhibitors.
Speaker Change: We saw that with lorandostats, saw that with baxterostat, and on par with what you typically see with an ACE inhibitor.
Speaker Change: or an ARB that have been used safely for decades at this point.
Speaker Change: So I think that will be an interesting addition to the pivotal program where all subjects in both studies are on a diuretic.
Dave Rodman: And in Target HTN, when we saw that modest impact, only half of the subjects were on a diuretic because it wasn't required per protocol. Let me have Dave add a comment on top of that, Colleen. Yeah, I'm gonna give you a clinician perspective. And we hear this all the time.
Speaker Change: This is about benefit-risk. The FDA has told us that. It's not p-values, it's nothing.
What that means for us is that
Speaker Change: We are looking at both. When you asked about the thiazides, they lower potassium.
Speaker Change: Ensuring that people are taking their thiazides improves benefit-risk both by increasing the response and decreasing the potassium.
Speaker Change: So think about it that way, it's benefit-risk. For the worst patients, the ones with CKD, the clinicians uniformly say we have great potassium binders, what we don't have are great antihypertensives.
Speaker Change: And so they're willing to tolerate almost any level of hyperkalemia and just treat it to get the maximum blood pressure response to laryngostat is the feedback we get.
Great, thank you.
Speaker Change: Thank you. Next question will be from Mohit Bansal at Wells Fargo. Please go ahead.
Mohit Bansal: Thank you very much for taking my questions. So, I have a couple of questions, so I'll start with first.
Speaker Change: Do you think we'll see meaningful differences in the SIBO adjusted results in terms of ABPM versus AOBP?
Speaker Change: And then, like, how do you think this, like, whatever a office reader reading is for from advanced HTN could read to launch HTN, where office reading is the primary endpoint? And I have one follow-up.
Mohit Bansal: Hey Mohit, I got your first question, can you repeat your second one though? I'm sorry, there was a little bit of a break up in the line.
Mohit Bansal: Sorry about that. So, so what I'm saying is that so, so
Mohit Bansal: From Advanced HTN, whatever you see in Office Blood Pressure Reduction, how much you could read that for or what is the read across for Launch HTN, because Launch HTN has AOBP as the primary endpoint.
Thank you. Thank you.
Yeah, okay. Thank you for clarifying that.
Mohit Bansal: What we saw in target HTN was about a four millimeter mercury change in the in-office measurement
Mohit Bansal: and in the 24-hour ambulatory, about a 1-2 mm mercury placebo change. So fairly tight concordance. I think it's a tribute to the team, the work they did to align to the AHA recommended best practices in measuring blood pressure. We've applied those same techniques.
Mohit Bansal: For an office measurement for both advance as well as launch I'd hate to opine on you know, are we going to see a replication of that? What's the read-through from advance to launch?
Mohit Bansal: They're different studies, but it's the same technology, the same technique, the training that we've done with the sites.
Mohit Bansal: So it's difficult to, you know, project what it could be. I just think the team has made the right choices as far as technology and technique that was validated in Target HTN, and that's what we're applying in advance and launch.
Speaker Change: No, fair enough, that's helpful. And then the second part is that how are you thinking about the nighttime coverage with Loranda Strat? The reason I'm asking is because half-life is shorter here. So do you think timing of the dose could impact the ABPM measure more than the AOBP here?
Speaker Change: I'll have Dave give a comment to this. I think it's important to reiterate that we think the 10-12 hour half-life of La Runderset is actually ideal for, as Dave articulated earlier, the benefit-risk.
of an ASI in the treatment of hypertension.
Speaker Change: I'll reiterate that in Target HTN where we saw that 8-10 mm mercury drop in an in-office measurement, that blood pressure measurement was in the morning at trough before that day's dose.
So we have strong confidence in the 24-hour coverage.
of La Runderstad with that 10- to 12-hour half-life.
Speaker Change: We also think it provides the ideal mix of efficacy and safety, particularly the on-target component, which is potassium and sodium, but Dave, do you want to add some thoughts on top of that? Well, I can just add a little bit. As Jon said… Thank you.
Speaker Change: We know from Novartis, and I was there, that a four-hour half-life isn't long enough.
Speaker Change: We also believe that leaving a window that recapitulates normal circadian rhythm, when Aldo does go up pre-arousal,
Speaker Change: is the best way to try to treat it, restore the normal rhythm.
Speaker Change: We have a hundred percent by our healthy volunteer studies suppression of aldo with our drug We can adjust how long that hundred percent lasts
Speaker Change: And so just to reiterate that last point for Jon, we tuned that so that it's 100% for until you go to sleep, essentially, and then it slowly comes up to only 30% of pretreatment baseline.
Speaker Change: which is 70% suppression and then goes back down to zero again after the morning dose. We just think that's...
Speaker Change: science based on what we know about circadian rhythm, and it's the most appropriate way to treat this disorder.
Speaker Change: Awesome. Thank you very much for this. Appreciate it. Thanks, Pavel.
Speaker Change: Next question will be from Rami Katkata at Lifesci Capital. Please go ahead.
and Adam Levy.
Adam Levy: Good morning, guys. Thanks for taking my questions. Maybe going off of the previous one, do you expect a delta in the treatment effect observed with lorandastat in the pivotal studies, just given the slight difference between trials and the fact that patients in advance are potentially enriched with aldosterone-driven hypertension? Then I have a follow-up.
Speaker Change: Yeah, Rami, thanks for the question. I think it's it's hard to predict, you know, the response in advance, the response in launch, and a differential. There are different studies as you
Speaker Change: I heard Dave articulate. I think the interesting aspect of ADVANCE is that we have a truly
Speaker Change: confirmed uncontrolled or resistant hypertension population. On the one hand, that may be a more rigorous, challenging population to treat. On the other, it may be somewhat enriched for an aldosterone-dependent form of hypertension.
Speaker Change: Launch is largely confirmatory to what we saw, or what we designed in Target HTN.
Speaker Change: with the exception of all subjects in LAUNCH are going to be on the diuretic and we know there was...
Speaker Change: A favorable synergy as far as more enhanced response there, so it's difficult to, you know, predict.
Speaker Change: You know across these two trails, we're just excited about the
Speaker Change: The design of these two, I think they address key aspects of the market. Advanced being as rigorous as it is, is really built for the specialists that are dealing with the difficult-to-treat patients.
Speaker Change: It's also the kind of study that gets us the opportunity to be included in hypertension guidelines and then launches the real-world setting of what the primary care physicians are going to be doing with LaRunderStats should we be able to bring it into the marketplace.
Speaker Change: Got it. Makes sense. And then a recent paper detailed that BI's aldosterone synthase inhibitor has a half-life of four to six hours, which is lower than what we've seen with laryngostat and Baxterstat. I guess, does this affect how you view their CKD data at all and laryngostat's, I guess, overall positioning in that population?
and Adam Levy. Thank you.
Speaker Change: Well, that's a very good question, and it is reminiscent of what happened with LCI-699 oselidrostat, which is pretty much the same half-life.
Speaker Change: And if you read the papers that were written, it was recommended that a longer half-life would be required to develop a massively efficacious dose. We agree with that. We are targeting in CKD.
Speaker Change: Not enough control with their blood pressure, which is damaging their glomeruli, scarring them every day and driving
Speaker Change: the deterioration in EGFR. If you don't treat that adequately, get it down to gold.
Speaker Change: You will continue to have progression of the CKD. So at least with our drug, with our tunable suppression in that disease...
and you'll remember we're testing 25 milligrams.
Speaker Change: and the other is that we have a lot of people who are interested in the real world. We have an optimum way to do that. I don't want to comment on somebody else's drug in their program. They probably know more than I do, but we like our approach.
Speaker Change: We also like the fact that we can add it on to an SGLT2 of choice, which we think may also be an advantage when you're mainly going after the hypertension and not using the combination for the metabolic syndrome component mainly.
Thanks so much. Thanks for having me.
Speaker Change: Attendee, Daniel Ferry, David Rodman, Adam Levy, Jon Congleton, Adam Levy, Jon Congleton,
Speaker Change: Next question will be from Matthew Caulfield at HC Wainwright. Please go ahead.
Matthew Caulfield: Hi, thank you. Good morning, guys, and thanks for the updates this morning. So, kind of changing gears, considering obstructive sleep apnea, can you speak a bit more to the mechanism expectations for ASI benefit for those patients, and then any read-through from the current pivotal developments? Thanks again.
So, so let me, um.
Speaker Change: address that in two ways. So there are two potential benefits. At this stage, near term, we're focused on the fact that these patients have 60 to 85% resistant hypertension. And on top of that, it's not being diagnosed or treated because it's at night.
and so
Speaker Change: Our goal there is to look at the aldosterone-dependent mechanism, which is right in the sweet spot for our hypertension program. What happens in these people, and it's often men and only postmenopausal women, is what's driving the aldo is the hypoxia.
Speaker Change: Remember, we say 15 apneas per hour. Think about that. Every four minutes you're unable to move oxygen from your airway down into your lungs. Your body responds to that with a stress response that drives aldosterone.
Speaker Change: And so that's the mechanism for why they have such exceptionally high incidence of dying in their sleep, arrhythmias like ventricular and atrial arrhythmias, etc.
Speaker Change: Even though you're trying to go after the hypertension primarily, it's a better way to do it and still get that window.
In our opinion,
Now the
Speaker Change: OSAPs, the airway obstruction itself, well we know you can treat that with CPAP, it's not a...
Speaker Change: people love. And if you don't use it six hours a day, you get essentially almost no benefit on either blood pressure or survival. And so, again, by adding our drug in, and we're going to study it during a two-day period off.
Speaker Change: The CPAP, you will get potentially additive benefits from the fact of the mechanisms I told you occurred to you before, which is primarily fluid shift and secondarily probably some inflammation.
Very helpful. Thanks a lot, guys.
Thanks Matt.
Jon Congleton: And at this time, we have no other questions registered, so I would like to turn the call back over to Jon for closing remarks.
Jon Congleton: Thank you, operator. And thank you to everyone for joining us today. We're very excited about the progress we made in 2024 and thus far in 2025.
Jon Congleton: in advancing our clinical programs and we remain enthusiastic about the upcoming data milestones planned for the first half of 2025. We look forward to keeping you updated. With that, we will close the call.
Speaker Change: Thank you, sir. Ladies and gentlemen, this does indeed conclude your conference call for today. Once again, thank you for attending. And at this time, we do ask that you please disconnect your lines.