Q2 2024 Mineralys Therapeutics Inc Earnings Call
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Speaker Change: [inaudible]
Operator: David Rodman, Seamus Fernandez, Michael DiFiore, David Rodman, Seamus Fernandez, Michael DiFiore, Michael DiFiore, Welcome to the Mineralys Therapeutics second quarter 2024. At this time, I'll... Question and Answer Session. We'll follow the questions if anyone should require operators. Unknown Attendee, Michael DiFiore, Jin Law, Jack Padovano, Adam Levy, Jon Congleton, Colleen, As a reminder, this conference is being recorded. It is now my pleasure to introduce your Dan Ferry of Lifesci Advisors. Please go ahead. Thank you, Operator.
Speaker Change: Welcome to the Mineralis Therapeutics second quarter 2024 conference call.
Speaker Change: At this time, all participants are in a listen-only mode. A question and answer session will follow the presentation. If anyone should require operator assistance during the conference, please let us know. It is now my pleasure to introduce your host, Dan Ferry of LifeSci Advisors. Please go ahead, sir.
Dan Ferry: Thank you, operator. Good afternoon, everyone, and welcome to our second quarter 2024 conference call.
Dan Ferry: Good afternoon, everyone, and welcome to our second quarter 2024 conference call. After the close of market trading today, we should have a press release providing our second quarter 2024 financial results and business update. 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 the close of market trading today, we issued a press release providing our second quarter 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.
Dan Ferry: After our prepared remarks, we will open up the call for Q&A. Before we begin, I would like to remind everyone that this commentary call and webcast will contain forward-looking statements about the company. Unknown Attendee, Daniel Ferry, Jin Law, Jack Padovano, Adam Levy, Jin Law, Jack Padovano, Associated with the company.
Speaker Change: Before we begin, I would like to remind everyone that this comments 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 four 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.
Dan Ferry: These forward-looking statements are qualified by the cautionary statements contained in today's press release and in our SEC filings, including our annual report on Form 10-K and subsequent files. Please note that these forward-looking statements reflect our opinions only as of today, August 13. 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.
Speaker Change: Please note that these forward-looking statements reflect our opinions only as of today, August 13.
Speaker Change: Acceptance required by law, we specifically disclaim any obligation to update or revise these forward-linking statements in light of new information or future events.
Speaker Change: I would now like to turn the call over to John Congleton, Chief Executive Officer of Mineralis Therapeutics. John.
John Congleton: Thank you, Dan. Good afternoon, everyone. Welcome to our second quarter 2024 financial results and corporate update conference call.
Jon Congleton: Thank you, Dan. Good afternoon, everyone. Welcome to our second quarter 2024 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, our clinical programs, and recent milestones, followed by Adam, who will review our second quarter financial results before we open up the call to your questions. Let me start out by saying that during the first half of the year, we made tremendous progress advancing the development program for our lead asset, Marunderstat.
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, our clinical programs, and recent milestones.
Speaker Change: followed by Adam who will review our second quarter financial results before we open up the call for your questions.
Speaker Change: Let me start out by saying that during the first half of the year, we made tremendous progress advancing the development program for our lead asset, Marunderstat.
Adam Levy: Specifically, we've been steadily moving towards several key milestones for our registration program in hypertension, which is comprised of two pivotal clinical trials titled ADVANCE H10 and LAUNCH H10.
Jon Congleton: Specifically, we've been steadily moving towards several key milestones for our registration program in hypertension, which is comprised of two pivotal clinical trials titled ADVANCE-H10 and LAUNCH-H10, an open-label extension trial called TRANSFORM-HTN to capture long-term safety and efficacy data, and the proof-of-concept trial EXPLORE-CKD, evaluated in LARUNDERSTAT in As noted previously, this is an extremely rigorous hypertension trial designed to demonstrate the value of lorandostat when added to standardized, optimized American Heart Association guideline treatment.
Adam Levy: An open-label extension trial called TRANSFORM-HTN to capture long-term safety and efficacy data. And the proof-of-concept trial EXPLORE-CKD, evaluated in LARUNDERSTAT in hypertensive CKD subjects.
Adam Levy: Enrollment continues to progress in the ADVANCE-HJN trial. As noted previously, this is an extremely rigorous hypertension trial designed to demonstrate the value of lorandostat when added to standardized, optimized American Heart Association guideline treatment.
Speaker Change: While we typically do not provide enrollment updates for our clinical trials, we are approximately 90% enrolled in Advanced HTN, and our projections place top-line data readout in the first quarter of 2025.
Jon Congleton: While we typically do not provide enrollment updates for our clinical trials, we are approximately 90% enrolled in Advanced HTN, and our projections place top-line data readout in the first quarter of 2025. While we're disappointed with the change in top-line data timing, we remain laser focused on executing the best-in-class trial and ensuring a high-quality data readout. We continue to work with our partners at the Cleveland Clinic to ensure we deliver the most robust data set possible.
Speaker Change: While we're disappointed with the change in top-line data timing, we remain laser-focused on executing the best-in-class trial and ensuring a high-quality data readout. We continue to work with our partners at the Cleveland Clinic to ensure we deliver the most robust dataset possible.
Speaker Change: In addition, we recently met with the FDA and aligned on maintaining the original primary endpoint of the ADVANCE-HTN trial, given that we have already accumulated or accrued substantial trial data.
Jon Congleton: In addition, we recently met with the FDA and agreed to maintain the original primary endpoint of the ADVANCE-HTN trial, given that we have already accumulated or accrued substantial trial data. As such, we will maintain the original 12-week time point of change in 24-hour ambulatory systolic blood pressure from baseline for active cohorts versus placebo. We will still collect and analyze all relevant efficacy measures at the 4-week and 12-week time points, so this does not impact the timing of data readout for Advanced HTN. The planned analysis of the Advanced HTN Trowel includes several important subset analyses.
Speaker Change: As such, we will maintain the original 12-week time point of change in 24-hour ambulatory systolic blood pressure from baseline for active cohorts versus placebo.
Speaker Change: We will still collect and analyze all relevant efficacy measures at the 4-week and 12-week time points.
Speaker Change: This does not impact the timing of the data readout for Advanced HTN.
Speaker Change: The planned analysis of Advanced HTN Trowel includes several important subset analysis.
Speaker Change: Subjects with uncontrolled hypertension, those on baseline regimen of two antihypertensives, and resistant hypertension on three baseline antihypertensive treatments were separately randomized, allowing us to perform a formal test in each population.
Jon Congleton: Subjects with uncontrolled hypertension, those on a baseline regimen of two antihypertensives, and resistant hypertension on three baseline antihypertensive treatments were separately randomized, allowing us to perform a formal test in each population. This will provide optionality and independent support for each population. We believe that demonstrating efficacy in confirmed resistant hypertension, the area of highest unmet medical need, will be important in positioning lorunnerset for individuals with presumed aldosterone-mediated hypertension, including obesity. We believe positioning lorandostat as an important option for obese individuals with increased cardiovascular risk due to resistant hypertension will be a straightforward message to prescribers, payers, and patients.
Speaker Change: This will provide optionality and independent support for each population.
Speaker Change: We believe that demonstrating efficacy in confirmed resistant hypertension, the area of highest unmet medical need, will be important in positioning larunerstat for individuals with presumed aldosterone-mediated hypertension, including obesity.
Speaker Change: We believe positioning lorandostat as an important option for obese individuals with increased cardiovascular risk due to resistant hypertension will be a straightforward message to prescribers, payers, and patients.
Speaker Change: In addition, as we accrue more experience and data with LORANDERSTAT, we plan to continue to explore other positive and negative predictive factors.
Jon Congleton: In addition, as we accrue more experience and data with larundrostat, we plan to continue to explore other positive and negative predictive factors using artificial intelligence to expand the precision toolkit for targeting larundrostat to individuals with uncontrolled and resistant hypertension who are likely to derive long-term clinical benefit. Moving to launch HTN, which is our second pivotal trial that was initiated in the fourth quarter of 2023. We are pleased to announce that enrollment in this trial is currently ahead of schedule, and we continue to expect top-line data to be available in the second half of 2025.
Speaker Change: using artificial intelligence to expand the precision toolkit for targeting lorandostat to individuals with uncontrolled and resistant hypertension who are likely to derive long-term clinical benefit.
Speaker Change: Moving to LAUNCH-H10, which is our second pivotal trial that was initiated in the fourth quarter of 2023. We are pleased to announce that enrollment in this trial is currently ahead of schedule and we continue to expect top-line data to be available in the second half of 2025.
Speaker Change: However, the time-to-data may accelerate and we will keep you informed as we move forward.
Jon Congleton: However, the time to data may accelerate, and we will keep you informed as we move forward. Launch HTN is a phase 3 trial of Lorunderstaff for the treatment of subjects with uncontrolled or resistant hypertension as add-on therapy who fail to achieve blood pressure control on their existing prescribed background treatment of 2 to 5 antihypertensive medications.
Speaker Change: Launch HTN is a phase 3 trial of Lorunderstaff for the treatment of subjects with uncontrolled or resistant hypertension as add-on therapy who fail to achieve blood pressure control on their existing prescribed background treatment of 2 to 5 antihypertensive medications.
Speaker Change: Launch HTN will enroll up to approximately 1,000 adult subjects, is designed with the objective of evaluating runnerset in a real-world setting when added to a subject's previously prescribed antihypertension regimen.
Jon Congleton: Launch HTNM will enroll up to approximately 1,000 adult subjects and is designed with the objective of evaluating the runner set in a real-world setting when added to a subject's previously prescribed antihypertension regimen. Subjects who fail to achieve blood pressure control on their prescribed background treatment during the run-in period will be randomized 1 to 2 to 1 to either placebo, once daily 50 mg of loranderstat, or once daily 50 mg of loranderstat with the option to titrate to 100 mg once daily as needed at week 6.
Speaker Change: Subjects who fail to achieve blood pressure control on their prescribed background treatment during the run-in period
Speaker Change: will be randomized 1-2-1 to either placebo, once daily 50mg of loranderacet, or once daily 50mg of loranderacet with the option to titrate to 100mg once daily as needed at week 6.
Speaker Change: The primary endpoint for this trial will be the change in systolic blood pressure as measured by automated office blood pressure. We believe this endpoint reflects real-world measurements that will be relevant to the primary care provider this trial targets.
Jon Congleton: The primary endpoint for this trial will be the change in systolic blood pressure as measured by automated office blood pressure. We believe this endpoint reflects real-world measurements that will be relevant to the primary care provider, the trial target. Subjects from these two trials will be offered the opportunity to roll over into the ongoing open-label extension trial called Transform HTN. In addition to our pivotal program in hypertension, we are conducting the EXPLORE-CKD Phase 2 clinical trial for lorandristat when added to background treatment with SGLT2 inhibitors in patients with uncontrolled or resistant hypertension and Stage 2, 2, and 3B chronic kidney disease.
Speaker Change: Subjects from these two trials will be offered the opportunity to roll over into the ongoing open label extension trial called Transform HTN.
Speaker Change: In addition to our pivotal program in hypertension, we are conducting the EXPLORE-CKD Phase 2 clinical trial for lorandastat when added to background treatment with SGLT2 inhibitor in patients with uncontrolled or resistant hypertension.
Speaker Change: and Stage 2-2-3-B chronic kidney disease. The amended protocol has been implemented and enrollment is ramping up. We anticipate announcing top-line data in the first half of 2025.
Jon Congleton: The amended protocol has been implemented, and enrollment is ramping up. We anticipate announcing top-line data in the first half of 2025. X4-CKD is a within-subject comparison trial designed to demonstrate the benefit of loranderstat in reducing blood pressure and provide supportive evidence for potential benefit in chronic kidney disease on the background of stable SGLT2 inhibitor treatment. This proof of concept trial will enroll approximately 60 subjects with hypertension in stage 2 to 3b CKD.
Speaker Change: Explore CKD is a within-subject comparison trial designed to demonstrate the benefit of lorandristat in reducing blood pressure and provide supportive evidence for potential benefit on chronic kidney disease on the background of stable SGLT2 inhibitor treatment.
Speaker Change: This proof-of-concept trial will enroll approximately 60 subjects with hypertension in Stage 2 to 3b CKD.
Speaker Change: We look forward to keeping you apprised of the status of the Lerner-Stadt Development Program over the coming weeks and months. Let me now turn the call over to Adam, who will provide a financial review for the second quarter of 2024.
Jon Congleton: We look forward to keeping you apprised of the status of the Lerner-Stadt Development Program over the coming weeks and months. Let me now turn the call over to Adam, who will provide a financial review for the second quarter of 2024. Thank you, Jon. Good afternoon, everyone.
Adam Levy: Thank you, John. Good afternoon, everyone. Today, I will discuss select portions of our second quarter 2024 financial results.
Adam Levy: Today, I will discuss select portions of our second quarter 2024 financial results. Additional details can be found in our Form 10-Q, which was filed with the SEC today. We ended the quarter with cash, cash equivalents, and investments of $311.1 million compared to $239 million as of December 31, 2023.
Adam Levy: Additional details can be found in our Form 10-Q, which was filed with the SEC today. We ended the quarter with cash, cash equivalents, and investments of $311.1 million, compared to $239 million as of December 31, 2023.
Adam Levy: We believe that our cash, cash equivalents, and investments will be sufficient to allow us to fund our planned clinical trials as well as support corporate operations into 2026.
Adam Levy: We believe that our cash, cash equivalents, and investments will be sufficient to allow us to fund our planned clinical trials as well as support corporate operations into 2026. R&D expenses for the quarter ended June 30, 2024, were $39.3 million compared to $11.9 million for the same quarter of 2023. The increase in R&D expenses was primarily due to increases of $22.8 million in preclinical and clinical costs driven by the initiation of the La Rundra Stat Pivotal Program in the second quarter of 2023 and the EXPLORE CK Day trial in the fourth quarter of 2023.
Adam Levy: $2.6 million in clinical supply, manufacturing, and regulatory costs; $1.7 million in higher compensation expenses resulting from additions to headcount increases in salaries and accrued bonuses and an increase in stock-based compensation; and $0.3 million in other research and development expenses. G&A expenses were $5.9 million for the quarter ended June 30, 2024, compared to $3.9 million for the same quarter of the prior year.
Adam Levy: RMD expenses for the quarter ended June 30, 2024, were $39.3 million, compared to $11.9 million for the same quarter of 2023.
Adam Levy: The increase in R&D expenses was primarily due to increases of $22.8 million in preclinical and clinical costs driven by the initiation of the Laurendra STAT Pivotal Program in the second quarter of 2023.
Adam Levy: and the EXPLORE CKD trial in the fourth quarter of 2023. $2.6 million in clinical supply, manufacturing, and regulatory costs.
Adam Levy: $1.7 million in higher compensation expenses resulting from additions to headcount, increases in salaries and accrued bonuses, an increase in stock-based compensation, and $0.3 million in other research and development expenses.
Adam Levy: G&A expenses were $5.9 million for the quarter ended June 30, 2024, compared to $3.9 million for the same quarter of the prior year.
Adam Levy: The increase in GNA expenses was primarily due to $1.5 million in higher compensation expenses resulting from additions to headcount.
Adam Levy: The increase in G&A expenses was primarily due to $1.5 million in higher compensation expenses resulting from additions to hedge funds, increases in salaries and accrued bonuses, and increased stock-based compensation, and 0.5 million dollars in higher professional fees and other administrative expenses. Total other income was $4.2 million for the quarter ended June 30, 2024, compared to $3.6 million for the same quarter of 2023. The increase was primarily attributable to increases in interest earned on our investments in money market funds and US Treasury securities. The net loss was $41 million for the quarter ended June 30, 2024 compared to $12.1 million for the same quarter of 2023.
Adam Levy: increases in salaries and accrued bonuses and increased stock-based compensation, and $0.5 million in higher professional fees and other administrative expenses.
Adam Levy: Total other income was $4.2 million for the quarter ended June 30, 2024, compared to $3.6 million for the same quarter of 2023.
Adam Levy: The increase was primarily attributable to increases in interest earned on our investments in money market funds and U.S. Treasuries.
Adam Levy: Net loss was $41 million for the quarter ended June 30, 2024, compared to $12.1 million for the same quarter of 2023.
Speaker Change: The increase was primarily attributed to the factors I described earlier. With that, I will ask the operator to open the call for questions. Operator?
Operator: The increase was primarily attributed to the factors I described earlier. With that, I will ask the operator to open the call for questions. Operator?
Speaker Change: Thank you. We will now conduct our question and answer session. To ask a question, press star 1 on your telephone keypad.
Operator: Thank you. We will now conduct our question and answer session. To ask a question, press star 1. That confirmation tone will indicate that your line is open. Press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.
Speaker Change: A confirmation tone will indicate that your line is in the question queue. You may press star 2 if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment please while we pull for questions.
Operator: One moment, please. Our first question comes from Michael DiFiore with Evercore ISI. Please state your question. Hi, guys. Thanks so much for taking my question. Two for me.
Speaker Change: David Rodman,
Speaker Change: Our first question comes from Michael DeFiori with Evercore ISI. Please state your question.
Speaker Change: Hi guys, thanks so much for taking my question. Two for me, I just want to get more clarity on why exactly the timelines were extended for ADVANCE, HTN and the CKD trial.
Jon Congleton: I just want more clarity on why exactly the timelines were extended for ADVANCE-HTN and the CKD trial. And then separately, obviously, the primary endpoint of the Phase 2 ADVANCE hypertension trial is now back at 12 weeks. The FDA's rationale was just because you had so much accrued data. I want to clarify that. And now that it's back at 12 weeks, are you concerned that the waters will be muddied at 12 weeks with the inclusion of patients on 100 milligrams? Thank you. Yeah, Mike, Jon, good, good chat.
Speaker Change: And then separately, obviously the, you know, the phase two advanced hypertension primary endpoint is now back at 12 weeks. The FDA's rationale was just because you had so much accrued data. I want to clarify that.
Speaker Change: Now that it's back at 12 weeks, are you concerned that now that the waters will be muddied at 12 weeks with the inclusion of patients on 100 milligrams? Thank you.
Mike: Yeah, Mike.
Jon Congleton: Glad to have the questions. The first one concerns the timing. When we originally established Q4, I think it was late last year for guidance on advanced HTN. At that point in time, we were still earlier in enrollment, particularly with the protocol amendment. As we've discussed before, the rigor and complexity of advanced HTN have made it difficult to really try to project when we think we would see top-line data as we've spent the last, You know, several months, six, seven, eight months since that guidance. You know, we've obviously gotten further along in the enrollment of the study. The ability to project the time for top line data has progressively become easier.
Speaker Change: John, good to chat. Glad to have the questions. The first one regarding the timing.
Speaker Change: When we originally established Q4, I think it was late last year, for guidance on Advanced HTN, at that point in time, we were still earlier in the enrollment, particularly with the protocol amendment.
Speaker Change: We as we've discussed before the the rigor and complexity of advanced HTN had made it difficult to really try to project when we thought we would see top-line data as we've spent the last
Speaker Change: Unknown Attendee, Daniel Ferry, Unknown Attendee, Adam Levy, David Rodman
Speaker Change: As we noted in the press release and in the earnings call here, we're at 90% enrolled at this point, so we have high confidence on where we're at currently with enrolled subjects, where we're forecasted to continue to enroll, that we'll have the top line data in Q1 of 2025.
Jon Congleton: As we noted in the press release and in the earnings call here, we're at 90% enrolled at this point, so we have high confidence in where we're at currently with enrolled subjects where we're forecasted to continue to enroll that will have the top line data in Q1 of 2025. Kind of a similar construct, Mike, with Explore CKD. We announced earlier this year that we were doing a protocol amendment just based on the changing dynamics within the hypertension CKD space and the utilization of SGLT2 inhibitors. We put that protocol in place. It's had the intended effect.
Speaker Change: Kind of a similar construct Mike with Explore CKD We announced earlier this year that we were doing a protocol amendment
Speaker Change: just based on the changing dynamics within the hypertension CKD space and the utilization of SGLT2 inhibitors. We put that protocol in place. It's had the intended effect.
Speaker Change: As far as improving enrollment within that study, as that protocol has gone into effect and we began to enroll subjects, it's been able to give us a clearer sense.
Jon Congleton: As far as improving enrollment within that study, as that protocol has gone into effect and we began to enroll subjects, it's been able to give us a clearer sense of timing, and that's why we adjusted the readout for Explore CKD from Q4, Q1 to Q1, Q2. And so that's really what's driving it, and it's just having more data, more experience with these trials, and trying to give a really clear sense of when we anticipate that top-line data.
Speaker Change: of timing and that's why we adjusted the readout for Explore CKD from Q4 Q1 to Q1 Q2 and so that's that's really what's driven and is just having more data more experience with these trials and to try to give a really clear sense of when we anticipate that top line data.
Jon Congleton: Before I turn it over to Dave to answer the, The Advanced HCM Primer Endpoint NE. New follow up on that. Just to clarify, too, you said that the protocol amendment you made now has boosted enrollment as intended, so why was the timeline moved up if enrollment has been enhanced? It's, it's been enhanced relative to what it was, Mike.
Speaker Change: Before I turn it over to Dave to answer the...
Speaker Change: Unknown Speaker The advanced HCM primary endpoint in a
Speaker Change: Can you follow up on that?
Speaker Change: Just to clarify too, you said that the protocol amendment you made now has boosted enrollment as intended, so why was the timelines moved up if enrollment has been enhanced?
Speaker Change: It's been enhanced relative to what it was, Mike. And we thought there was an opportunity to see that top line data in Q4 to Q1. While it's been enhanced, it's, from our perspective, it's prudent to change that guidance to Q1, Q2 at this point.
Jon Congleton: And we thought there was an opportunity to see that top-line data in Q4 to Q1. While it's been enhanced, it's, from our perspective, prudent to change that guidance to Q1, Q2 at this point.
Mike: Got it, okay.
Mike: Dave, do you want to address Mike's question on the primary?
Dave Rodman: Okay. Yeah, Dave, do you want to address Mike's question about the primary? Hey, Mike, it's Dave Rodman.
Mike: Hey Mike, it's Dave Rodman and thanks for the question. So the question, just to reiterate it, let me know if I've got it right.
Dave Rodman: And thanks for the question. So the question just to reiterate it, and let me know if I've got it right, is, are we going to encounter less confusion or less clarity, let's say at 12 weeks, because we have some people on 50 milligrams straight through and others who could have their dose increased to 100? Is that your question? That's correct. And also want to clarify the FDA's rationale for keeping it at 12 weeks, which is purely because you have so much data already accumulated. Got it. I'll answer the second one first.
Mike: is
Dave Rodman: Are we going to encounter less, more confusion or less clarity, let's say, at 12 weeks because we have some people on 50 milligrams straight through and others who could have their dose increased to 100? Is that your question?
Mike: That's correct and also want to clarify if the FDA's rationale for keeping it at 12 weeks which is purely because you had so much data already accumulated.
Speaker Change: Got it. I'll answer the second one first. The answer to that is yes, it was just simply.
Dave Rodman: The answer to that is yes, it was just simply that we were past halfway enrollment. They just thought, you know, stay the course at that point. So in terms of your other question, it's a good question. We're going to kind of have our cake and eat it too, in a sense, because we are going to do the full analysis at four weeks that we propose, and we're going to do the 12-week analysis.
Speaker Change: that
Speaker Change: We're past halfway enrollment. They just thought
Speaker Change: Unknown Attendee, Adam Levy, David Rodman, Unknown Attendee, Adam Levy, David Rodman,
Speaker Change: at that point.
Speaker Change: So, in terms of your other question,
Operator: Welcome to the Mineralys, Therapeutics, Second Quarter, 2024 Conference Call. At this time, I want to show a presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad.
Speaker Change: It's a good question. We're going to kind of have our cake and eat it too, in a sense, because
Speaker Change: We are going to do the full analysis at four weeks that we proposed, and we're going to do the 12-week analysis.
Speaker Change: So, we'll have the clarity of the analysis when everybody's on 50 milligrams in four weeks, but then the primary...
Dave Rodman: So we'll have the clarity of the analysis when everybody is on 50 milligrams in four weeks, but then the primary is going to be done at 12 weeks. So the only difference is really when is that primary going to be done?
Operator: As a reminder, this conference is being recorded.
Daniel Ferry: It is not my pleasure to introduce your host, Dan Ferry, of Life Side Visors. Please go ahead, sir. Thank you, operator.
Speaker Change: is going to be done at 12 weeks.
Speaker Change: So the only difference is really what
Daniel Ferry: Good afternoon, everyone, and welcome to our second quarter, 2024 Conference Call. After the close of market trading today, we should press release, providing our second quarter, 2024 financial results, and business updates. Our replay of today's call will be available on the investor's section of our website approximately one hour after its completion. After our prepared remarks, we will open up the call for Q&A.
Speaker Change: When is that primary going to be done? That's kind of just a key value question, if you will.
Dave Rodman: That's kind of just a key value question, if you will. We'll have the clarity at four weeks that will allow us to have lots of power for subset analyses like obesity, etc. So we won't really lose anything there. And we'll still have apples to apples between the two trials because of that as well. Did I answer your question? Yes, very much. Thanks so much.
Speaker Change: We'll have the clarity at four weeks that will allow us to have lots of power for subset analyses like obesity, etc.
Speaker Change: So we won't really lose anything there, and we'll still have apples to apples between the two trials because of that as well. Did I answer your question?
Daniel Ferry: Before we begin, I would like to remind everyone that this comments 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 RSEC filings, including our annual report on form 10K and subsequent filings. Please note that these forward-looking statements reflect our opinions only as of today, August 13. Except as required by law, we specifically disclaim any obligation to update or advise these forward-looking statements in light of new information or future events.
Speaker Change: Yes, very much. Thanks so much.
Speaker Change: Thanks, bye.
Dave Rodman: Thanks, bye. Our next question comes from Richard Law with Goldman Sachs. Hey guys,
Speaker Change: Our next question comes from Richard Law with Goldman Sachs. Please state your question.
Richard Law: Hey guys, thanks for taking my question. Just following up on that What patients will be included in the 12-week employee analysis for Advantage TN? So were the patients in that 50 to 150?
Richard Law: Thanks for taking my question. Just following up on that, patients will be included in the 12-week endpoint analysis for Advantage TN, so will the patients in that 50-200... Unknown Attendee, Michael DiFiore, Jin Law, Jack Padovano, Adam Levy, Jon Congleton, Colleen Garvey, Mineralys, and a couple more.
Speaker Change: Unknown Attendee, Daniel Ferry, Unknown Attendee, Adam Levy, David Rodman
Speaker Change: And I have a couple more questions.
Speaker Change: Good question. So, the primary analysis at 12 weeks is a comparison between placebo and each of the active arms.
Dave Rodman: Good question. So the primary analysis at 12 weeks is a comparison between placebo and each of the active arms. They're not co-primaries where you have to get both; they're just dual primaries.
Daniel Ferry: When we now like to turn the call over to John Cogleton, Chief Executive Officer of Mineral Syracuse, John. Thank you, Dan. Good afternoon, everyone.
John Congleton: We welcome to our second quarter, 2024 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. Professor.
Speaker Change: They're not co-primaries where you have to hit both.
Speaker Change: They're just dual primaries. And so the way that works is we'll take everybody who started on 50 and ended on 50 in well and
Dave Rodman: And so the way that works is we'll take everybody who started on 50 and ended on 50, and those who started on 50 in that second arm, they'll all be essentially treated with 50 milligrams compared to placebo. And then on the other arm, if they went up to 100, they're still included in the analysis. So it doesn't matter if they end on 50 or 100.
John Congleton: I'll begin with an overview of the business, our clinical programs, and recent milestones followed by Adam, who will review our site and quarter financial results, before we open up the call for your questions. Let me start out by saying that during the first half of the year, we made tremendous progress advancing the development program for our lead asset, and the Runder Stat. Specifically, we've been steadily moving towards several key milestones for our registration program and hypertension, which is comprised of two pivotal clinical trials to advance H-10 and launch H-10.
Speaker Change: Unknown Attendee, Adam Levy, David Rodman
Speaker Change: So it doesn't matter if they end on 50 or 100. There's a second. So and that's again versus placebo. So that's for the P values. You'll see two one for
Dave Rodman: There's a second, and that's again versus placebo. So that's for the P values. You'll see two, one for arm two, one for arm three.
Speaker Change: Unknown Attendee, Adam Levy, David Rodman, Unknown Attendee, Adam Levy, Unknown Attendee,
John Congleton: An open-level extension trial called Transform H-10 to capture long-term safety and efficacy data, and the proof-of-concept trial explores C-Q-D, evaluating the Runder Stat in the hypertensive C-Q-D subjects. Enrollment continues to progress in the advance H-10 trial. As noted previously, this is an extremely rigorous hypertension trial designed to demonstrate the value of the Runder Stat when added to standardized, optimized American Heart Association guideline treatment. While we typically do not provide enrollment updates for our clinical trials, we are approximately 90% enrolled in advance H-10, and our projections place top-line data readout in the first quarter of 2025.
Dave Rodman: There's also a key thing here, which is what we want to know in arm three. The reason we're doing it is that if you're a clinician and somebody doesn't respond to 50 milligrams, you think they belong on the drug and everything else looks good, potassium, everything else. What you want to know is, can I just double the drug safely and rescue that guy and get him the benefit I think he should get? That's a within-subject question, right? Take a person who hasn't responded, give them the drug, and now you say, did he get better from that point? So that's what's going to happen at 12 weeks.
Dave Rodman: Let me stop there and see if that was responsive to your question. Yeah, so the patients who are on the 50 to 150 mg arm, so just that titration cohort, can you pull those 50 mg patients who did not get titrated to 100 mg, can you pull them into the other arm, like the pure 50 mg cohort? Or are these patients completely separate, like separately analyzed by a specialist? Yeah, it's a good question. So in terms of 12 weeks, no, you can't pool them.
Speaker Change: And everything else looks good, potassium, everything else.
Speaker Change: What you want to know is can I just double the drug safely and rescue that guy and get him the benefit I think he should accrue. That's a within-subject question, right? Take a person who hasn't responded, give him the drug, and now you say, did he get better from that point?
Speaker Change: So that's what's going to happen at 12 weeks. Let me stop there and see if that was responsive to your question.
Speaker Change: Yeah, so the patient who are on the 50 to 150 mg arm, so just that titration cohort.
John Congleton: While we're disappointed with the change in top-line data timing, we remain laser-focused on executing the best-in-class trial and ensuring high-quality data readout. We continue to work with our partners at the Cleveland Clinic to ensure we deliver the most robust data set possible. In addition, we recently met with the FDA and aligned on maintaining the original primary endpoint of the advance H-10 trial given that we have already accumulated or accrued substantial trial data.
Speaker Change: Can you pull those 50-meg patients who did not get hydrated to 100-meg? Can you pull them into the other, like the pure 50-meg cohort? Or are these patients completely separate, like separately analyzed by itself?
Speaker Change: Yeah, it's a good question. So in terms of 12 weeks, no, you can't pool them.
Speaker Change: But in terms of the four-week analysis, absolutely. And we know from the TARGET-HTN trial that we saw the full benefit by four weeks.
Dave Rodman: But in terms of the four-week analysis, absolutely. And so, and we know from the Target HTN trial that we saw the full benefit by four weeks. So we'll also be looking at four weeks and 12 weeks in the same people and ask the question, did they maintain the benefit within subjects? And so that'll also be answered. Now, I forgot to answer your burning question, and let me just repeat that.
John Congleton: And such, we will maintain the original 12-week time point of change in 24-hour ambulatory systolic blood pressure from baseline for active cohorts versus placebo. We will still collect and analyze all relevant efficacy measures at the four-week and 12-week time points. This does not impact the timing of the data readout for advance H-10. The planned analysis of advance H-10 trial includes several important subset analysis. Subjects with uncontrolled hypertension, those on baseline regimen of two anti-pretensives, and resistant hypertension on three baseline anti-hypertensive treatments were separately randomized.
Speaker Change: So, we'll also be looking at 4 weeks and 12 weeks in the same people and ask the question, did they maintain the benefit within subject? And so, that'll also be answered. Now, I forgot to answer your powering question.
Dave Rodman: You said, "What's our power going to be for just the 50 milligram arm at 12 weeks?" Is that what you were asking? Yes.
Speaker Change: and let me just repeat that you said what's our power going to be for just the 50 milligram arm at 12 weeks is that what you were asking?
Speaker Change: Yeah.
Speaker Change: Yeah, so our initial power calculations were designed to have 90% power.
Dave Rodman: Yeah, so our initial power calculations were designed to have 90% power to do that. And we were looking at, I think, something like maybe a six or seven was a seven millimeter mercury difference. So, that's where our pairing estimates were, you know, obviously, at the end, we'll redo that based on a bunch of other things. And it's, you know, it's, the statistics are obviously complicated, but that's the bottom line. 90% power difference of seven in HR.
John Congleton: Allowing us to perform a formal test in each population. This will provide optionality in independent support for each population. We believe that demonstrating efficacy and confirmed resistant hypertension, the area of highest unmet medical need, will be important in positioning the runner set for individuals with presumed aldosterone mediated hypertension, including obesity. We believe positioning the runner set as an important option for obese individuals with increased cardiovascular risk due to resistant hypertension will be a straightforward message to prescribers, payers and patients.
Speaker Change: for to do that.
Speaker Change: And we were looking at.
Speaker Change: Unknown Attendee, Daniel Ferry, Unknown Attendee, Adam Levy, David Rodman
Speaker Change: A bunch of other things and it's.
Speaker Change: Unknown Attendee, Daniel Ferry, Unknown Attendee, Adam Levy, David Rodman, Unknown Attendee,
Speaker Change: It's, you know, the statistics are obviously complicated, but that's the bottom line. 90% power difference of seven in HR.
Speaker Change: I see. So is the data for that 50 to 100 mg cohort for the patient who did not get a pressure to 100 mg, is there any use for that 12-week data point for those patients?
Dave Rodman: I see. So is the data for that 50 to 100 mg cohort for the patient who did not get a patcher to 100 mg, is there any use for that 12-week data point for those patients? Yeah, absolutely. So we can do a sensitivity analysis on that, and we will.
John Congleton: In addition, as we accrue more experience and data with the runner set, we plan to continue to explore other positive and negative predictive factors using artificial intelligence to expand the precision toolkit. For targeting more runner set, individuals with uncontrolled and resistant hypertension, who are likely to derive long-term clinical benefit. Dean.
Speaker Change: Yeah, absolutely. So we can do a sensitivity analysis on that, and we will. We can do a pooling analysis.
Dave Rodman: We can do a pooling analysis, as you suggested. All of those are essentially sort of sensitivity analysis kind of questions. And so, you know, there probably won't be enough power. We could ask, do the people who finish on 50 differ from the people who increase to 100? But there's just so much you can do.
Speaker Change: As you suggested,
John Congleton: Moving to Launch HTN, which is our second pivotal trial that was initiated in the fourth quarter of 2023. We are pleased to announce that the enrollment in this trial is currently ahead of schedule, and we continue to expect top-line data to be available in the second half of 2025. However, the time to date may accelerate, and we will keep you informed as we move forward.
Speaker Change: All of those are essentially sort of
Speaker Change: sensitivity analysis kind of questions.
Speaker Change: And so, you know, there probably won't be enough power. We could ask, do the people who finish on 50 differ from the people who increase to 100?
Speaker Change: But there's just so much you can do, but to answer your question, yes, there's going to be used to them. Those things will be deep in the data, but they'll be available.
Dave Rodman: But to answer your question, yes, there's going to be a use for them. Those things will be deep in the data, but they'll be available. I think I've got it.
John Congleton: Launch HTN is a phase three trial of the Runderstab for the treatment of subjects with uncontrolled or resistant hypertension as add-on therapy, who fail to achieve blood pressure control on their existing prescribed background treatment of two to five anti-pretensive medications. Launch HTN and Royal Enroll up to approximately 1,000 adult subjects is designed with the objective of evaluating and Runderstab in a real-world setting when added to a subject previously prescribed anti-hypertension regimen.
Speaker Change: I think got it. And then the last set of question for me is that do you control or cap the number of patients coming into the study who previously been exposed to MRA or spironolactone? And if not, what proportion of these patients do expect to be enrolled in the advanced HTN study?
Dave Rodman: And then the last set of questions for me is that do you control or cap the number of patients coming into the study who have previously been exposed to MRA or spironolactone? And if not, what proportion of these patients do you expect to be enrolled in the advanced HTN study? So they all have to wash out of any MRA or an ENAC blocker. On the other hand, they will have a medical history. So if we choose to do so, we could take a look back.
Speaker Change: So they all have to wash out of any MRA or an ENAC blocker.
Speaker Change: On the other hand, they will have a medical history. So if we choose to do so, we could do a look back, but we're not gonna, they can't come in and just switch into the new regimen right off of.
Dave Rodman: But we're not going to make them can't, they can't come in and just switch into the new regimen right off the MRI, that has to be washed out. Okay, got it. Great. Thank you. Thanks, Rich. Our next question is from Annabelle Samimi.
John Congleton: Subjects who fail to achieve blood pressure control on their prescribed background treatment during the run-in period will be randomized one to two to one to either placebo, one-staley 50 milligrams on the Runderstab, or one-staley 50 milligrams on the Runderstab with the option to tie a treat to 100 milligrams one-staley as needed at week six. The primary endpoint for this trial will be the change in systolic blood pressure as measured by automated office blood pressure. We believe this endpoint reflects real-world measurements that will be relevant to the primary care provider this trial targets.
Speaker Change: The MRI, that has to be washed out.
Speaker Change: Okay, got it. Great. Thank you.
Rich: Thanks, Rich.
Speaker Change: Our next question comes from Annabelle Samimi with Stiefel. Please state your question.
Annabelle Samimi: Hi. Thanks for taking my question. Just on the four-week measurement, can you remind us the rationale for wanting to look at the four-week time point in the first place? I just want to make sure I understand what importance that four-week time point is for you. And I have some follow-up from that.
Annabelle Samimi: Hi Annabelle, thanks for taking my question. Just on the four-week measurement, can you remind us the rationale for wanting to look at the four-week time point in the first place? I just want to make sure I understand what importance that four-week time point is for you, and I have some follow-up.
John Congleton: Subjects from these two trials will be offered the opportunity to roll over into the ongoing open label extension trial called Transform HTN.
John Congleton: In addition to our pivotal program in hypertension, we are conducting the Explorer CKD phase two clinical trial for Runderstab when added to background treatment with SGLT2 inhibitor in patients with uncontrolled or resistant eye for tension and stage two to three B chronic kidney disease. The amended protocol has been implemented and enrollment is ramping up. We anticipated announcing top line data in the first half of 2025. Explore CKD is a within-subject comparison trial designed to demonstrate the benefit of Runderstab in reducing blood pressure and provide supportive evidence for potential benefit on chronic kidney disease on the background of stable SGLT2 inhibitor treatment. This proof of concept trial will enroll approximately 60 subjects with hypertension and stage two to three B CKD.
Annabelle Samimi: Hi Annabelle, it's Dave. So your question, just to repeat it so I've got it right, is what was the rationale for wanting to make the change or why are we looking at it just...
Dave Rodman: So, um, so your question, just to repeat it so I've got it right, is, what was the rationale for wanting to make the change or why are we looking at it just on basic principles? Well, why were you looking at it in the basis of basic principles? You just had a four-week endpoint and a 12-week endpoint. I'm just curious what the four-week endpoint measurement was going to give you. Unknown Attendee, Unknown Attendee, Unknown Attendee, for just the importance of that. So it's a good question, by four weeks.
Basic Principles: on Basic Principles.
Dave Rodman: Well, why were you looking at it for basic principles? You had a four-week endpoint and a 12-week endpoint. I'm just curious what the four-week endpoint measurement was going to give you.
Speaker Change: Unknown Attendee, Adam Levy, Unknown Attendee, Unknown Attendee, Unknown Attendee, Unknown Attendee,
Speaker Change: for just the importance of that endpoint.
Speaker Change: So it's a good question. By four weeks,
Speaker Change: You've achieved the maximum benefit.
Dave Rodman: You've achieved the maximum benefit, and by having two data points, so baseline, but then four weeks and 12 weeks, you cover a lot of issues to answer the question.
Speaker Change: And by having two data points, so baseline, but then four weeks and 12 weeks.
Speaker Change: You manage a lot of issues. To answer the question, we think four weeks will be the maximum.
John Congleton: We look forward to keeping you apprised with the status of the Runderstab Development Program over the coming weeks and months.
Dave Rodman: We think four weeks will be the maximum. Is it predictive of 12 weeks? In other words, is there any loss of activity over at least the 12 week time period? Because we only went out to eight weeks before and didn't see any loss.
Speaker Change: Is it predictive of 12 weeks? In other words, is there any loss of activity over at least the 12-week time period? Because we only went out to eight weeks before and didn't see any loss.
Adam Levy: Let me now turn the call over to Adam who will provide a financial review for the second quarter of 2024. Thank you, John. Good afternoon, everyone. Today, I will discuss select portions of our second quarter 2024 financial results. Additional details can be found in our form 10Q which was filed with the SEC today. We ended the quarter with cash, cash equivalence and investments of 311.1 million dollars compared to 239 million dollars as a December 31, 2023.
Speaker Change: From a statistical standpoint, it allows you to.
Dave Rodman: From a statistical standpoint, it allows you to, let's just say somebody later in the trial. You know, someone has a problem or whatever, and you stop their drug. As long as we have the four weeks, we do have mechanisms for imputation that can be used. Now, that's a complicated thing, but
Speaker Change: Let's just say somebody later in the trial.
Speaker Change: has a problem or whatever and you stop their drug, as long as we have the four-week, we do have mechanisms for imputation that can be used. Now, that's a complicated thing, but...
Speaker Change: As long as they stay in the study.
Dave Rodman: As long as they stay in the study, that four-week data point is informative for the modeling. So there are a couple reasons to do it. The third one is the ability to pool the two groups that are replicates up to four weeks, and so you do have a four-week superpower in terms of getting a point estimate. That's helpful.
Speaker Change: Unknown Attendee, Adam Levy, David Rodman
Adam Levy: We believe that our cash, cash equivalence and investments will be sufficient to allow us to fund our planned clinical trials as well as support corporate operations into 2026. R&D expenses for the quarter ended June 30, 2024 were $39.3 million, compared to $11.9 million for the same quarter of 2023. The increase in R&D expenses was primarily due to increases of $22.8 million in preclinical and clinical costs driven by the initiation of the LaRunder Stat Pivotal Program, the second quarter of 2023, and the Explorer CKD trial in the fourth quarter of 2023.
Speaker Change: The ability to pool the two groups that are replicates up to four weeks.
Speaker Change: And so you do have a four-week superpower in terms of getting a point estimate.
Speaker Change: Okay, that's helpful. Thank you. And then just a question that we've...
Dave Rodman: Thank you. And then just a question that we've been grappling with some investors. Just can you remind us again what the difference was in a patient who saw 24-hour blood pressure monitoring benefits and target versus those who did not? And I guess how it could have been that the AOBP measurements overall saw such a strong response while the 24-hour could not? So I just want to try to reconcile those two figures. If I understand your question, I'm not sure. Let me just say what we saw.
Speaker Change: and grappling with some investors. Just can you remind us again what the difference was in the patients who saw 24-hour blood pressure monitoring benefits and target versus those who did not
Adam Levy: $2.6 million in clinical supply, manufacturing, and regulatory costs, $1.7 million in higher compensation expenses resulting from additions to headcount, increases in salaries, and accrued bonuses, and increase in stock-based compensation, and $0.3 million in other research and development expenses. GNA expenses were $5.9 million for the quarter ended June 30, 2024, compared to $3.9 million for the same quarter of the prior year. The increase in GNA expenses was primarily due to $1.5 million in higher compensation expenses resulting from additions to headcount, increases in salaries and accrued bonuses, and increase stock-based compensation, and $0.5 million in higher professional fees and other administrative expenses.
Speaker Change: Unknown Attendee, Daniel Ferry, Unknown Attendee, Adam Levy, David Rodman
Speaker Change: [inaudible]
Speaker Change: If I understand your question, I'm not sure. Let me just say what we saw. So, first of all, ABPM, because of the replicate measures every 20 to 30 minutes over the course of the day, you get lots of measurements.
Dave Rodman: So first of all, ABPM, because of the replicate measures every 20 to 30 minutes over the course of the day, you get lots of measurements. So the precision is better when you average them. So the standard deviation is smaller. But remember, a normal person's blood pressure goes down significantly overnight.
Speaker Change: So the precision is better when you average it. So the standard deviation is smaller.
Speaker Change: But remember, a normal person's blood pressure goes down significantly overnight, and so the average blood pressure over the course of 24 hours will be lower with ABPM than the automated office done just in the morning.
Dave Rodman: And so the average blood pressure over the course of 24 hours will be lower with ABPM than with the automated office done just in the morning. The same is true of changes, then, because you're changing from a lower baseline. So, typically, what you'll see is a lower baseline pressure with ABPM and a smaller treatment effect, but a smaller standard deviation. So, we saw extremely good concordance between AOBP and ABPM, but there is this systematic difference in smaller numbers.
Adam Levy: Total other income was $4.2 million for the quarter ended June 30, 2024, compared to $3.6 million for the same quarter of 2023. The increase was primarily attributable to increases in interest earned our investments in money market funds and U.S. Treasury. Net loss was $41 million for the quarter ended June 30, 2024, compared to $12.1 million for the same quarter of 2023. The increase was primarily attributed to the factors I described earlier.
Speaker Change: The same is true of changes then, because you're changing from a lower baseline. So typically what you'll see is a lower baseline pressure with ABPM and a smaller treatment effect.
Speaker Change: but a smaller standard deviation.
Speaker Change: So, we saw extremely good concordance between AOBP and ABPM, but there is this systematic difference of smaller numbers.
Operator: With that, I will ask the operator to open the call for questions. Operator? Thank you.
Speaker Change: Now, the other thing that happened, however, is there is this phenomenon of white coat hypertension. In other words, when you get an AOBP, when you come into the clinic at 10 in the morning,
Dave Rodman: Now, the other thing that happened, however, is this phenomenon of white coat hypertension. In other words, when you get an AOBP, when you come into the clinic at 10 in the morning, Michael DiFiore, Unknown Attendee, Daniel Ferry, Michael DiFiore, Unknown Attendee, Unknown Attendee, Michael DiFiore, Jin Law, Jack Padovano, Adam Levy, Jin Law, I'm just curious about the AVPM, where you reach statistical significance when you reach statistical significance after you move some outliers of the study.
Operator: We will now conduct our question and answer session. To ask a question, press star one on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press star two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions.
Speaker Change: You've got a lot of adrenergic tone because you had to find a parking space, you had to walk up two flights of stairs, you had to wait in the waiting room, etc. And so that all goes away with a 24 hour.
Speaker Change: And so we have this thing where people have hypertension with AOVP, but not with ABPM. And we tend to assume they don't have.
Michael DiFiore: Our first question comes from Michael D. Fiori with Evercore ISI. Please say your question. Hi guys, thanks so much for taking my question. Two for me. I just want to get more clarity on why exactly the timelines were extended for advanced HTN and the CKD trial. And then separately, obviously, the phase two advanced hypertension primary endpoint is now back at 12 weeks. The FDA's rationale was just because you had so much accrued data.
Speaker Change: true hypertension that leads to adverse outcomes, but rather they just have apparent hypertension. Was that the question kind of you were thinking of asking?
Speaker Change: A little bit. I'm just curious about the AVPM.
Speaker Change: Unknown Attendee, David Rodman, Unknown Attendee, Unknown Attendee, Unknown Attendee, Unknown
Dave Rodman: So I'm just trying to understand what those outliers were. They made you comfortable that it was a fair assessment, and how do you control for those outliers in this next coming trial so that you don't have some of those divergences? Yeah, good question.
Speaker Change: were, they made you comfortable that it was a fair assessment, and how do you control for those outliers in this next coming trial so that you don't have some of those divergences?
Michael DiFiore: I want to clarify that. And now that it's back at 12 weeks, are you concerned that now that the waters will be at 12 weeks with the inclusion of patients on 100 milligrams? Thank you. Yeah, Mike. John, good to chat. Glad to have the questions.
Speaker Change: Yeah, good question. So first of all, those were small trials, Ns of 30 with ABPM and all the technical issues with it are extremely challenging to get to statistics.
Dave Rodman: So first of all, those were small trials ends of 30 with a BPM, and all the technical issues with it were extremely challenging to get statistics. And the, for instance, it was a few patients. There was one patient in particular, who on the office blood pressures had a 60 millimeter mercury increase, I think, in blood pressure recorded. In other words, an implausible value.
John Congleton: The first one regarding the timing, when we originally established Q4, I think it was late last year for guidance on advanced HTN. At that point in time, we were still earlier in the enrollment, particularly with the protocol amendment. We, as we've discussed before, the rigor and complexity of advanced HTN had made it difficult to really try to project when we thought we would see top-line data as we'd spent the last, you know, several months, six, seven, eight months since that guidance.
Speaker Change: and the for instance it was a few patients there was one patient in particular who on the office blood pressures had a 60 millimeter mercury I think increase
Speaker Change: in blood pressure recorded. In other words, an implausible value. It just can't be accurate. And that's what kind of thing we censored was just numbers that were just not plausible and not reproduced.
Dave Rodman: It just can't be accurate. And that's the kind of thing we censored: just numbers that were just not plausible and not reproduced. So there were only a few. It was really white coat hypertension where most of the... Loss of information from ABPM was the issue. Yeah, and Annabelle, just to add to Dave's point, the distinction between target in advance and target AOBP was part of the randomization rule, not ABPM, and AOBP was the primary endpoint.
Speaker Change: So, there was only a few. It was really the white coat hypertension where most of the
John Congleton: You know, we've obviously gotten further along in the enrollment of the study. The ability to project the time for the top-line data has progressively become easier. As we noted in the press release and in the learnings call here, we're at 90% enrolled at this point, so we have high confidence on where we're at currently with enrolled subjects where we're forecasted to continue to enroll, then we'll have the top-line data in Q1 of 2025.
Speaker Change: loss of information from ABPM was the issue.
Speaker Change: Yeah, and Annabelle, just to add to Dave's point, the distinction between target in advance and target AOBP.
Annabelle Samimi: was part of the randomization rule, not ABPM, and AOBP was the primary endpoint. In this case of advanced HTN, they have to be hypertensive on the 24-hour ABPM to be randomized.
Dave Rodman: In the case of advanced HTN, they have to be hypertensive on the 24-hour ABPM to be randomized. And so that rule, or the randomization rule itself, should eliminate that phenomenon that we saw on target HTN. Okay, great. Thank you. Unknown Attendee.
John Congleton: Kind of a similar construct, Mike with Explore, CKD. We announced earlier this year that we were doing a protocol amendment just based on the changing dynamics within the high-pretension CKD space and the utilization of SGLT2 inhibitors. We put that protocol in place. It's had the intent of the fact as far as improving enrollment within that study. As that protocol has gone into effect and we began to enroll subjects, it's been on to give us a clearer sense of timing, and that's why we adjusted the readout for Explore, CKD, from Q4, Q1 to Q1, Q2. And so that's really what's driven, and there's just having more data, more experience with these trials and to try to give a really clear sense of when we anticipate that top-line data.
Speaker Change: And so that rule, a randomization rule itself, should eliminate that phenomenon that we saw on target HTN.
Speaker Change: Okay, great. Thank you.
Hannibal: Yeah. Thanks, Hannibal.
Dave Rodman: Thank you. Yeah. Thanks, Hannibal.
Speaker Change: Our next question comes from Mohit Bansal with Wells Fargo. Please state your question.
Mohit Bansal: Our next question comes from Mohit Bansal with Wells Fargo. Thank you very much for taking my questions. I have two, but I'll ask them one by one.
Mohit Bansal: Thank you very much for taking my questions. I have two, but I'll ask one by one. So, first question, I'm a little bit confused by all the talk about advanced HTN and then 12-week thing. If I go back to the launch trial,
Mohit Bansal: So first question, I'm a little bit confused by all the talk about advanced HTN and then the 12-week thing. If I go back to the launch trial, can you just help us understand? What was the confounding issue that probably made FDA ask you to move to six weeks versus 12 weeks? Because the way I see the trial, there are three different arms; there is one 50 milligram, there is another 50 milligram moving to 100 milligram.
Mohit Bansal: Can you just help us understand?
Mohit Bansal: What was the confounding issue that
John Congleton: Before I turn it over to Dave, they answered the advanced ECM primary endpoint, any new follow-up on that. Just to clarify, too, you said that the protocol amendment you made now has boosted enrollment as intended. So why would the timelines moved up if enrollment has been enhanced? It's been enhanced relative to what it was, Mike. And we thought there was an opportunity to see that top-line data in Q4 to Q1. While it's been enhanced, it's from our perspective, it's prudent to change that guidance to Q1, Q2 at this point. Got it. Okay.
Speaker Change: That probably are made FDA to ask you to move to six weeks versus 12 weeks Because the way I see the trial there are three different arms. There is one 50 milligram. There is There's another 50 milligram moving to 100 milligram. So you can still compare the 50 milligram arm
Mohit Bansal: So you can still compare the 50 milligram arm to the placebo arm, so I'm a little bit confused by the change here. Thank you. So, it wasn't them telling us what to do; it was us suggesting that it would be better to do it that way. It doesn't have to do with the primary. It didn't matter in that trial, with as big as it was.
Speaker Change: to the placebo arm. So I'm a little bit confused by the change here. Thank you.
Speaker Change: So it wasn't them telling us what to do. It was us suggesting that it would be better to do it that way. It doesn't have to do with the primary.
Dave Rodman: If you did the primary four weeks or twelve weeks, it has to do with power for the subset analysis. In other words, because you have two replicant arms, both at 50 milligrams, we can do the independent tests for the primary, each arm versus placebo. But let's say we want to ask a question, does it matter whether you're African-American?
unknown: ........
Speaker Change: It didn't matter in that trial as big as it was if you did the primary at 4 weeks or 12 weeks. It has to do with power of the subset analysis. In other words,
David Rodman: Dave, do you want to address Mike's question on the primary? Hey, Mike, it's Dave Rodman, and thanks for the question. So the question just to reiterate, and let me know if I've got it right, is are we going to encounter less, more confusion or less clarity, let's say, at 12 weeks because we have some people on 50 milligrams straight through and others who could have their dose increase to 100? Is that your question? That's correct. And also want to clarify, if the FDA's rationale for keeping it at 12 weeks, which is purely because you had so much data already accumulated. Got it.
Speaker Change: Because you have two replicant arms, both at 50 milligrams, we can do the independent tests for the primary, each arm versus placebo. But let's say we want to ask a question, does it matter whether you're African American?
David Rodman: I'll answer the second one first. The answer to that is yes, it was just simply that we're past halfway enrollment. They just thought, you know, stay the course at that point. So in terms of your other question, it's a good question. We're going to kind of have our kick and eat it too in a sense because we are going to do the full analysis at four weeks that we proposed. And we're going to do the 12 week analysis.
David Rodman: Services. So we'll have the clarity of the, the analysis when everybody's on 50 milligrams in four weeks, but then the primary is going to be done at 12 weeks. So the only difference is really what, when is that primary going to be done? That's kind of just a key value question, if you will. We'll have the clarity at four weeks that'll allow us to have lots of power for subset analyses like obesity, et cetera. So we won't really lose anything there and we'll still have apples to apples between the two trials because of that as well. Did I answer your question? Yes, very much. Thanks so much. Thanks, Mike.
Dave Rodman: Well, we expect maybe 40% of the subjects will be African American. So now you're down to half the sample size. But by pooling the two, now you get backed up to the number.
Speaker Change #100: Well, we expect maybe 40% of the subjects will be African-American, so now you're down to half the sample size. But by pooling the two, now you get backed up to the number, and so you get much more precision to get...
Dave Rodman: And so you get much more precision to get accurate answers to the subset. So that's what we went back to the agency with and said, in this big data set, we want to make sure that we can. Fully realized the power of the study, and we think for the subsets, we'd be better at six weeks, and basically, the decision was, okay, if you're going to do that, let's just do the primary at six.
Speaker Change #100: accurate answers to the subsets.
Speaker Change #100: So that's what we went back to the agency with and said in this big data set we want to make sure that we can
Speaker Change #101: Unknown Attendee, Adam Levy, David Rodman
Speaker Change #101: Got it. So that is basically to make sure that you can do the subgroup analysis properly with the bigger data set here.
Dave Rodman: Got it. So that is basically to make sure that you can do the subgroup analysis properly with the bigger data. It just makes it much simpler and higher productivity. It's just, It's just a good, good idea.
Speaker Change #101: It just makes it much more simple and higher productivity. It's just...
Speaker Change #101: It's just a good, good idea.
Speaker Change #102: And then I have one more question. So we have seen a couple of readouts from MRAs. So obviously Novo had some data which was not that successful, but then Bayer had some data in.
Mohit Bansal: Got it. And then I have one more question. So we have seen a couple of readouts from MRAs. Obviously, NOVO had some data, which was not that successful, but then Bayer had some data on type 2 diabetes-related CKD, and that was quite successful. How do you see, obviously, different classes, but related? How do you see these two data sets and what do you learn from them? Use those data sets to inform your own CKD study?
Speaker Change #103: type 2 diabetes related CKD and that was quite successful. So how do you see, like obviously different classes but related, how do you see these two data sets and and what do you learn from them, those data sets, to inform your own CKD studies?
Speaker Change #104: Well first of all, MRAs
Mohit Bansal: Well, first of all, MRAs are generally pretty similar. It doesn't matter if it's spironolactone from 1959 or a very new one. The only difference is the steroidal side effects, things like breast development in men and impotence and that bleeding and that kind of stuff. As far as everything else mechanistically, they're the same.
Speaker Change #105: generally are pretty similar. It doesn't matter if it's spironolactone from 1959 or a very new one, the only difference are the steroidal side effects. Things like
Speaker Change #106: Breast development in men and impotence and venom bleeding and that kind of stuff. As far as everything else mechanistically they're the same.
Richard Law: Now our next question comes from Richard Law with Goldman Sachs, please state your question. Hey guys, thanks for taking my question. Just following up on that, what patients will be included in the 12 week end point analysis for FNHTN? So what are the patients in that 50 to 100 make cohort? Would those be included in the 12 week primary analysis? And also what is the powering on just that pure 50 make group?
Speaker Change #106: What we observe with the MRAs is almost always
Dave Rodman: What we observed with the MRAs is almost always you are unable to achieve the maximum therapeutic benefit on something like blood pressure because you're limited by the on target increases in potassium and, and also, you know, sodium going down those kinds of For instance, with spironolactone, the maximum efficacious dose is probably 200 milligrams, while the conventional dose that's used is 25 milligrams. 50 milligrams by nephrology specialists. That's different.
Speaker Change #106: You are unable to achieve the maximum therapeutic benefit on something like blood pressure because you're limited by the on-target increases in potassium and also sodium going down, those kinds of things.
Richard Law: I don't know. And I have a couple more questions. Good question. So the primary analysis at 12 weeks is a comparison between placebo and each of the active arms. They're not co-primaries where you have to hit both. They're just dual primaries. And so the way that works is we'll take everybody who started on 50 and ended on 50 in well and that started on 50 in that second arm. They'll all be essentially treated with 50 milligrams compared to placebo.
Speaker Change #106: For instance, with spironolactone, the maximum efficacious dose is probably 200 milligrams. The conventional dose that is used is 25 milligrams, 50 milligrams by a nephrology specialist sometimes.
Richard Law: And then the other arm, if they went up to 100, they're still included in the analysis. So it doesn't matter if they end on 50 or 100. There's a second, so and that's again versus placebo. So that's for the P values. You'll see two, one for the arm two, one for arm three. There's also a key thing here which is what we want to know is in arm three. The reason we're doing it is if you're a clinician and somebody doesn't respond to 50 milligrams, you think they belong on the drug and everything else looks good potassium, everything else.
Speaker Change #107: Unknown Attendee, Adam Levy, David Rodman
Dave Rodman: So we found that in our drug, we can go above the maximum efficacious dose 100 milligrams is the same as 50. So we can safely give 50 milligrams, which is the maximum effective dose. Overall, what I would say is the biggest difference that's apparent in the trials we're running is that the benefit risk, the ability to dose people all the way up to their efficacious dose from getting rid of aldo is probably more.
Speaker Change #108: We can go above the maximum efficacious dose, 100 milligrams is the same as 50. So we can safely give 50 milligrams, which is the maximum efficacious dose.
Speaker Change #109: So, overall, what I would say is the biggest difference that's apparent in the trials we're running is that the benefit risk, the ability to dose people all the way up to their applications, those from getting rid of Aldo is probably more.
Speaker Change #109: achievable with an ASI like ours than an MRA.
Dave Rodman: Achievable with an ASI like ours than an MRA. Now, long term, there are a lot of aldo effects that aren't blood pressure and kidney, their effects on adipocytes, on insulin sensitivity, on inflammation, on heart and blood vessel fibrosis.
Speaker Change #109: Now, long term, there are a lot of aldo effects that aren't blood pressure and kidney.
Speaker Change #109: their effects on adipocytes, on insulin sensitivity, on inflammation, on heart and blood vessel fibrosis. And not all of them.
Dave Rodman: And not all of them are mediated through the MR that's blocked by those MRAs. And in fact, if you give an MRA, you increase aldosterone by two or 300%, and you drive it into these other pathways. So if you did a longer trial and looked at things like vascular stiffness, maybe even half-path, I think eventually they would differentiate. But that's for us to define.
Speaker Change #109: are mediated through the MR that's blocked by those MRAs. And in fact, if you give an MRA, you increase aldosterone by two or three hundred percent, and you drive it into these other pathways.
Richard Law: What you want to know is can I just double the drug safely and rescue that guy and get him the benefit I think he should accrue. That's a within subject question, right? To take a person who hasn't responded, give him the drug and now you say did he get better from that point? So that's what's going to happen at 12 weeks. Let me stop there and see if that was responsive to your question.
Speaker Change #109: So if you did a longer trial and looked at things like vascular stiffness, maybe even half path
Speaker Change #110: I think eventually they would differentiate, but that's for us something to define. Once we're in the market for hypertension, we will certainly be looking at that. Those are really the two aspects. We would say that.
Dave Rodman: Once we're in the market for hypertension, we will certainly be looking at that. Those are really the two aspects we would say that look pretty likely to differentiate and show the advantage of ASI over MRA. Great. Thank you very much, Michael. Thanks, Malhead.
Speaker Change #110: look pretty likely to differentiate and show the advantage of ASI over MRA.
Richard Law: Yeah, so the patients who are on the 50 to 150 make arm, so just that hydration cohort, can you pull those 50 make patients who did not get the pressure into 100 make? Can you pull them into the other like the pure 50 make cohort or are these patients completely separate like separately analyzed by? So yeah, it's a good question. So in terms of 12 weeks, no, you can't pool them, but in terms of the four week analysis, absolutely.
Speaker Change #111: Great. Thank you very much.
Mohammed: Thanks Mohammed.
Speaker Change #113: Thank you and a reminder to queue up for a question, press star 1. To remove your question press star 2.
Operator: Thank you. And a reminder to queue up for a question; press star one to remove your question. Our next question is from Rami Kudhuda with LifeSciCapital. Hey, guys.
Speaker Change #113: Our next question comes from Rami Kudhuda with LifeSci Capital. Please state your question.
Rami Kudhuda: Hey, guys. Thanks for taking my questions as well. First, I just wanted to make sure that I heard you correctly in that you'll be able to do a subset analysis of Loranderstadt's efficacy in uncontrolled and resistant hypertensive patients in advance. I guess, do you expect a difference in efficacy between these populations?
Rami Kudhuda: Thanks for taking my questions as well. First, I just wanted to make sure that I heard you correctly in that you'll be able to do a subset analysis of Loranderstadt's efficacy in uncontrolled and resistant hypertensive patients in advance. I guess, do you expect a difference in efficacy between these populations? Well, I can answer the first question.
Richard Law: And so, and we know from the target, HTN trial that we saw the full benefit by four weeks. So we'll also be looking at four weeks and 12 weeks in the same people and ask the question, did they maintain the benefit within subjects. And so that'll also be answered. Now I forgot to answer your power in question. And let me just repeat that. You said, what's our power going to be for just the 50 milligram arm at 12 weeks?
Speaker Change #115: Well, I can answer the first question. So we separately block randomized.
Dave Rodman: So we separately block randomized, uncontrolled, and resistant. In other words, if we have 150 people who are resistant, and we have 200 people who are uncontrolled, we'll have 200 uncontrolled placebos and 150 resistant placebos. They're matched in terms of randomization. And so that means we have full statistical power to do those comparisons, and they are with informative. Now, your question of whether I can be prophetic and tell you whether it's going to work better in one or the other? I can't answer that. In the Target HTN trial, when we asked that question, we didn't see any difference. But let's wait and see on this trial. I don't want to predict.
Rami Kudhuda: Uncontrolled and resistant. In other words,
Speaker Change #116: If we have 150 people who are resistant and we have 200 people who are uncontrolled,
Speaker Change #116: We'll have 200 uncontrolled placebo and 150 resistant placebo. They're matched in terms of
Richard Law: Is that what you were asking? Yeah. So our initial power calculations were designed to have 90% power for to do that. And we were looking at, I think, as let me like, maybe a six or seven was a seven millimeter mercury difference. So, so that's where our powering estimates were. You know, obviously at the end will redo that based on a bunch of other things. And it's, you know, it's, it's, you know, the statistics are obviously complicated, but that's the bottom line.
Speaker Change #116: the randomization. And so that means we have
Speaker Change #116: Full statistical power to do those comparisons and they're informative.
Speaker Change #116: Now, your question of can I be prophetic and tell you whether it's going to work better in one or the other, I can't answer that. In the target HTN trial, when we asked that question, we didn't see a difference.
Speaker Change #116: But let's wait and see on this trial. I don't want to predict.
Speaker Change #117: Fair enough. And then maybe switching to TKD, I guess, given the previous results we saw with Bowringer's ASI, the recent failure with the MRA, is there a threshold of systolic blood pressure reductions that you're looking for in Xplorer to advance Florender's STAT into a larger trial?
Dave Rodman: Fair enough. And then maybe switching to TKD, I guess given the previous results we saw with Bowringer's ASI, and the recent failure with the MRA, is there a threshold of systolic blood pressure reductions that you're looking for in Xplorer to advance the Lorendar Stat into a larger trial? for CKD. Oh, where we think our drugs are going to differentiate is we made primary hypertension the primary, and the secondary is going to be albuminuria. And the reason for that is we're going to be dosing at antihypertensive doses in people who have a hypertensive component to their CKD and probably also a metabolic syndrome component.
Richard Law: 90% power difference of seven in HR. I see. So it's a data for that 50 to 100 make cohort for the patient who did not get a pleasure to make. Is there any use for that that 12 week data point for those patients? Yeah, absolutely. So we can do a sensitivity analysis on that. And we will, we can do a pooling analysis. As you suggested, all of those are essentially sort of sensitivity analysis kind of questions.
Speaker Change #118: Unknown Attendee for CKD.
Speaker Change #119: So, where we think our drug is going to differentiate is we made the primary hypertension and the secondary is going to be albuminuria. And the reason for that is
Speaker Change #119: We're going to be dosing at anti-hypertensive doses in people who have both a hypertensive component to their CKD and probably also a metabolic syndrome component. And so
Richard Law: And so, you know, there probably won't be enough power. We could ask to the people who finish on 50 different from the people who increased to 100. But there's just so much you can do. But to answer your question, yes, there's going to be use to them. Those things will be deep in the data, but they'll be available. I think got it. And then the last question from me is that do you control a cap?
Dave Rodman: And so, we believe that by targeting that subpopulation, we will define a niche where our drug can differentiate from other approaches which are much more effective in the general CKD population. Unknown Attendee Um, that's why, even though it's a crowded field with multiple players, we still think we've probably got the best in class ASI, and it has potential in that way. Got it. And I guess one more, if you don't mind, can you just remind us of the rationale for using the 25 mg dose instead of 50 mg in the EXPLORE-CKD study?
Speaker Change #119: We believe that by targeting that subpopulation we will define a niche where our drug can differentiate from other approaches which are much more a general CKD population.
Speaker Change #119: That's
Speaker Change #119: That's why even though it's a crowded field with multiple players, we still think we've probably got the best in class ASI and it has potential in that way.
Richard Law: The number of patients coming into the study who previously been exposed to MRA or spiritual acto? And if not, what proportion of the patient do expect to be enrolled in the events? It's the answer. So they all have to wash out of any MRA or an ENAC blocker. On the other hand, they will have a medical history. So if we choose to do so, we could do a look back. But we're not going to make they can't come in and just switch into the new regimen right off of the MRA. That has to be washed out. Okay, got it. Great. Thank you.
Richard Law: Thanks for it.
Speaker Change #120: And I guess one more, if you don't mind, can you just remind us of the rationale for using the 25 mg dose instead of 50 mg in the Explore CKD study? Is it just hyperkalemia and lower EGFR patients, or is there more to it?
Dave Rodman: Is it just hyperkalemia and lower EGFR patients, or is there more to it? Right, so it's an abundance of caution at this exploratory stage; we didn't want to take on the hyperkalemia risk. Now, I'll tell you, our nephrology advisors say they're perfectly comfortable using potassium binders if needed to get the blood pressure down in these patients. So this is just the first step on the journey. But that's the main reason; it makes sense.
Speaker Change #121: Right, so it's an abundance of caution at this exploratory stage. We didn't want to
Speaker Change #122: Take on the hyperkalemia risk. Now I'll tell you our nephrology advisors say they're perfectly comfortable using potassium binders if needed to get the blood pressure down in these patients. So this is just the first step on the journey.
Annabel Samimy: Our next question comes from Annabelle Samimi with... DeFold, please state your question. Hi, thanks for taking my question. Just on the four-week management, can you remind us the rationale for wanting to look at the four-week time point in the first place? I just want to make sure I understand what importance that four-week time point is for you, and I have some follow-ups from that. Hi, Annabel, it's Dave. So your question, just to repeat it, so I've got it right, is what was the rationale for wanting to make the change?
Speaker Change #122: But that's the main reason.
Speaker Change #123: Make sense. Thanks so much.
Annabel Samimy: Or why are we looking at it just on basic principles? Well, why were you looking at it for basic principles? You had a four-week endpoint and a 12-week endpoint. I'm just curious what the four-week endpoint measurement was going to give you. Was it? Right, if you want to see how we just for just name points at that end point. So it's a good question. By four weeks, you've achieved the maximum benefit, and by having two data points, so baseline, but then four weeks and 12 weeks, you manage a lot of issues to answer the question.
Speaker Change #124: Thanks for having me.
Speaker Change #125: Thank you. There are no further questions at this time. I would like to turn the floor back over to John Congleton for closing comments.
Dave Rodman: Thanks so much. Thanks for having me. Thank you. There are no further questions at this time. I would like to turn the floor back over to Jon Congleton for questions.
John Congleton: Thank you, operator, and thank you to everyone for joining us today.
Jon Congleton: Thank you, operator, and thank you to everyone for joining us today. We're very excited about the program's progress to date that we've made in the first half of twenty twenty four and advances in our clinical programs. And we remain very enthusiastic about the upcoming milestones for the rest of the year and into twenty twenty five. We look forward to updating you as our pivotal program from Rundersack continues to advance. With that, we will close the call. Thank you. Conference call, all parties may disconnect; have a good conference.
John Congleton: We're very excited about the program's progress to date, that we've made in the first half of 2024, and advancing our clinical programs, and we remain very enthusiastic about the upcoming milestones for the rest of the year and into 2025.
John Congleton: We look forward to updating you as our pivotal program for La Rundersac continues to advance. With that, we will close the call.
Speaker Change #126: Thank you. This concludes today's conference. All parties may disconnect. Have a good day.
Annabel Samimy: We think four weeks will be the maximum. Is it predictive of 12 weeks? In other words, is there any loss of activity over at least the 12-week time period? Because we only went out to eight weeks before and didn't see any loss. From a statistical standpoint, it allows you to, let's just say somebody later in the trial, you know, has a problem or whatever and you stop their drug. As long as we have the four-week, we do have mechanisms for imputation that can be used.
Annabel Samimy: Now, that's a complicated thing, but as long as they stay in the study, that four-week data point is informative for the modeling. So there's a couple of reasons to do it. The third one is the ability to pool the two groups that are replicates up to four weeks, and so you do have at four weeks super power in terms of getting a point estimate.
David Rodman: Okay, that's helpful. Thank you. And then, just a question that we've been grappling with, with some investors. Just can you remind us, again, what the difference was in the patients who saw 24-hour blood pressure monitoring benefits and target versus those who did not, and I guess how it could have been at the AOVP measurements overall, such a strong, such a strong response while the 24-hour cannot. So I just want to try to reconcile those two figures.
David Rodman: If I understand your question, I'm not sure, let me just say what we saw. So first of all, ABPM, because of the replicate measures every 20 to 30 minutes over the course of the day, you've got lots of measurements. So the precision is better when you average it. So the standard deviation is smaller, but remember, a normal person's blood pressure goes down significantly overnight. And so the average blood pressure over the course of 24 hours will be lower with ABPM than the automated office done just in the morning.
David Rodman: The same is true of changes then because you're changing from a lower baseline. So typically what you'll see is a lower baseline pressure with ABPM and a smaller treatment effect, but a smaller standard deviation. So we saw extremely good concordance between ALBPM and ABPM, but there is this systematic difference of smaller numbers. Now the other thing that happened, however, is there is this phenomenon of weight code hypertension. In other words, when you get an ALBP, when you come into the clinic at 10 in the morning, you've got a lot of adrenergic tone because you had to find a parking space, you had to walk up two flights of stairs, you had to wait in the waiting room, et cetera.
David Rodman: And so that all goes away with a 24 hour. And so we have this thing where people have hypertension with ALBPM, but not with ABPM. And we tend to assume they don't have true hypertension that leads to adverse outcomes, but rather they just have apparent hypertension. Was that the question kind of you were thinking of asking? Um, a little bit. I'm just curious about the ABPM where you reach statistical significance with when you reach statistical significance after you move some outliers of the study.
David Rodman: So I'm just trying to understand what those outliers were. They made you comfortable that it was a fair assessment and how do you control for those outliers in this next coming trial so that you have some of the type regences? Yeah, good question. So first of all, those were small trials, ends of 30 with ABPM and all the technical issues within our extremely challenging to get to statistics. And the, for instance, it was a few patients, there was one patient in particular who on the office blood pressures had a 60 millimeter mercury, I think, increase in blood pressure recorded.
David Rodman: In other words, an implausible value. It just can't be accurate. And that's what kind of thing we censored was just numbers that were just not plausible and not reproduced. So there was only a few. It was really the white code hypertension where most of the loss of information from ABPM was the issue. And in Annabelle, just to add to Dave's point, the distinction between target and advance and target AOBP was part of the randomization rule, not ABPM.
David Rodman: And AOBP was the primary and point. In this case of advanced HTN, they have to be hypertensive on the 24-hour ABPM to be randomized. And so that rule or randomization rule itself should eliminate that phenomenon that we saw in target HTN.
David Rodman: Okay, great. Thank you. Yeah, thanks, Annabelle.
Mohit Bansal: Our next question comes from Mohit Bansal with Wells Fargo, and so please stay a question.
David Rodman: I would like to ask you to move to six weeks versus 12 weeks because the way I see the trial, there are three different arms, there's 150 milligram, there's under 50 milligram moving to 100 milligram. So you can still compare the 50 milligram arm to the placebo arm. So I'm a little bit confused by the change here. Thank you. So it wasn't them telling us what to do. It was us suggesting that it would be better to do it that way.
David Rodman: It doesn't have to do with the primary. It didn't matter in that trial, but as big as it was, if you did the primary four weeks or 12 weeks, it has to do with power for the subset analysis. In other words, because you have two replicate arms, both at 50 milligrams, we can do the independent tests. For the primary each arm versus placebo, but let's say we want to ask a question, does it matter whether you're African American?
David Rodman: Well, we expect maybe 40% of the subjects of the African American. So now you're down to half the sample size, but by cooling the two now you get backed up to the number and so you get much more precision to get accurate answers to the subsets. So that's what we went back to the agency with and said in this big data set, we want to make sure that we can fully realize the power of the study and we think for the subsets, we'd be better at six weeks and basically the decision was, okay, if you're going to do that, let's just do the primary six weeks too.
David Rodman: God it, so that is basically to make sure that you can do the subgroup analysis properly with the bigger data set here. It just makes it much more simple and higher productivity. It's just, it's just a good, good idea.
David Rodman: God it, and then I have one more question. So we have seen a couple of readouts from MR is so obviously no, had some data, which was not that successful, but then buyer had some data in type 2 diabetes related CKD and that was quite successful. So, how do you see like obviously different classes, but related, how do you see these two data sets and and what do you learn from them, those data sets to to inform from your own CKD studies?
David Rodman: Well, first of all, MRAs generally are pretty similar. It doesn't matter if it's for an electron from 1959 or a very new one, the only difference are the stiroidal side effects, things like rest development and man and impedance and then completing and that kind of stuff. As far as everything else mechanistically, there's the same. What we observed with the MRAs is almost always you are unable to achieve the maximum therapeutic benefit on something like blood pressure because you're limited by the on target increases in potassium and also sodium going down those kinds of of things.
David Rodman: For instance, with frontal actone, the maximum efficacious dose is probably 200 milligrams, the conventional dose that he used is 25 milligrams, 50 milligrams by nephrology specialist sometimes. That's different. So we found in our drug, we can go above the maximum efficacious dose. 100 milligrams is the same as 50. So we can safely give 50 milligrams, which is the maximum efficacious dose. So overall, what I would say is the biggest difference that's apparent in the trials we're running is that the benefit risks, the ability to dose people all the way up to their efficacious dose from getting rid of Aldo is probably more achievable with an ASI-like hours than an MRA.
David Rodman: Now, long term, there are a lot of Aldo effects that aren't blood pressure and kidney. There are effects on adipocytes, on insulin sensitivity, on inflammation, on heart and blood vessel fibrosis. And not all of them are mediated through the MR that's blocked by those MRAs. And in fact, if you give an MRA, you increase aldosterone by two or three hundred percent and you thrive it into these other pathways. So if you did a longer trial and looked at things like best for stiffness, maybe you even have to have, I think eventually they would differentiate, but that's for us something to define once we're in the market for hypertension, we will certainly be looking at that.
David Rodman: Those are really the two aspects we would say that look pretty likely to differentiate and share the advantage of ASI over MRA. Okay. Thank you very much. Thanks, Mel. Head. Thank you, Inner Miner, to queue up for a question, press star one to remove your question, press star two.
Rami Katkhuda: Our next question comes from Rami Kuhuta with Lifestyle Capital. Please do your question. Hey guys, thanks for taking my questions as well. First, I just wanted to make sure that I heard you correctly in that you'll be able to do a subset analysis of LaRunder's test efficacy and uncontrolled and resistant hypertensive patients in advance. I guess do you expect a difference in efficacy between these populations? Well, I can answer the first question.
Rami Katkhuda: So we separately block randomized, uncontrolled and resistant. In other words, if we have 150 people who are resistant and we have 200 people who are uncontrolled, we'll have 200 uncontrolled placebo and 150 resistant placebo. They're matched in terms of the randomization. And so that means we have full statistical power to do those comparisons and they're with informative. Now your question of can I be prophetic and tell you whether it's going to work better in one or the other, I can't answer that. In the target HTN trial, when we asked that question, we didn't see a difference, but let's wait and see on this trial. I don't want to predict. Fair enough.
John Congleton: And then maybe switching to TKD, I guess given the previous results we saw with Bea Ringer's ASI, the recent failure with the MRA, is there a threshold of to talk about pressure reductions that you're looking for and explore to advance LaRunder's stat into a larger trial? for CKD. So what we think our drug is going to differentiate is we made the primary hypertension and the secondary is going to be albuminuria. And the reason for that is, we're going to be dosing at any hypertensive doses in people who have a both a hypertensive component to their CKD, and probably also a metabolic syndrome component.
John Congleton: And so we believe that by targeting that subpopulation, we will define a niche where our drug can differentiate from other approaches which are much more a general CKD population. That's why even though it's a crowded field with multiple players, we still think we've probably got the best in class ASI and it has potential in that way. Got it.
John Congleton: And I guess one more if you don't mind. Can you just remind us of the rationale for using the 25-mic dose instead of 50-mic and explore CKD study? Is it just hypercolinia and lower EGFR patients or is there more to it? Right. So it's an abundance of caution at this exploratory stage. We didn't want to take on the hypercalumina risk. Now I'll tell you our nephrology advisors say they're perfectly comfortable using potassium binders if needed to get the blood pressure down in these patients. So this is just the first step on the journey. But that's the main reason. Make sense. Thanks so much. Thanks, Ramay. Thank you, there are no further questions at this time.
John Congleton: I would like to turn the floor back over to John Congleton for closing comments. Thank you, operator. And thank you to everyone for joining us today.
John Congleton: We're very excited about the program's progress to date that we've made in the first half of 2024. And advance in our clinical programs. And we remain very enthusiastic about the upcoming milestones for the rest of the year and into 2025. We look forward to updating you as our pivotal program for the runner said continues to advance with that.
John Congleton: We will close the call. Thank you.
Operator: This concludes today's conference.
Operator: All parties may disconnect.