Q3 2024 Mineralys Therapeutics Inc Earnings Call
Greetings welcome to many rallies third quarter 'twenty 'twenty four financial results conference call. At this time all participants are in a listen only mode. A question and answer session will follow the formal presentation.
Operator: Welcome to Mineralys' third quarter 2024 financial results conference call. At this time, all participants are in a listen-only mode.
Operator: A question and answer session will follow the formal presentation. If anyone should require operator assistance, please press star zero on your telephone keypad. As a reminder, this conference is being recorded.
If anyone should require operator assistance. Please press star zero on your telephone keypad. As a reminder, this conference is being recorded its now my pleasure to introduce Dan sorry of life Science Advisors. Please begin.
Daniel Ferry: It is now my pleasure to introduce Dan Ferry of Lifesize Advisors. Please begin.
Unknown Attendee: Thank you, operator.
Dan sorry: Thank you operator.
Daniel Ferry: Good afternoon, everyone. And welcome to our third quarter 2024 conference call. After the close of market trading today, we issued a press release providing our third quarter 2024 financial results and business updates. A replay of today's call will be available on the investor section of our website approximately one hour after its completion. After our prepared remarks, we will open the call for Q&A.
Dan sorry: Afternoon, everyone.
Dan sorry: And welcome to our third quarter 2024 conference call after.
Dan sorry: After the close of market trading today, we issued a press release, providing our third quarter 2024 financial results and business updates.
Dan sorry: A replay of today's call will be available on the investors section of our website approximately one hour after its completion.
Dan sorry: After our prepared remarks, we will open the call for Q&A.
Daniel Ferry: Before we begin, I would like to remind everyone that this conference call and webcast will contain forward-looking statements about the company. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our annual report on Form 10-K. and subsequent filings. Please note that these forward-looking statements reflect our opinions only as of today, November 11.
Dan sorry: Before we begin I would like to remind everyone that this conference call and webcast will contain forward looking statements about the company.
Dan sorry: Actual results could differ materially from those stated or implied by these forward looking statements see the rest of uncertainties associated with the Companys business.
Dan sorry: These forward looking statements are qualified by the cautionary statements contained in today's press release interest SEC filings.
Dan sorry: Our annual report on Form 10-K.
Dan sorry: And subsequent filings. Please note that these forward looking statements reflect our opinions only as of today November 11th except as required by law, we specifically disclaim any obligation to update or revise these forward looking statements.
Unknown Attendee: Unknown Attendee, Michael DiFiore, Rami Katkhuda, Daniel Ferry, Jin Law, Jack Padovano, Mineralys I would now like to turn the call over to Jon Congleton.
Dan sorry: In light of new information or future events.
Speaker Change: I would now like to turn the call over to John Cognizant.
Jon Congleton: Chief Executive Officer of Mineralys Therapeutics, Jon.
John Cognizant: Chief Executive officer of minerals Therapeutics John.
Jon Congleton: Thank you, Dan.
John Cognizant: Thank you Dan Good afternoon, everyone and welcome to our third quarter 2024 financial results and corporate update conference call.
Jon Congleton: Good afternoon, everyone. And welcome to our third 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. Then Adam will review our third quarter financial results before we open up the call for your questions.
John Cognizant: I'm joined today by Adam <unk>, our Chief Financial Officer, and Dr. David Rodman, our Chief Medical Officer.
John Cognizant: Beginning with an overview of the business, our clinical programs and recent milestones.
John Cognizant: And then Adam will review, our third quarter financial results before we open up the call for your questions.
Jon Congleton: I want to kick things off with a recap of the progress the Mineralys team has made these past several months, advancing our pivotal clinical development of lorandostat in hypertension, and then discuss the upcoming milestones we anticipate throughout the first half of 2025. We recently completed enrollment in our Pivotal Advanced HTN trial, which is evaluating the efficacy and safety of lorandastat for the treatment of uncontrolled or resistant hypertension when used as an add-on therapy to a standardized background treatment of two or three antihypertensive medications. Subjects were randomized across three arms, including placebo, lorandastat 50 mg once daily, or lorandastat 50 mg once daily, with the possibility to titrate up to 100 mg once daily.
John Cognizant: To kick things off with a recap of the progress. The Minerality team has made these past several months advancing our pivotal clinical development of Laura understand in hypertension.
John Cognizant: And then discuss the upcoming milestones we anticipate throughout the first half of 2025.
John Cognizant: We recently completed enrollment in our pivotal advanced H D N trial, which is evaluating the efficacy and safety of Laura understand for the treatment of uncontrolled or resistant hypertension when used as an add on therapy to a standardized background treatment of two or three antihypertensive medications.
John Cognizant: Subjects were randomized across three arms, including placebo, Laura understand 50 milligrams once daily all of renders that 50 milligrams once daily with a possibility to titrate up to 100 milligrams once daily.
Jon Congleton: We announce the key characteristics of subjects enrolled in the trial include more than 66% of the subjects have a BMI equal to or greater than 30, more than 40% of the subjects are women, and more than 50% of the subjects are black or African American race. Notably, in terms of demographics, we took extra steps to broaden the diversity of the subjects in this trial to provide a better representation across different populations with the goal of showing equivalency across race and sex. As a reminder, this trial was designed in collaboration with the Cleveland Clinic based on the most rigorous standards.
John Cognizant: We announced the key characteristics of subjects enrolled in the trial include more than 66% of the subjects have a BMI equal to or greater than 30 more.
John Cognizant: More than 40% of the subjects are women and more than 50% of the subjects are black or African American race.
John Cognizant: Notably in terms of demographics, we took extra steps to broaden the diversity of the subjects in this trial to provide a better representation across different populations with a goal of showing equivalency across race and sex.
John Cognizant: As a reminder, this trial was designed in collaboration with the Cleveland Clinic based on the most rigorous standards.
Jon Congleton: The trial will be utilizing 24-hour ambulatory blood pressure monitoring, or 24-hour ABPM, which is the gold standard for blood pressure measurement, and historically has shown lower rates of white coat hypertension and has better managed placebo responses compared to other measurement approaches. Additionally, 24-hour ABPM has the ability to assess nighttime blood pressure and nighttime blood pressure dipping status, which have been shown to play a role in adverse cardiovascular risk and outcomes. Advanced HTN is utilizing smartphone-based technology to track and manage participant compliance to understand with a partner called AI Cure, which helps ensure the participants take all medication as prescribed under the trial protocol.
John Cognizant: The trial will be utilized in 24 hour ambulatory blood pressure monitoring or 24 hour a b P M, which is the gold standard for blood pressure measurement and historically has shown a lower rates of whitecoat hypertension and is better managed placebo responses compared to other measurement approaches.
John Cognizant: Additionally, 24 hour a b P. M. It has the ability to assess nighttime blood pressure and nighttime blood pressure dipping status, which have been shown to play a role in adverse cardiovascular risk and outcomes.
John Cognizant: Advanced H T and is utilizing smartphone based technology to track and manage participant compliance still are understand with a partner called AI cure.
John Cognizant: Which helps ensure the participants take all medications as prescribed under the trial protocol.
Jon Congleton: The primary endpoint for this trial is change in 24-hour ambulatory systolic blood pressure at week 12 from baseline for active cohorts versus placebo. The planned analysis includes several important subset analysis in an effort to identify predictors of enhanced response to lorandostad, such as obesity that was demonstrated in the phase two target HDN trial. Subjects with uncontrolled or resistant hypertension were stratified, providing balanced distribution across each of the three arms of the trial to allow us to perform a formal test in each population. We believe demonstrating robust efficacy and confirmed resistant hypertension, the area of highest medical need, will be important in positioning lorandostat for rapid access and uptake by payers and physicians.
John Cognizant: The primary endpoint for this trial is change in 24 hour ambulatory systolic blood pressure at week 12 from baseline for active cohorts versus placebo.
John Cognizant: The planned analysis includes several important subset analysis in an effort to identify predictors of enhanced response to Laura understand such as obesity that was demonstrated in the phase III target H T in trial.
John Cognizant: Subjects with uncontrolled or resistant hypertension were stratified for.
John Cognizant: Abiding balanced distribution across each of the three arms of the trial to allow us to perform a formal test in each population.
John Cognizant: We believe demonstrating robust efficacy and confirmed resistant hypertension the area of highest unmet medical need will be important in positioning Laura understand for rapid access and uptake by payers and physicians.
Jon Congleton: Positioning laryngostat for obese, uncontrolled hypertension patients who are at increased cardiovascular risk will provide an expanded market opportunity. In addition, as we accrue more experience and data with loranderstat, we plan to continue to explore other positive and negative predictive factors, including using artificial intelligence to expand the precision toolkit for targeting loranderstat to individuals with uncontrolled or resistant hypertension who are likely to derive long-term clinical benefit.
Positioning or under stat for obese uncontrolled hypertension patients who were at increased cardiovascular risk will provide an expanded market opportunity.
John Cognizant: In addition, as we accrue more experience and data with Laura understand we plan to continue to explore other positive and negative predictive factors, including using artificial intelligence to expand the precision tool kit for targeting Laura I understand to individuals' with uncontrolled or resistant hypertension.
John Cognizant: Who are likely to drive long term clinical benefits.
Jon Congleton: We look forward to announcing the top line data, which we anticipate sharing in March of 2025.
We look forward to announcing the top line data, which we anticipate sharing in March of 2025.
Jon Congleton: Moving to Launch H10, our second pivotal trial, which is designed to be a confirmatory trial with the objective of evaluating lorander stat in a real-world setting when added to a subject's previously prescribed antihypertension regimen. We were excited to announce just a few weeks ago that we completed enrollment in this trial. With enrollment of LaunchDate HTN completed ahead of schedule, we updated our guidance for top-line data, pulling these results forward to mid-first half 2025. Launch HTN is a phase 3 trial of Lorandersat 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.
Moving to launch aid stand our second pivotal trial, which is designed to be a confirmatory trial with the objective of evaluating render staff in a real world setting when added to a subjects previously prescribed anti hypertension regimen.
John Cognizant: We were excited to announce just a few weeks ago that we completed enrollment in this trial.
John Cognizant: With enrollment of launch D. H D and completed ahead of schedule, we updated our guidance for top line data pulling these results forward to mid first half 2020 five.
John Cognizant: Launch H D. N is a phase III trial novel or under Stat for the treatment of subjects with uncontrolled of resistant hypertension as add on therapy, who failed to achieve blood pressure control on their existing prescribed background treatment of two to five antihypertensive medications.
Jon Congleton: Subjects enrolled in the trial who failed to achieve blood pressure control on their existing prescribed treatment were randomized one to two to one to either placebo, once daily 50 milligrams of lorandastat, or once daily 50 milligrams of lorandastat with the option to titrate to 100 milligrams once daily 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 at week six for the pooled 50 milligram subjects compared to placebo. This trial is well-powered at six weeks for the primary endpoint, as well as subset analysis, such as BMI status, to inform the clinical label of lorander stat.
John Cognizant: Subjects enrolled in the trial, who failed to achieve blood pressure control on their existing prescribed treatment were randomized one to two to one to either placebo. Once daily 50 milligrams of Laura understand our once daily 50 milligrams of Lora understaffed with the option to titrate, each 100 milligrams once daily as needed.
John Cognizant: At week six.
The primary endpoint for this trial will be the change since the starlink blood pressure as measured by automated office blood pressure at week six for the pooled 50 milligram subjects compared to placebo.
John Cognizant: This trial is well powered at six six weeks for the primary end point as well as subset analysis, such as BMI status to inform the clinical label of Laura understand.
Jon Congleton: We believe this trial is reflective of clinical practice utilizing the real world and office measurement. And when LaRunderSTAT is added to an existing treatment regimen that will be relevant to primary care providers.
John Cognizant: We believe this trial is reflective of clinical practice utilized in the real World and office measurement and when Laura understand is added to an existing treatment regimen that will be relevant to primary care providers.
Jon Congleton: In addition to our pivotal program in hypertension, we're conducting the Explore CKD phase two clinical trial for lorandostat when added to background treatment with SGLT2 inhibitor in patients with uncontrolled or resistant hypertension in stage two to three B chronic kidney. Enrollment is ongoing and we anticipate announcing top line data in the second quarter of 2025. Explore CKD as a within-subject comparison trial designed to demonstrate the benefit of lorandastat in reducing blood pressure and provide supportive evidence for potential benefit for subjects with chronic kidney disease on the background of stabilized GLT2 inhibitor treatment. This proof-of-concept trial will enroll approximately 60 subjects with hypertension in stage 2 to 3b CKD.
John Cognizant: In addition to our pivotal program in hypertension, we're conducting the explore CK two phase two clinical trial for lenders that weren't added tabak round treatment with S. G. L. T. Two inhibitor in patients with uncontrolled or resistant hypertension.
John Cognizant: Stage two to three be chronic kidney disease enrollment is ongoing in wind and anticipate announcing top line data in the second quarter of 2025.
Explore C K D as a within subject comparison trial designed to demonstrate the benefit of law render stat, and reducing blood pressure and provide supportive evidence for potential benefit for subjects with chronic kidney disease on the background of stabilized G. L. T. Two inhibitor treatment. This.
John Cognizant: This proof of concept trial will enroll approximately 60 subjects with hypertension and stage two to three B C. J D.
Jon Congleton: Before I turn the call over to Adam, I just want to remind everyone that a replay of the KOL event we hosted October 30th is still available on the investor section of the Mineralys website. We are very fortunate to have three leaders in the hypertension field join us on the call, including Dr. Luke Laughlin of the Cleveland Clinic, Dr. James Luther of Vanderbilt University Medical Center, and Professor Rhian Touyz of McGill University Health. They each offered valuable insights on the unmet medical need and uncontrolled and resistant hypertension, as well as the potential for larundrastat to change the current treatment paradigm.
Speaker Change: Before I turn the call over to Adam I, just want to remind everyone that a replay of the Kols event. We hosted October 30th is still available on the investors section of the mineralogy website.
Speaker Change: We are very fortunate to have three leaders in the hypertension field join us on the call, including Dr. Luke often of the Cleveland Clinic, Dr. James Luther and Vanderbilt University Medical Center, and Professor ran Twos Mcgill University Health Center.
Speaker Change: They each offered valuable insights on the unmet medical need in uncontrolled and resistant hypertension as well as the potential for Lam understaffed to change the current treatment paradigm.
Jon Congleton: We also included a detailed review of the ongoing Advanced HTN and Launch HTN pivotal trials and their design.
Speaker Change: We also included a detailed review of the ongoing advance H D N and launch H T in pivotal trials and their designs.
Adam Levy: I'll now turn the call over to Adam to review our financial results for the court. Thank you, Jon. Good afternoon, everyone. Today I will discuss select portions of our third quarter 2024 financial results.
I'll now turn the call over to Adam to review, our financial results for the quarter.
Adam: Thank you John Good afternoon, everyone today, I'll discuss select portions of our third quarter 2024 financial results. Additional details can be found in our Form 10-Q, which will be filed with the SEC Tomorrow November 12.
Adam Levy: Additional details can be found in our Form 10Q, which will be filed with the SEC tomorrow, November 12. We ended the quarter with cash equivalents and investments of $263.6 million as of September 30, 2024, compared to $239 million as of December 31, 2023. The company believes that its current cash equivalents and investments will be sufficient to fund its planned clinical trials, as well as support corporate operations into 2026. R&D expenses for the quarter ended September 30, 2024 were $54 million compared to $22.5 million for the same quarter of 2023. The increase in R&D expenses was primarily due to increases of $26.1 million in preclinical and clinical costs driven by the initiation of the La Ronda Stat Pivotal Program in the second quarter of 2023.
Adam: We ended the quarter with cash cash equivalents and investments of $263 $6 million as of September 32024, compared to $239 million as of December 31, 2023. The company believes that its current cash cash equivalents and investments will be.
Adam: Sufficient to fund its planned clinical trials as well as our corporate operations into 2026.
Adam: R&D expenses for the quarter ended September 32024 were $54 million compared to $22.5 million for the same quarter of 2023.
Adam: The increase in R&D expenses was primarily due to increases of $26.1 billion in preclinical and clinical costs driven by the initiation of the law or under Stat pivotal program in the second quarter of 2023 three.
Adam Levy: $3.4 million in clinical supply, manufacturing, and regulatory costs, $1.7 million in higher compensation expense resulting from additions to headcount, increases in salaries, and accrued bonuses, and increased stock-based compensation of $0.3 million in other research and development expenses.
Adam: $3 $4 million and clinical supply manufacturing and regulatory costs, $1 $7 million and higher compensation expense as well.
Adam: <unk> from additions to head count increases in salaries and accrued bonuses and increased stock based compensation of zero point $3 million in other research and development expenses.
Adam Levy: GNA expenses were $6.1 million for the quarter ended September 30, 2024, compared to $3.8 million for the same quarter of the prior year. The increase in GNA expenses was primarily due to $1.7 million in higher compensation expense resulting from additions to headcount, increases in salaries and accrued bonuses, an increased stock-based compensation, and $0.8 million in higher professional partially offset by a decrease of $0.2 million in other administrative expenses.
Adam: G&A expenses were $6 $1 million for the quarter ended September 32024, compared to $3 $8 million for the same quarter of the prior year.
Adam: The increase in G&A expenses was primarily due to $1 $7 million and higher compensation expense, resulting from additions to head count increases in salaries and accrued bonuses and increased stock based compensation and zero point $8 million and higher professional fees.
Adam: Partially offset by a decrease of zero point $2 million and other administrative expenses total other income was $3 $8 million for the quarter ended September 32024, compared to three $5 million for the same quarter of 2023.
Adam Levy: Total other income was $3.8 million for the quarter ended September 30, 2024, compared to $3.5 million for the same quarter of 2023. The increase was primarily attributable to increased interest earned on the company's investments in money market funds in U.S. Treasury.
Adam: The increase was primarily attributable to increased interest earned on the company's investments in money market funds and U S treasuries and.
Adam Levy: Net loss was $56.3 million for the quarter ended September 30, 2024, compared to $22.8 million for the same quarter of 2023. The increase was primarily attributable to the factors I described earlier.
Adam: Net loss was $56 $3 million for the quarter ended September 32024, compared to $22 $8 million for the same quarter of 2023.
Speaker Change: The increase was primarily attributable to the factors I described earlier with that I'll ask the operator to open the call for questions operator.
Operator: With that, I'll ask the operator to open the call for questions.
Operator: Operator? Thank you. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. And for participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys.
Speaker Change: Yes.
Thank you if you would like to ask a question. Please press star one on your telephone keypad.
Speaker Change: For me to tell will indicate your line is in the question queue. You May press star two if he 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. He has one moment, while we poll for questions.
Operator: One moment while we poll for questions.
Michael DiFiore: Our first question is from Michael DiFiore with Evercore ISI. Please proceed. Hey guys, thanks so much for taking my question and congrats on all the progress.
Speaker Change: Our first question is from Michael T floor with.
Speaker Change: Evercore ISI. Please proceed.
Hey, guys. Thanks, so much for taking my question and congrats on all the progress a three for me first one is just in reviewing the target 18 dataset I'm looking at the nighttime.
Unknown Attendee: Three for me. First one is just in reviewing the the target 18 data I'm looking at the nighttime blood pressure results. In a sensitivity analysis, even after the white coat hypertension patients were eliminated, we noticed that there wasn't any nocturnal dipping at eight weeks in the 50 milligram Unknown Speaker.
Blood pressure results and.
Speaker Change: In the sensitivity analysis, even after the white coat hypertension patients were eliminated.
Speaker Change: We noticed that there wasn't any nocturnal dipping at eight weeks in.
In the 50 milligram QD group.
Speaker Change: Any color explain that would be great and then I have two follow ups.
David Rodman: Unknown Speaker, Yeah, so this is Dave Rodman. Why don't I take that question? So first of all, you're absolutely right that the big value driver in 24-hour ambulatory measurements is, first of all, you get a lot of measurements, so you get much quieter data, a lot less noise. But you also get this segmented into nighttime and daytime. And as you mentioned, nighttime is particularly important. because untreated nocturnal hypertension is a big risk factor for adverse cardiovascular outcomes and MACE. So, if I can point you first to the 100 milligram cohort where we had a very little white coat hypertension, there the nighttime response to laryngostat was comparable to what was seen in wakefulness, even though the dose was taken in the morning and those measurements were in the evening.
Speaker Change: Yeah. So this is Dave Rodman why don't I take that question.
Speaker Change: So your.
Speaker Change: First of all.
Speaker Change: You're absolutely right that the big value driver in 24 hour ambulatory measurements is first of all you get a lot of measurements you get much quieter.
Speaker Change: Data a lot less noise, but you also get to segment it into nighttime in daytime and as you mentioned nine times, particularly important.
Speaker Change: Because.
Speaker Change: Untreated nocturnal hypertension is a big risk factor for adverse cardiovascular outcomes.
Speaker Change: And mace.
Speaker Change: So if.
If I can point you first to the 100 milligram.
Speaker Change: <unk> well we had.
Speaker Change: Very little White coat hypertension, there. The night time response to better understand was comparable to what was seen in wakefulness, even though the dose was taken in the morning and those measurements. We are in the evening and so that's what you would expect.
David Rodman: And so, that's what you would expect. The 50 milligrams a little more problematic to interpret because there was a very high proportion of patients who on the ABPM appeared to have a lower blood pressure than they had with AOBP or so-called white coat hypertension. So, we had to subtract all those people out to do the sensitivity analysis. And when we did that, it was about a 50% reduction compared to daytime. I think it's unlikely that that's true because the numbers got too small. I do think the 100 milligrams probably a better guidepost. But in any event, we'll be looking and controlling for that in the trial.
Speaker Change: There's 50 milligrams, a little more problematic to interpret because there was a very high proportion of patients who are on the a b P. M appeared to have a kind of a lower blood pressure than they had with a O V. P of our so called white.
White coat hypertension, so we had to subtract all those people out to do the sensitivity analysis and when we did that it was about a 50%.
Speaker Change: Reduction compared to daytime.
I think it's unlikely that that's <unk>.
True because the numbers got too small I do think the 100 milligram is probably a better guidepost, but in any event, we'll be looking in controlling for that in the trial.
David Rodman: So we'll have the accurate answer for that.
Speaker Change: So we will have the accurate answer for that.
Speaker Change: Yeah.
Unknown Attendee: Thank you, very helpful.
Got it. Thank you. Thank you very helpful and my two follow ups are we were just reviewing the early safety database I was like the first in human study data set and I noticed that in the phase one Mad trial. There was one case of sinus tachycardia at 360 milligram.
Unknown Attendee: And my two follow-ups are, we were just reviewing the early safety database of like the first in human study data set. And I noticed that in a phase one MAD trial, there was one case of sinus tachycardia at 360 milligrams. And my question is, how big of a safety margin relative to the NOAEL is 360 milligrams? And separately, in the same data set, there was also one case of dysgeusia at 40 milligrams. And just ask me, because that could potentially be an unblinding, a functional unblinding. type of thing. Any explanation of those two aides?
Speaker Change: My question is how big of a safety margin relative to the N O N E. L is free and 15 milligram and separately I'm in the same data set there was also a one case of this Julia at 40 milligram and I'm, just asking because that could potentially be an unwinding of functional and blinding.
A thing any explanation of those two as it would be great. Thank you.
David Rodman: So the first one, I'll take the first one first. So that's a pretty big dose, 360 milligrams. How does this drug work? Well, acutely, it causes volume loss. So you urinate out sodium and water. The response to that is sinus tachycardia. So when you get dehydrated or volume depleted, that's what happened. So it's not really a safety finding. It's a pharmacodynamic effect of a healthy volunteer having too much volume depletion. And so that we don't expect to read through at the lower doses, especially in these hypertensive patients.
So the first one I'll take the first one first so that's a pretty big dose 360 milligrams. How does this drug work well acutely it causes volume loss. So you urinated out sodium and water. The response to that is sinus tachycardia. So when you get dehydrated or volume.
Speaker Change: Depleted that's what happened so it's not really a safety finding it's a pharmacodynamic effect.
Speaker Change: The healthy volunteer having too much volume depletion and so that we don't expect to read through at the lower doses, especially in these hypertensive patients.
David Rodman: Now, your second question, Dysgusia, I got no idea on that one. I just don't know. We didn't, you know, haven't seen it again. Whether it's unblinding or not, it just hasn't been a functional problem in our trial. Okay.
Speaker Change:
Speaker Change: Now your second question.
Just goes yeah.
Speaker Change: I got no idea on that one I just don't know we didn't you know so I haven't seen it again.
Speaker Change: Whether it's on blinding or not it just hasn't been a functional problem in our trials.
Speaker Change: Okay.
Unknown Attendee: Thank you.
Speaker Change: Very helpful.
Speaker Change: Yeah.
Unknown Attendee: Anything else, Mike? Now that's it, thank you. You bet.
Speaker Change: Anything else Mike.
Speaker Change: That's it thank you appreciate it.
You bet. Thank you.
Richard Law: Our next question is from Richard Law with Goldman Sachs. Please proceed. Hey guys, a couple of questions from me. The first one is for Advanced HTN, you guys are tracking and proactively enforcing adherence. Can you discuss what is the adherence rate for Target HTN? How much do you think that the adherence can improve in Advanced HTN? So the question was, what's the adherence rate in the TARGET-HTN trial versus ADVANCE, or? No, you're looking for what is the goal.
Speaker Change: Our next question is from Richard <unk> with Goldman Sachs. Please proceed.
Speaker Change: Hey, guys a couple of questions from me. The first one is for advent 60, and you guys are tracking and proactively enforcing adherence can you discuss what does the adherence rate for target H P and how much do you think that the hearings can improve.
Speaker Change: 16.
So the question was what's the adherence rate in.
Speaker Change: The target H TN trial versus Vance or no youre looking for what is the goal rich can you restate your question again sorry.
Richard Law: Rich, can you restate your question again? Sorry. Yeah, so for ADVANCE-HTN, you guys are tracking and proactively enforcing adherence, but you guys are not doing, you guys didn't do that for TARGET-HTN. So just curious to see, what was the adherence rate for TARGET-HTN, and how much do you think that could improve as you move into ADVANCE-HTN by that proactively tracking and enforcing? Okay, gotcha. Good question. So, we didn't, the only thing we did was really was to do pill counts when people came in to see if they had taken their drug or not. We piloted some technologies, but we didn't really use the data.
Speaker Change: So for <unk> T and you guys are tracking and proactively enforcing adherence, but you guys are not doing it you guys didn't do that for targeting 10. So just curious to see what would that adherence way for talking about T. N at how much do you think that could improve.
Speaker Change: As you move into at that thank you tien by by that proactively tracking and enforcing.
Speaker Change: Okay Gotcha good question so.
Speaker Change: We didn't the only thing we did was really was to do pill counts when people came in to see if they had taken their drug or not we piloted some technologies, but we didn't really use the data.
David Rodman: That's how we ultimately ended up choosing the AI cure method that we're using now. So, I can't give you any accurate information because pill counts are notoriously ineffective because people know you're doing it. And so they might just dump them in the sink or whatever. But in the launch trial, we are also doing adherence, but we're not actively supporting that in terms of reaching out or telling them much. And so other than the normal reminders. So I think there and there, we're going to do a subset analysis that looks at your question, which is how much.
Speaker Change: That's how we ultimately ended up choosing the AI cure method that we're using now.
Speaker Change: So.
Speaker Change: I can't give you any accurate information.
Speaker Change: Cause pill counts are notorious Lee ineffective, because people know you're doing it and so they might just dump them in the sink or whatever.
But.
Speaker Change: In the launch trials, we are also doing adherence, but we're not actor actively supporting that in terms of reaching out or telling them much and so other than the normal reminders. So I think they're and they're we're gonna do a subset analysis that looks at your question.
Speaker Change: Which is how much.
David Rodman: is non-adherence a problem in terms of responses? So we'll, you know, do a sensitivity analysis on people who took more than 75% or not. So I can't really comment too much on the target, but we will have an answer to your question.
Speaker Change: Is non adherence is a problem in terms of responses. So well you don't do a sensitivity analysis on people, who took more than 75% or not.
Speaker Change: So I can't really comment too much on the track that target, but we will have an answer to your question.
Unknown Attendee: I see. Got it.
Speaker Change: I see got it and then.
Richard Law: And then another question. You guys mentioned a lower absolute SBP value with the ABPM measurement. How do you think about a placebo-adjusted ABPM and how would that change compared to placebo-adjusted ALBP, for example, in advanced HTN? Is it safe to assume that both are very similar if the study is well controlled?
Speaker Change: Another question you guys mentioned, a lower absolute S. B P value with the a P. P M measurement.
How do you think about a placebo like jet that a b P M and how would that change compared to placebo at just the a L. P. P.
Speaker Change: For example in that thank you.
Speaker Change: It's T N is it safe to assume that both are very similar type of studies well control.
David Rodman: Well, I'll give a quick heads up on that, Rich. We typically see with 24-hour ambulatory, it's plus or minus one, maybe two millimeters of mercury with a placebo with that 24-hour. AOBP, you see a little bit more variability with that because it's in office. It's, you know, a single time point from a measurement standpoint, you know, from target HTN because of the technique we use in doing five measurements in a quiet room unattended and averaging the last two, we saw about a four millimeter mercury change. We know prior studies that have used different methodologies around that, such as the SYNCOR trials actually saw higher figures than that.
Speaker Change: Well I'll give a quick.
John Cognizant: Up on that rich, we typically see with 24 hour ambulatory, it's plus or minus one maybe two millimeters of mercury with a placebo.
John Cognizant: With that 24 hour.
John Cognizant: A L b P, you'll see a little bit more variability with that because it's an office.
John Cognizant: As you know.
John Cognizant: A single time point from a measurement standpoint, you know from target H T and because of the technique. We use in doing five measurements in a quiet room unintended and averaging in the last two we saw about a four millimeter mercury change.
John Cognizant: We know prior studies that have used different methodologies around that such as the same core trials actually saw higher figures than that.
David Rodman: So from our standpoint, following the recommendations from the AHA, we're continuing to repeat our technique for in-office measurement, and have not only 24 ambulatories, the primary and advanced, along with in-office, we also have in-home. So we have three different measures with an advanced HTN and then the in-office practice that we use for launch HTN. And so we feel confident that we've controlled for the variables within the different techniques.
John Cognizant: So from our standpoint, following the recommendations from the a J, we're continuing to repeat our technique for an office measurement and have not only 24 hour ambulatory as the primary in advance along with an office. We also have in home. So we have three different measures with an advanced stage.
John Cognizant: Stan and Deanne office practice that we use for launch H T M.
John Cognizant: And so we feel confident we've controlled for the variables within the different techniques.
Unknown Attendee: Unknown Attendee. And we'll, you know, that's based on the work that we've done with Target HTN. Hey, Rich, one other comment here is that the measurements with ABPM, because they average in nighttime, which tends to be lower in people that don't have, say, sleep apnea, tend to be about five millimeters mercury lower, and response to hypertension drugs is proportionate to the level of the baseline blood pressure. So if you have a lower baseline blood pressure, you can go down less, so you have a little bit smaller response. So most people say you have one or two millimeters smaller placebo adjusted treatment effect when you do ABPM versus AOBP.
John Cognizant:
John Cognizant: Then more.
John Cognizant: That's based on the work that we've done with target H D N pay.
Speaker Change: Hey, Richard one other comment here is that.
Speaker Change: That's with a b P M. Because they average in night time, which tends to be lower and people that don't have to say sleep apnea.
Speaker Change: Tend to be about five millimeters of Mercury lower and response to hypertension drugs is.
Speaker Change: Proportionate to the level of the baseline blood pressure. So if you have a lower baseline blood pressure you have.
Speaker Change: You can go down unless you have a little bit smaller response. So it's you know that.
Speaker Change: So most people say you have one or two millimeters.
Speaker Change: Smaller placebo adjusted treatment effect, when you do a b P M versus a L. B P. And then as John mentioned those numbers are just shifted up with the a b P M, but there's more variability in the placebo effect. There. So they're just a little bit noisier, maybe that was more than you.
Unknown Attendee: And then as Jon mentioned, those numbers are just shifted up with the ABPM, but there's more variability in the placebo effect there. So they're just a little bit noisier.
Unknown Attendee: Maybe that was more than you wanted to know, but just thought I'd pass it on.
Speaker Change: Wanted to know, but just thought I'd pass it on.
Unknown Attendee: No, I think that that helps a lot. So you're saying about five or so on an absolute basis. But once you adjust for placebo, that should be about one to two.
Speaker Change: No I think that that that helps a lot so you're saying about five or so on an absolute basis, but once you adjust for placebo that should be about one to two.
Unknown Attendee: I'm not sure of that, but so so the difference is that. that with ABPM, because of all the multiple measurements, your placebo effect is going to be pretty small. You know, I would say one to four is what I've seen in the literature. In a big enough study, it'll be one or two. And that's what we were with our target study. ABPM, you know, up to seven, AOBP, I mean, AOBP, sorry, up to seven millimeters of mercury, or even if you look at BaxterSat, they had nine, I think, in their first trial, up to seven's acceptable, you know, in general, it's in the range.
Speaker Change: I'm not sure of that but so so the differences.
Speaker Change: Okay.
Speaker Change: That with a.
Speaker Change: H.
Speaker Change: B P M because of all the multiple measurements you placebo effect is going to be pretty small.
Speaker Change: I would say one to four is what I've seen in the literature.
Speaker Change: And a big enough study it'll be one or two and that's what we were with our target study.
Speaker Change: P M.
Speaker Change: Up to seven <unk>, I mean, I I O b piece already up to seven millimeters of Mercury mm or even if you look at.
Speaker Change: Baxter's that they had nine I think in their first trial up to Sevens acceptable you know in general it's in the range we had for so.
Unknown Attendee: We had four. So, and we put a lot of work into making sure we get the best data we can. Obviously, when you get to bigger trials and more sites, you tend to have slightly more variability.
And we put a lot of work into making sure we get the best data. We can obviously when you get to bigger trials and more sites you tend to have slightly.
Speaker Change: More variability.
Unknown Attendee: I'm not sure I understood your question per se, but I hope that gives you the answer you needed.
Speaker Change: I'm not sure I understood. Your question per Se, but I hope that gives you the answer you need it.
Unknown Attendee: Okay, got it. Thanks.
Speaker Change: Okay got it. Thanks, and then just one final question you guys mentioned greater than 66% patients with BMI greater than 30, what is the power assumption for that like greater than 30 in less than 30 P. M. A group from the ethics, 6% number I think you guys mentioned, a 90% powering assumptions for the overall group. So just wanted to see what that.
Unknown Attendee: And then just one final question. You guys mentioned greater than 66% patients with BMI greater than 30. What is the power assumption for that like greater than 30 and less than 30 BMI group from that 66% number? I think you guys mentioned a 90% powering assumption for the overall group. So just want to see what that powering assumption looks like when you go down to these pre-specified subgroups.
Speaker Change: Powering assumptions look like when you go down to these pre specified subgroups and thank you yeah rich. Thanks for the questions advance H T. M. Overall has 90% power for seven millimeter Mercury change relative to placebo launch H T and greater than 95% power for the same reduction.
Unknown Attendee: And thank you. Yeah, right. Thanks for the questions. Advanced HTN overall is 90% power for 7-millimeter mercury change relative to placebo. Launch HTN greater than 95% power for the same reduction.
Unknown Attendee: And we haven't disclosed at this point in time any of the subset analysis power calculations.
Speaker Change: And we haven't disclosed at this point in time any of the subset analysis powering calculations.
Unknown Attendee: Okay, thanks guys. Thank you.
Speaker Change: Okay. Thanks, guys.
Speaker Change: Thank you.
Annabel Samimy: Our next question is from Annabel Samimy with Stiefel. Please proceed.
Speaker Change: Our next question is from Annabel <unk> with Stifel. Please proceed.
Annabel Samimy: Hi. Thanks for taking my question. I just wanted to clarify a couple of things. For advanced HCN, the primary endpoint is at 12 weeks with titration at four weeks, and then launch has up titration at six weeks with the primary endpoint there, but runs to 12 weeks, if I'm reading your presentation correctly. So, is the six-week sufficient for that separation given the possible additional noise that might be introduced with real-world background meds? I guess, how are you managing the placebo response in that scenario? Are there going to be more confounding results possibly, and is six weeks sufficient?
Speaker Change: Hi, Thanks for taking my question I, just want to clarify a couple of things for advanced HCM. The primary endpoint is at 12 weeks of titration at four weeks and then launch has up titration at six weeks with a primary end point, there, but rest of 12 weeks.
Speaker Change: If I'm reading your presentation correctly. So is that is this six week.
Speaker Change: For that separation given the possible additional noise that might be introduced with real world background Meds I guess, how are you managing the placebo response in that scenario.
Speaker Change: Are there going to be more confounding results, possibly and a six week sufficient why I guess why not run it to 12 weeks with that kind of background variability.
Annabel Samimy: I guess, why not run it to 12 weeks with that kind of background variability?
Jon Congleton: Yeah, Annabel, appreciate the question. I think it's important to think of LAUNCH-HTN very much as a confirmatory study to TARGET-HTN. There are a lot of similarities as far as the construct. As you know, in TARGET, as in LAUNCH, we allow subjects to stay on their background medication of two to five antihypertensive treatments. We have that two-week run-in period on placebo where we get them compliant to their existing background meds. We're using AOBP and Launch HTN, same technique, same technology that we used in Target. What we saw in Target HTN was about 70% plus or minus of the effect at week two and by week four, the vast majority of the effects.
Speaker Change: Yeah Annabel appreciate the question I think it's important to think of launch age 10, very much as a confirmatory study the target age 10, there are a lot of similarities as far as the construct.
Speaker Change: As you know and target is in launch we allowed subjects to stay on their background medication of two to five.
Speaker Change: Hypertensive treatments, we have that two week run in period on placebo, when we get them compliance of their existing background meds were you.
Speaker Change: Using a OBP and launch age 10 same technique same technology that we used in target.
Speaker Change: What we saw in target age Tien was about 70% plus or minus of the effect at week, two and by week four the vast majority of the effects were more comfortable that that six week data readout, we're not gonna be missing.
Jon Congleton: So we're comfortable that that six-week data readout, we're not going to be missing really any significant reduction in blood pressure within that time course, just based on what we saw within Target HTN at week four. And I'll just highlight that maybe one of the biggest distinctions between the two studies is we definitely saw a potential synergy with the diuretic in Target, where about half the subjects were on a diuretic. And by design, both in Advance and in Launch HTN, all subjects are on a diuretic. So, I think we've factored in the profile of lorandristat within this confirmatory design of Launch HTN that we don't feel we're going to be missing anything.
Speaker Change: Really any significant reduction in blood pressure.
Speaker Change: Within that time course, just based on what we saw within target H T N at week, four and I'll just highlight that maybe one of the biggest distinctions between the two studies as well.
Speaker Change: We definitely saw a potential synergy with the diabetic in target where about half the subjects run a diuretic and by design both in advance and in launch H T. In all subjects are on a diuretic.
Speaker Change: So I think we've factored in the profile of Lorenzo stat.
Speaker Change: Within this confirmatory design of launch H T N. A the way we don't feel we're gonna be Miss anything plus as part of the secondaries, we will be looking at that 12 week time point.
Jon Congleton: Plus, as part of the secondaries, we will be looking at that 12-week time point for both the 50-milligram arm and the 50-up titrated to 100-milligram arm.
Speaker Change: Both the 50 milligram arm and the 50 up titrated to 100 milligram arms.
Annabel Samimy: Okay, got it. And just to go back to the last question for a minute, I know you haven't disclosed the pairing for obese versus non-obese, but is there a possibility to see statistical significant separation between the two? Well, I think we'll be looking at, you know, as we did in target HCN, these pre-specified subsets in both advance and in launch.
Speaker Change: Okay got it and just to go.
Speaker Change: Go back to the last question for I mean, I know you haven't disclosed the hiring for obese versus non obese, but is there a possibility to see statistically significant separation between the two.
Speaker Change: Well I think we will be looking at you know as we did in target H T. In these pre specified subsets in both advance and in launch.
Jon Congleton: You know, the primary benefit of moving the primary endpoint of launch HCN from week 12 to week 6 was not power for the primary, but was power for those subset analysis. And so we feel very confident that we're going to be able to If the trend reconfirms, as we saw on Target H10, be able to have the statistical power to evidence that. But again, we've got to get to the data, but that's going to be part of the pre-specified analysis as we did in Target H10.
Speaker Change: You know the primary benefit of moving the primary endpoint of lunch HCN from week 12 to week six was not powered for the primary but was power for those subset analysis.
Speaker Change: So we feel very confident that we're going to be able to.
Speaker Change: If the trend reconfirms as we saw in target aged and be able to have the statistical power to evidence that but again, we've got to get to the data.
Speaker Change: That's going to be part of the pre specified analysis is we didn't target age 10.
Annabel Samimy: Okay, got it. And then just to also clarify.
Speaker Change: Okay got it and then just sit also clarify.
Unknown Attendee: Should we expect any dose response between the 50 and the 100 milligrams arms, or is this more about getting patients to the right exposure so they can actually have a response as opposed to, like, in other words, should we be looking for a dose response, or should we just be looking for blood pressure control period? Yeah, what a good question. So, two ways to look at that. At 12 weeks, say, let's just talk about advance. At 12 weeks in advance, there'll be three arms, right? There'll be, and the same thing's true in launch. There'll be a placebo group, there'll be a group that stayed on 50, and then there'll be a group that got escalated if they hadn't reached goal to 100.
Speaker Change: Should we expect any dose response between the 50 and 900 milligrams arms or is this more about getting patients to the right studies. So they can actually have a response as opposed to like in other words should we be looking for a dose responsive he would just be looking for.
Speaker Change: Blood pressure control period.
Yeah, what a good question. So two ways to look at that at 12 weeks say, let's just talk about advance at 12 weeks in advance there'll be three arms right there'll be and the same thing's true and in launch there'll be a placebo group there'll be a group that stayed on 50, and then there'll be a group that got.
Escalated if they hadn't reached skull to 100 and so if.
Unknown Attendee: And so if The If people didn't have a high enough exposure at 50 because they didn't absorb it well or whatever, 100 might fix that. If people just have a lot of aldosterone production and they aren't completely suppressed at 50, then 100 would fix that. So we won't know for sure if it's exposure to drug or individual biology. Until we start looking at maybe downstream mechanistic biomarkers, which won't come for a while. So I hope that answered your question. You're absolutely right. Yeah, okay, thank you.
The.
Speaker Change: If people didn't have at a high enough exposure to food safety, because they didnt absorb it well or whatever 100 might fix that if people just have a lot of aldosterone production.
Speaker Change: And they arent completely suppressed at 50, and 100 would fix that so we won't know for sure if its exposure to drug or individual biology.
Speaker Change: Until we start looking at maybe downstream mechanistic, biomarkers, which won't come for a while.
Speaker Change: So I hope that answered your question you're absolutely right.
Yeah. Okay. Thank you that's helpful. Thanks.
Unknown Attendee: That's helpful.
Unknown Attendee: Thanks Annabel.
Speaker Change: Thanks Annabel.
Sadia Rahman: Our next question is from Mohit Bansal with Wells Fargo. Please proceed.
Speaker Change: Our next question is from Mohit Bansal with Wells Fargo. Please proceed.
Sadia Rahman: Hi, this is Sadia Rahman. I'm for Mohit. Thanks for taking our questions. So you've outlined patient demographics for the advanced trial. I'm wondering if in launch, you're targeting similar demographics in terms of the percentage of obese patients and the percentage of African Americans. Will they be similar or should we expect differences in any of these? And can you remind us how these rates in advance compared to the population that was enrolled in Target? Yeah, we haven't. We haven't updated on the demographics of launch HTN. We may do that in the future. Target HTN, I believe we had about the BMI average was 31 or mean in target HTN was 31.
Speaker Change: Hi, This is Saudi are going on for Raimo, thanks for taking our questions.
Speaker Change: So you've outlined patient demographics for the advance trial I'm wondering if and launch you're targeting similar demographics in terms of the percentage of obese patients.
Speaker Change: And the percentage of African Americans.
Speaker Change: Or will they be similar.
Speaker Change: You shouldn't expect differences in any of these and can you remind us how these rates in advance.
Speaker Change: Compared to the population that was involved in target.
Speaker Change: Yeah, we haven't.
We haven't updated on the demographics of launch H T and we may do that in the future.
Speaker Change: Target H T and I believe we had about the BMI average was 31 or mean.
Speaker Change: And target H soon was 31.
Jon Congleton: What are the kilograms per meter squared, Dave? And the black or African-American population, I believe, is around 39 percent. Um. So not terribly dissimilar from what we saw in advance. I think it's fair to point out that both advance and target probably beyond what you typically see as far as representation for black or African-American, that's important to really show equivalency between Caucasian and black or African-American hypertension patients, because that's not always the case with all antihypertensives. Sometimes you can see disparity in response. We wanted to be able to evaluate that as a part of our precision toolkit.
Speaker Change: What does it kilograms per meter squared, Dave and the black or African American population.
Speaker Change: I believe it was around 39%.
Speaker Change:
Speaker Change: So not terribly dissimilar from what we saw in advance I think it's fair to point out that both advance and target them.
Speaker Change: Beyond what you typically see as far as representation for black or African American women that's important.
Speaker Change: Truly show equivalency.
Speaker Change: Between Caucasian in Black or African American.
Speaker Change: Hypertension patients.
Speaker Change: Because that's not always the case with all anti hypertensive, sometimes you can see disparity in response, we wanted to be able to evaluate that as a part of our precision tool kit.
Jon Congleton: As far as LAUNCH-HTN, it is a global study. We've gotten questions, is that going to dilute the BMI effect? I think the counterpoint to that is, you know, the obesity correlation with hypertension holds pretty strong globally. And so we don't have a concern that, you know, the makeup of LAUNCH-HTN is going to look too terribly dissimilar from what we saw in TARGET-HTN, even though it is a global study versus U.S. alone for TARGET.
Speaker Change: As far as launch H T urn it is a global study.
Speaker Change: We've gotten questions is that going to dilute the BMI effect I think the counterpoint to that is.
Speaker Change:
The obesity correlation with hypertension holds pretty strong globally.
Speaker Change: And so we don't have a concern that the makeup of launch H 10 is going to look too terribly dissimilar from what we saw in target H T and even though it is a global study versus the U S alone for target.
David Rodman: Jon, if I could just add one thing, and that was a very nice discussion. There's a difference between African-Americans and black Africans, as well as the European population, which tends to be doesn't have the same admixture of the white of the Caucasian genes. So African-Americans are on the whole. super sensitive to aldosterone. Lower levels of aldo produce more hypertension. That's not true in Europe. And so since we have European sites, we are going to have to distinguish between those two, and we will. Got it.
Speaker Change: And if I could just add one thing and that was very nice discussion.
Speaker Change: There is a difference between African Americans and Black Africans.
Speaker Change: As well as the European population, which tends to be.
It doesn't have the same admixture of the white.
Speaker Change: Of the Caucasian genes So African Americans are.
Speaker Change: And on the whole.
Speaker Change: Super sensitive to aldosterone and lower levels of al do produce more hypertension.
That's not true in Europe, and so since we have European sites, we are gonna have to distinguish between those two and we will.
Got it that's helpful things here and then with respect to the number of sites and geographies that are being in Burlington lines versus the other house. How are you thinking about the placebo response and why do you think there could be a higher placebo response.
Unknown Attendee: That's helpful. Thank you.
Unknown Attendee: And then with respect to the number of sites and geographies that are being enrolled in LAUNCH versus the other trials, how are you thinking about the placebo response in LAUNCH? Do you think there could be a higher placebo response? And was that part of your powering assumption for LAUNCH?
Was that part of your powering assumption.
Unknown Attendee: Thanks. So launch is pretty much superpowered because it's such a big study and looking at similar effect size. So if your question is, well, if there's an upward shift, from the placebo effect, which presumably would affect both arms. Is that going to introduce more variability and therefore decrease the power? And the answer is it'll be it won't be a significant problem in a trial of that size with the powering it has.
Speaker Change: Your line.
Speaker Change: So.
Speaker Change: Well, let's just pretty much superpower, because it's such a big study.
Speaker Change: And looking at similar effect size, so if you're.
Speaker Change: If your question is well if theres an upward shift.
Speaker Change: From the placebo effect, which presumably would affect both arms.
Speaker Change: Is that gonna and produce more variability and therefore.
Speaker Change: Decrease the power and the answer is it'll be.
Speaker Change: Won't be a significant problem in a trial of that size with the powering it has.
Unknown Attendee: got it.
Speaker Change: Okay.
Unknown Attendee: Thank you.
Speaker Change: Thank you.
Rami Katkhuda: Our next question is from Rami Katkhuda with Lakeside Capital. Please proceed. Hey guys, thanks for taking my questions as well. Just a couple quick ones from me.
Our next question is from Rami causes of death, with let's say capital. Please proceed.
Speaker Change: Hey, guys. Thanks for taking my questions as well just a couple of quick ones from me I guess based on the inclusion criteria advancing launch are treating patients with lower Egfr then doesn't target does that have the potential to affect hyperkalemia rates at all in the pivotal studies.
Rami Katkhuda: I guess based on the inclusion criteria, advanced and launcher recruiting patients with lower EGFR than those in Target, does that have the potential to affect hyperkalemia rates at all in the pivotal studies?
David Rodman: You're right, Rami. We looked at 60 EGFR and above for target. Based on that, we were comfortable going down to the 45 for both launch and advance.
Speaker Change: You're right Ravi we are looked at 60, Egfr and above for target based on that we were comfortable going down to the 45 for both launch in advance.
David Rodman: I think it's too early to tell at this point. We'll have to see what the data indicates. But we know from the 50 milligram arm and target HTN, we really saw a modest change in potassium, similar to what you would expect with an ACE or an ARB. The Xplore CKD study where we're going down to an EGFR of 30 is allowable. We've actually reduced the dose to 25 milligrams QD. I think it's within that population that we want to move cautiously as we investigate lorandristat and both the benefits as well as the safety profile specifically related to this pharmacological effect on sodium and potassium.
Speaker Change: I think it's too early to tell at this point, we'll have to see what the data indicates but we know from the 50 milligram.
Speaker Change: Arm and target age 10, we really saw a modest change in potassium similar to what you would expect with an ace or an arb.
The explore CTD study, where we're going down to an egfr of 30 is allowable we've actually reduced the dose to 25 milligrams QD I think its within that population that we want to move cautiously as we investigated render stat and both the benefits as well as the safety profile.
Speaker Change: Specifically related to this pharmacological effect on sodium and potassium.
Unknown Attendee: Got it. Makes a lot of sense.
Speaker Change: Got it thanks, a lot of sense and then in lunch, obviously compliance is not being enforced as it is in advance.
David Rodman: And then in launch, obviously, compliance is not being enforced as it is in advance. Do you plan to do kind of an analysis of those patients who were compliant throughout the trial versus those who are not? Yeah, the, you know, the technology of AI cure is really It's been validated but it's really just a next level advancement and how do we really ensure patients take the drug. For those that may not be aware, subjects have to take a picture of not only their background meds but also either the placebo or the active ones. They're randomized.
Speaker Change: Do you plan to do kind of an analysis of those patients who are compliant throughout the trial versus those who are not.
Speaker Change: Yeah. The you know the technology of AI cure is really.
Speaker Change: It's been validated but it's really just a next level of advancement in the how do we really ensure patients take the drug.
Speaker Change: For those that may not be aware subjects have to take a picture of.
Speaker Change: Not only their background meds, but also either placebo or the active once the randomized. They also have to film themselves consuming it.
David Rodman: They also have to film themselves consuming it. That technique and that technology is being used both in advance and in launch. In advance, we're proactively reaching out to subjects if they're not being compliant and reminding them of the importance of that. As you note, in launch we are not, but we are going to pre-specify an analysis looking at compliance. I believe it's for those above 75% compliant and those below 75%. So we'll have that as a pre-specified analysis so that we can look at that impact.
Speaker Change: That technique and that technology is being used both in advance and in launch in advance we're proactively reaching out to subjects, if theyre not being compliant and reminding them of the importance of that as you know and launch we are not but we are going to pre specify and analysis looking at compliance.
Speaker Change: I believe it's for those above 75% compliant and those below 75%. So we will have that as a pre specified analysis. So that we can look at that impact and I think just to build on Dave's point.
Jon Congleton: And I think just to build on Dave's point, You know, we saw really nice compliance in Target HTN, but it was with less advanced technologies that You know, are not completely foolproof. In other words, pill counts are kind of a standard way to do it, but we know patients can manipulate that. We're progressively trying to use technology to help patients help us with one of the most important things they can do, and that is being compliant to the pill. So I think we've. Currently using state-of-the-art but validated technology to really help ensure that we've addressed one of the bigger questions in these kind of studies that we know has been an issue with other hypertension studies contemporaneously.
Speaker Change: We saw really nice compliance and target H T N, but it was with less advanced technologies that.
Speaker Change: You know are not completely foolproof. Another words pill counts are kind of a standard way to do it but we know patients can manipulate that we're progressively trying to use technology to help patients help us with one of the most important things. They can do and that is b compliance of the pill. So I think we've.
Currently using state of the art, but validated technology to really help ensure that we have addressed one of the bigger questions. In these kinds of studies that we know has been an issue with other hypertension studies.
Speaker Change: Separate easily.
Unknown Attendee: Got it. Thanks.
Got it thanks, so much.
Matthew Caulfield: Thanks, Rami. Our next question is from Matthew Caulfield with H.C. Wainwright. Please proceed. Hey, good afternoon, guys. So you kind of touched on this with powering. But for advanced HTN, during the KOL event, it was mentioned that six to eight millimeters of ambulatory BP benefit could be clinically meaningful. Does that range translate the same to potential target ranges or better for launch and explore be considered successful? Thanks a lot. Yeah.
Thanks Rami.
Speaker Change: Our next question is from Matthew Coffield with H C. Wainwright. Please proceed.
Speaker Change: Hey, good afternoon, guys. So you kind of touched on this with the powertrain, but for advanced H T. N. During the Kols event. It was mentioned that six to eight millimeters of ambulatory BP benefit could be clinically meaningful does that range translate the same to potential target ranges are better for launch in <unk>.
Speaker Change: Floor be considered successful.
Speaker Change: Thanks, a lot.
Jon Congleton: Matt, appreciate the call. Yeah, I think the KOL call was really instructive because I think they started by highlighting the fact that. you know, one or two millimeter mercury change, particularly in a truly resistant or even uncontrolled hypertension patient is meaningful as far as reducing cardiovascular risk. So it's always important to put that into context. I think the six to eight millimeter that Luke Laughlin alluded to, you know, in a broad population is absolutely on point. There's a clear correlation to reduced risk from an outcome standpoint. Based on the market research we've done with payers and with physicians, that's certainly within the realm of what's important and transformative for them.
Speaker Change: Yeah, Matt I appreciate the call.
Speaker Change: Yeah, I think the care what I'll call was really instructive, because I think they started by highlighting the fact that.
Speaker Change: You know one or two millimeter mercury change, particularly in a truly resistant or even uncontrolled hypertension populate a hypertension patients.
Speaker Change: As meaningful as far as reducing cardiovascular risk.
Speaker Change: So it's always been important to put that into context, I think the six to eight millimeter that Luke laughing alluded to.
Speaker Change: You know in a broad population is is absolutely on point, there's a clear correlation to reduced risk from an outcome standpoint.
Speaker Change: Based on the market research, we've done with payers and with physicians that certainly within the <unk>.
Speaker Change: The realm of what's important and transformative for them.
Jon Congleton: You know, we've always guided that that eight to 10 millimeter mercury change that we saw in target HTN, if replicated in advance and within launch, would be truly meaningful to the market. And based on meta-analysis that show with currently available generic treatments, when you add a third or fourth line agent, you typically get a five millimeter mercury further reduction in systolic. New advances like renal denervation or apricin 10-10, you know, have found four to six millimeter mercury reduction. So that replication of eight to 10 is truly meaningful. And if we find subsets. such as an obese population that have a more pronounced effect, that becomes even more transformative.
Speaker Change: We always guided that that eight to 10 millimeter Mercury change that we saw in target H T N if replicated in advance and within launch.
Speaker Change: Would be truly meaningful to the market and that's based on.
Speaker Change: Meta analysis that show with currently available generic treatments when you add a third or fourth line agent you typically get a five millimeter mercury further reduction in systolic.
Speaker Change: New advances like renal denervation or apperson tend to and you know have found four to six millimeter Mercury production.
Speaker Change: So that replication of eight to 10 is truly meaningful and if we find subsets.
Speaker Change: Such as in obese population that have a more pronounced effect that becomes even more transformative and ultimately the goal is getting patients below their prescribed V. P goal and that's something we'll be looking at within both of these studies as well as not only the absolute and placebo adjusted production, but what is the percent of <unk>.
Unknown Attendee: And ultimately, the goal is getting patients below their prescribed BP goal. And that's something we'll be looking at within both of these studies as well, is not only the absolute and placebo-adjusted production, but what is the percent of subjects actually getting to goal and having a foundational shift in their cardiovascular risk profile. Very helpful.
Speaker Change: It's actually getting to goal and having a foundational shift in their cardiovascular risk profiles.
Jon Congleton: And you would say that applies to Explore CKD as well? Yeah, I think it does. It certainly does. And XPLOR is not only that benefit from a BP standpoint, but really investigating what we think is now a de-risked benefit of an ASI in combination with an SGLT2 on renal function as well. Very helpful, I appreciate that. You bet.
Speaker Change: Very helpful and you'd say that applies to explore C J D as well.
Yeah, I think it does it certainly does and explore.
Speaker Change: It's not only that benefit from a b piece standpoint, but really investigating what we think is now a derisked.
Speaker Change: Benefit of in ASI in combination with an S. G. L T two on renal function as well.
Speaker Change: Mhm.
Speaker Change: Very helpful. I appreciate that.
Speaker Change: You bet Thanks, Matt.
Unknown Attendee: Thanks Matt.
Jon Congleton: With no further questions in the queue, I would like to turn the conference back over to Jon for closing remarks. Thank you, operator, and thank you to everyone for joining us today. We're very excited about the progress we've made thus far in 2024 in advancing our clinical programs, and we remain enthusiastic about the upcoming data milestones planned for the first half of 2025. We look forward to updating you as our pivotal program for La Runderstad continues to advance.
Speaker Change: With no further questions in the queue I would like to turn the conference back over to John for closing remarks.
Thank you operator, and thank you to everyone for joining US today, we're very excited about the progress we've made thus far in 'twenty 'twenty, four and advancing our clinical programs and we remain enthusiastic about the upcoming data milestones planned for the first half of 2025.
Speaker Change: We look forward to updating you as our pivotal program for <unk> continues to advance with that we will close the call.
Jon Congleton: With that, we will close the call.
Operator: Thank you.
Speaker Change: Thank you. This does conclude today's conference you may disconnect at this time and thank you for your participation.
Operator: This does conclude today's conference. You may disconnect at this time and thank you for your participation.
Speaker Change: Yeah.
Speaker Change: Okay.
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