Q1 2024 Mineralys Therapeutics Inc Earnings Call
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Hum.
Yes.
Speaker Change: Yeah.
This call is being recorded on Thursday, May 9, 2024. I would now like to turn the conference over to Garth Russell of Lifesai Advisors. Please go ahead.
Speaker Change: Okay.
Speaker Change: Yeah.
Thank you, operator. Good morning everyone and welcome to our first quarter 2024 conference call.
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Earlier this morning, we issued a press release, providing our first quarter, 2024 financial results and business updates. A 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'll open up the call for Q&A.
Speaker Change: Uh huh.
Speaker Change: Uh huh.
Speaker Change: Yeah.
Speaker Change: Okay.
Speaker Change: Okay.
Speaker Change: Yeah.
Before we begin, I would like to remind everyone that this conference call and webcasts will contain certain 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.
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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 10K and subsequent filings.
Please note that these forward-looking statements reflect our opinions only as of today, May 9th. Accept as required by law, we specifically describe any obligation to update or advise these forward-looking statements in light of new information or future events.
Speaker Change: Hum.
Speaker Change:
I would now like to turn a call over to John Congleton, Chief Executive Office, or Mineralis. John ?
Speaker Change: Okay.
Speaker Change: Mhm.
Speaker Change: Sure.
Thank you, Garth. Good morning, everyone. Welcome to our first quarter, 2024, financial results, and corporate update conference call. I'm going today by Adam Levy, our chief financial officer, and Dr. David Aradman, our chief medical officer.
Speaker Change: Hum.
Speaker Change: Sure.
Speaker Change: Yeah.
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Speaker Change: Yeah.
Considering the relatively short period of time between this call and our fourth quarter call, we're going to keep our prepared remarks today fairly brief. I'll begin with an overview of the business and recent milestones, followed by Adam, who will review our first quarter financial results before we open up the call for your questions.
Speaker Change: Yeah.
Speaker Change: [music].
Speaker Change: Welcome to the Conferencing center, please hold for the next available operator.
Let me start out by stating that we continue to make great progress with our clinical trials and reaffirm our previously stated guidance on the timing of our top-line data readouts, which I will review in a moment.
Speaker Change: Oh.
Speaker Change: Oh.
Speaker Change: Thank you for calling the conferencing Center would you call your joining.
Before getting into each trial in detail, let me take a moment to touch on our overall strategy and basis for our pipeline, which is focused on targeting dysregulated aldosterone.
Speaker Change: Hello.
Aldosterone is known to be a significant driver of cardio-rinal metabolic diseases.
And thus, we're developing an aldosterone targeted treatment approach with Lirondostadt. We believe Lurundersat has the potential to benefit millions of patients who are impacted by hypertension, kidney disease, and heart disease.
For example, dysregulated aldosterone levels are a key factor in driving hypertension in approximately 25% of all hypertension patients.
This is a significant population, is there an estimated 115 million patients in the United States who have hypertension, and of the 60 million treated patients more than half failed to achieve their blood pressure goal.
The outcome can be severe for these patients, as according to the World Health Organization, there are 7.5 million deaths attributable to hypertension per year globally.
Given the impact of uncontrolled hypertension on cardiorenal outcomes, we made hypertension our lead indication for the development of Lorunderstad. In addition to hypertension, we're currently investigating the benefits of Larundersat in subjects with hypertension and KD.
Time between this call in our fourth quarter call, we're going to keep our prepared remarks today fairly brief I'll begin with an overview of the business in recent milestones followed by Adam who will review our first quarter financial results before we open up the call for your questions.
We entered 2024 with clear goals for our registration program and hypertension, which is comprised of two pivotal clinical trials, titled Advance H-10 and Launch H-10.
An open label extension trial called TransformHCN to capture long-term safety and efficacy data, and the proof-of-concept trial explore CKD, evaluating Lurundersat and hypertensive CKD subjects.
Let me start by stating that we continue to make great progress with our clinical trials and reaffirm our previously stated guidance on the timing of our topline data Readouts, which I'll review in a moment.
Before getting into each trial in detail, let me take a moment to touch on our overall strategy and basis for our pipeline, which is focused on targeting dysregulation aldosterone.
Advanced H-10 is the first of the two pivotal trials we have initiated, which started enrolling patients one year ago.
Enrollment in the trial remains ongoing, and we anticipate top-line data to be available in the fourth quarter of this year.
Although <unk> is known to be a significant driver of cardio renal metabolic diseases and thus we are developing and aldosterone targeted treatment approach with Laura understand we will able to understand has the potential to benefit millions of patients who are impacted by hypertension kidney disease and heart disease for.
This is a state-of-the-art extremely rigorous hypertension trial, which is designed and executed in collaboration with the experienced cardiovascular research team at the Cleveland Clinic.
The trial is designed to demonstrate the value of Lerundersat when added to standardized, optimized AHA guideline background treatment in patients with uncontrolled or resistant hypertension, as confirmed by 24-hour ambulatory BP measurement.
For example, this regulated aldosterone levels are a key factor in driving hypertension, and approximately 25% of all hypertension patients.
This is a significant population is there are an estimated 115 million patients in the United States, who have hypertension and of the $60 million treated patients more than have failed to achieve their blood pressure goal.
We believe this is the only trial of an aldosterone directed therapy that is utilizing this rigorous, standardized background treatment approach.
The outcome can be severe for these patients is according to the World Health organization. There are $7 5 million deaths attributable to hypertension per year globally.
As such, this trial has the potential to generate high-quality evidence that will be important for potential inclusion and hypertension guidelines, for treating physicians, and for creating favorable access via payers.
Speaker Change: The impact of uncontrolled hypertension on cardio renal outcomes, we made hypertension, our lead indication for the development of lower understaffed.
As you may be aware, the targeted treatment of hypertension is a major point of our strategy.
Data presented last year from Target H.T.N. T. T. T. T. Lade the foundation for identifying patients who best respond to Lerunderstaff, such as those patients with an elevated BMI.
Speaker Change: In addition to hypertension and were currently investigating the benefits of <unk> and <unk>.
Speaker Change: Subjects with hypertension and CK D.
Speaker Change: We entered 2024 with clear goals for a registration program in hypertension, which is comprised of two pivotal clinical trials titled Advanced HCN and launch <unk>.
The plan analysis of the Advanced H.T.N. trial includes a well-powered confirmatory test of the predictive value of obesity on the efficacy of Lurundersd.
Speaker Change: An open label extension trial called transform HCN to capture long term safety and efficacy data and the proof of concept trial explore CTD evaluated and Laura understand in hypertensive <unk> subjects.
We believe the inability of an optimized two or three drug standard anti-hypertensive regimen to reduce BP to goal in the setting of obesity will be a straightforward approach to identifying candidates for treatment with LerunnerStat.
Speaker Change: Advanced <unk> standards. The first of the two pivotal trials, we have initiated which started enrolling patients one year ago.
In addition, we plan to continue to explore other positive and negative predictive tools using an unbiased artificial intelligence model to expand the repertoire of useful tools for targeting Lurunderset to individuals most likely to derive long-term clinical benefit.
Speaker Change: Enrollment in the trial remains ongoing and we anticipate top line data to be available in the fourth quarter of this year.
Speaker Change: This is a state of the art extremely rigorous hypertension trial, which is designed and executed in collaboration with the experienced cardiovascular research team at the Cleveland Clinic.
Launch HDN is our second pivotal trial, which we initiated in the fourth quarter of 2023. We continue to anticipate top-line data to be available in the second half of 2025.
Speaker Change: The trial is designed to demonstrate the value of Lora understand when added to standardized optimized AAJ guideline background treatment in patients with uncontrolled or resistant hypertension as confirmed by 24 hour ambulatory BP measurement.
This phase three trial, which will enroll up to approximately 1,000 adult subjects, is designed with the objective of evaluating the Runderstead in a real-world setting, when added to subjects previously prescribed background regimen of 2-5 anti-hypertensives.
Speaker Change: We believe this is the only trial of an aldosterone directed therapy that is utilizing this rigorous standardized background treatment approach as such this trial has the potential to generate high quality evidence that will be important for potential inclusion in the hypertension guidelines for treating physicians and for creating favorable access via payers.
Subjects who fail to achieve blood pressure control on their prescribed background treatment during the running period will be randomized one to two to one, try the placebo,
once daily 50 milligrams of Lerundra stat or once daily 50 milligrams of Lerundra statte with the option to titrate to 100 milligrams once daily as needed at week six.
Speaker Change: <unk>.
Speaker Change: As you may be aware the targeted treatment of hypertension is a major point of our strategy.
Speaker Change: Data presented last year from target age TN trial laid the foundation for identifying patients who best respond to we're understaffed such as those patients with an elevated BMI.
The primary endpoint for this trial will be changed 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 provided this trial targets.
Speaker Change: <unk> analysis of the advance HCN trial includes a well powered confirmatory test of the predictive value of obesity on the efficacy of Laura understand.
In addition, subjects from these two trials will be offered the opportunity to roll over into the ongoing open label extension trial called TransformHTN.
Speaker Change: We believe the inability of an optimized two or three drug standard antihypertensive regimen to reduce <unk> to golar in the setting of obesity will be a straightforward approach to identifying candidates for treatment with or understand.
In addition to the hypertension pivotal program, we're conducting the Explore-CKD Phase 2 clinical trial for Lurunders' death in patients with hypertension in stage 2 to 3B chronic kidney disease.
Speaker Change: In addition, we plan to continue to explore other positive and negative predictive tools using an unbiased artificial intelligence model to expand the repertoire of useful tools for targeting lore under stat to invent to individuals' most likely to derive long term clinical benefit.
We continue to anticipate top line data to be available in Q4, 2024, to Q1, 2025.
Explore, KD is a within-subject comparison trial, designed to demonstrate the benefit of Leranderset in reducing blood pressure, and provide supportive evidence for potential benefit on chronic kidney disease on the background of a stable SGLT2 inhibitor treatment.
Speaker Change: Launch H standards, our second pivotal trial, which we initiated in the fourth quarter of 2023.
Speaker Change: Continue to anticipate top line data to be available in the second half of 2025.
This proof of concept trial will enroll approximately 60 subjects with hypertension in stage 2 to 3B, CKD.
Speaker Change: This phase III trial, which will enroll up to approximately 1000 adult subjects is designed with the objective of evaluating <unk> in a real world setting when added to subjects previously prescribed background regimen of two to five anti hypertensive.
We are pleased with the steady progress the team has made in the strengthening of our clinical program for this promising new approach to treating hypertension and the associated complications like chronic kidney disease and heart disease. We look forward to keeping you apprised of the status of the Lurunderset Development Program.
Speaker Change: Subjects, who failed 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 once daily 50 milligrams or understand our once daily 50 milligrams or understand with the option to titrate to a 100 milligrams once daily as needed at week six.
Let me now turn the call over to Adam. We'll provide a financial review for the first quarter of 2024. Adam.
Thank you, John . Good morning, everyone. Today I will discuss select portions of our first quarter 2024 financial results. Additional details can be found in our Form 10Q, which was filed with the SEC earlier today.
Speaker Change: Thanks.
Speaker Change: The primary endpoint for this trial will be changed in systolic blood pressure as measured by automated office blood pressure.
Speaker Change: We believe this endpoint reflects real world measurements that will be relevant to the primary care provided this trial targets.
We ended the quarter with cash, cash equivalents, and investments of $338.6 million, compared to $239 million as of December 31st, 2023.
Speaker Change: In addition subjects from these two trials will be all for the opportunity to rollover in the ongoing open label extension trial called transform HCN.
In February 2024, we completed a private placement financing for net proceeds of approximately $116 million.
Speaker Change: In addition to the hypertension pivotal program, we're conducting the explorer <unk> phase II clinical trial for <unk> in patients with hypertension and stage two to three <unk> chronic kidney disease. We continue to anticipate top line data to be available in Q4 2024 to Q1 2020.
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 March 31st, 2024 were $30.8 million compared to $12.3 million for the same quarter of 2023.
Speaker Change: 2025.
Speaker Change: Explore <unk> within subject comparison trial designed to demonstrate the benefit of Laura understand and reducing blood pressure and provide supportive evidence for potential benefit on chronic kidney disease on the background of a stable <unk> two inhibitor treatment.
The increase in R&D expenses was primarily due to increases of $16.8 million in preclinical and clinical costs.
Speaker Change: This proof of concept trial will enroll approximately 60 subjects with hypertension in stage two to <unk>.
$3.7 million in clinical supply, manufacturing, and regulatory costs
$1.7 million in higher compensation expenses resulting from additions to Headcamp and stock-based compensation, and $0.3 million in other research and development expenses, partially offset by a decrease of $4 million in license fees.
Speaker Change: We're pleased with the steady progress the team has made and the strengthening of our clinical program for this promising new approach to treating hypertension and the associated complications like chronic kidney disease and heart disease.
Speaker Change: Forward to keeping you apprised of the status of the lenders that development program.
G&A expenses were $4.6 million for the quarter ended March 31st, 2024.
Speaker Change: Let me now turn the call over to Adam who will provide a financial review for the first quarter of 2020 for Adam.
compared to $2.6 million for the same quarter of the prior year. The increase in GNA expenses was primarily due to $1.3 million in higher compensation expenses resulting from additions to headcount and stock-based compensation.
Adam: Thank you John Good morning, everyone. Today, I will discuss select portions of our first quarter 2024 financial results. Additional details can be found in our Form 10-Q, which was filed with the SEC earlier today.
$0.5 million in higher professional fees associated with operating as a public company and $0.2 million in higher insurance and other administrative expenses.
Adam: We ended the quarter with cash cash equivalents and investments of $338 6 million compared to $239 million as of December 31, 2023.
Total other income was $3.9 million for the quarter ended March 31st, 2024 compared to $2.3 million for the same quarter of 2023.
Adam: In February 2024, we completed a private placement financing for net proceeds of approximately $116 million.
The increase was primarily attributable to increased interest earned on our investments in money market funds in U.S. Treasuries.
Adam: 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.
Net loss was $31.5 million for the quarter ended March 31st, 2024, compared to $12.6 million for the same quarter of 2023. The increase was primarily attributable to the factors I described earlier.
Adam: R&D expenses for the quarter ended March 31, 2024 were $38 million compared to $12 3 million for the same quarter of 2023 the.
With that, I'll ask the operator to open the call for questions. Operator?
Adam: The increase in R&D expenses was primarily due to increases of $16 $8 million in preclinical and clinical costs $3 $7 million and clinical supply manufacturing and regulatory costs $1 $7 million and higher compensation expenses, resulting from <unk>.
Thank you, ladies and gentlemen, we will now conduct the question and answer session. If at any time, if you wish to ask a question, please press star, followed by the number one on your telephone keypad. And if you wish to cancel your request, please press star 2.
Adam: <unk> to head count and stock based compensation.
Your first question comes from Jeff Meekam from Bank of America. Your line is now open.
Adam: And zero point $3 million in other research and development expenses, partially offset by a decrease of $4 million in license fees.
Hey, thanks for the question. This is John Joy on for Jess. So with top plan data expected in 4Q24, what would be a positive readout for you in terms of clinical response and safety profile?
Adam: G&A expenses were $4 6 million for the quarter ended March 31, 2024, compared to $2 6 million for the same quarter of the prior year. The increase in G&A expenses was primarily due to $1 3 million and higher compensation expenses, resulting from additions to head count and stock base.
Yeah, John , thanks for the question.
We've had a fair amount of market research with payers and physicians with the target H-TN data, where we saw an 8 to 10-millimeter mercury placebo-adjusted drop. We believe if we replicate that, that is a transformative change for subjects.
Adam: Compensation, <unk> $5 million and higher professional fees associated with operating as a public company and <unk> 2 million and higher insurance and other administrative expenses.
using Lurundersad in the third or the fourth line. Now that's based on the fact that with the currently available treatments,
Adam: Total other income was $3 $9 million for the quarter ended March 31, 2024, compared to $2 3 million for the same quarter of 2023. The increase was primarily attributable to increased interest earned on our investments in money market funds and U S treasuries.
When you go to a third and fourth line agent, you typically see a 5 to 6 millimeter mercury drop at best.
And so if we replicate what we've seen in target HTN of 8 to 10 millimeters of mercury placebo adjusted, we believe that will be very resonant within the market and support the opportunity that Lerunner stat represents in the hypertension space.
Adam: Net loss was $31 $5 million for the quarter ended March 31, 2024, compared to $12 6 million for the same quarter of 2023.
Awesome, thank you.
Yeah.
Adam: The increase was primarily attributable to the factors I described earlier.
Your next question comes from Annable Samimi from Stifal. Your line is now open.
Speaker Change: With that I'll ask the operator to open the call for questions operator.
Hi, this is Jack on for Annabelle. Thanks for taking our questions.
Speaker Change: Thank you, ladies and gentlemen, we will now conduct a question and answer session.
So could you remind us the powering for the advanced HTN trial and what magnitude of placebo response you might be expecting here, acknowledging that these patients should have the truly uncontrolled hypertension?
Speaker Change: Anytime if you wish to ask a question. Please press star followed by the number one on your telephone keypad and if you wish to cancel your request. Please press star two.
And then with launch HTN, because those background treatments are going to be variable, what kind of steps have you taken to help minimize the noise and the variability there when it comes to the top line beta generation?
Speaker Change: Your first question comes from Geoff Meacham from Bank of America.
Geoff Meacham: Your line is now open.
Speaker Change: Hey, Thanks for the question. This is John <unk> on for Jeff.
Geoff Meacham: With topline data expected in <unk> 24, what would be a positive read out for you in terms of clinical response and safety profile.
This is Bidtoddman, GMO. Thanks for the questions. So the first question was in the advanced trial, some of the statistical questions, what's the powering and what do we expect the placebo to be? So I'll remind you in advance, we're using
Speaker Change: Yes, John Thanks for the question.
Speaker Change: We've done a fair.
Speaker Change: Amount of market research with payers and physicians with the target HCN data, where we saw an 8% to 10 millimeter Mercury placebo adjusted drop we believe if we replicate that.
24-hour ABPM is the primary.
Speaker Change: As a transformative change for subjects.
And with 24-hour ABPM, because you're averaging over the course of the day, you get much more stable averaging measurements. We saw a placebo effect of around 2 millimeters of mercury.
Speaker Change: Using our understanding in the third or the fourth line. That's based on the fact that with the currently available treatments.
Speaker Change: You go to a third and fourth line agent you typically see 5% to six millimeter of Mercury drop at best.
in our first trial, and I think that's about what we would expect. That's obviously a very, very quiet placebo effect.
Speaker Change: And so if we replicate what we've seen in target HCN of eight to 10 millimeters of Mercury placebo. Adjusted we believe that will be very resident within the market and support the opportunity that we're under stat represents in the hypertension space.
As far as powering, we're certainly sufficiently powered to detect the range that John mentioned at 8 to 10 and actually overpowered for that.
Speaker Change: Awesome. Thank you.
Speaker Change: Yes.
Now you asked also in your second questions, launch, which is more real world, what steps have we taken? Let me first say that our placebo effects when we did the target H.T.N. trial on that population was about four millimeters of mercury.
Speaker Change: Your next question comes from animals, So maybe from Stifel. Your line is now open.
Speaker Change: Hi, This is Jack on for Annabel, Thanks for taking our questions.
Jack: <unk> you remind us the powering for the advance HTM trial, and what magnitude of placebo response, you might be expecting here acknowledging that these patients should have it truly uncontrolled hypertension.
And so all of the steps we took in that trial to get essentially a best
placebo effects and lowest variability are incorporated into this trial. We've made a few other
Jack: And then with launch HTM, because those background treatments are going to be variable.
Jack: What kind of steps have you taken to help minimize that noise and the variability there when it comes to that top line data generation.
steps to look at things further, probably the most important one is we do use a home, an app-based AI interpreted adherence tool. And as you probably know, a great proportion of
TMO: This is a problem and TMO thanks for the questions.
Speaker Change: So the first question was in the advance trial some of the statistical questions, what's the powering and what do we expect the placebo.
The reason why people don't respond to their anti-hypertensive regimen is in fact that they don't take it.
Speaker Change: So I'll remind you in advance we're using.
A great contributor to placebo effect is that people do start taking it
Speaker Change: 24 hour <unk>.
on trials.
Speaker Change: <unk> is the primary.
We get rid of that problem because in the run-in, we do the adherence already. Then we use a placebo in the run-in. So we already have a baseline taking that big variable out of the picture.
Speaker Change: And with 24 hour, a BPM because youre averaging over the course of the day you get much more stable averaging measurements we saw.
Speaker Change: Placebo effect of around two millimeters of Mercury.
We piloted a number of different adherence tools and target. This was the one that has the best performance and it's really proven itself to be a remarkable way to get better data. There are other things, but that's really what I would emphasize.
Speaker Change: And our first trial and I think that's about what we would expect that's obviously.
Speaker Change: Very very quiet.
Speaker Change: Placebo effects.
Speaker Change: As far as powering we're certainly sufficiently powered to detect a range that John mentioned that eight to 10 and actually overpowered for that.
Got it. And then if I could just sneak in one more, maybe, so now that you mentioned the differences in the placebo effect of maybe the...
Speaker Change: Now you asked also in your second questions launch, which is more real world what steps that we've taken.
2 millimeters, 4 millimeters, about how much variance is there between the ABPM and AOP measures? Basically trying to ask here if you're expecting to see vastly different result ranges in advance versus launch.
Speaker Change: Let me first say that our placebo effect when we did the target HCM trial on that population was about four millimeters of Mercury and so all of the steps we took in that trial to get essentially a best.
Well, that's a great question. And when John mentioned 8 to 10 millimeters of mercury earlier, the primary was A-O-B-P.
Speaker Change: Placebo effects and lowest variability are incorporated into this trial.
in the Target HTN trial and the primary in the launch trial is also
Speaker Change: <unk> made a few other.
Speaker Change: Steps to look at things third and probably the most important one is we do use a home.
AobP. So in that trial, we expect things to be pretty comparable to 8 to 10. Now, when you, in a person with normal blood pressure control, when you go to sleep, your blood pressure goes down.
Speaker Change: And App based AI interpreted adherence tool and as you probably know a great proportion of.
And so when you average 24 hours, you end up with a lower value for blood pressure
Speaker Change: So the reason why people don't respond to their antihypertensive regimen is in fact that they don't take it.
and a proportionately lower response.
Speaker Change: Great contributor to placebo effect is that people do start taking it on trials, we get rid of that problem because we in the run and we do the adherence already and we use a placebo in the run in so we already have a baseline taking that big variable out of the picture.
The primary in the advanced trial is 24-hour average ABPM. And typically you will see about a 1 to 1 1 1 1.5 millimeter lower
to solid blood pressure and change in trials when you compare the two.
Speaker Change: We piloted a number of different different adherence tools and target. This was the one that has the best performance and it's really proven itself to be a remarkable ways to get better data.
We also have the ability, however, to look at 24-hour daytime, and that'll be closer to what you see with A-B-O-B-P. Did that answer your question?
Speaker Change: There are other things, but that's really what I would emphasize.
Yes, that was very helpful. Thank you.
Speaker Change: Got it and then if I could just sneak in one more maybe.
Speaker Change: You mentioned the differences in the placebo effect in <unk>.
Your next question comes from Seamus Fernandez from Guggenheim Securities. Your line is now open.
Speaker Change: Two millimeters four millimeters.
Speaker Change: About how much variance is there between the a BPM and <unk> BP measures basically trying to ask here, if youre expecting to see like vastly different result ranges in advance versus launch.
Hey guys, thanks for the question. So just wanted to clarify Dave's a couple of those last points. So when we're thinking about the difference between 24-hour ABPM,
Speaker Change: Well, that's a great question and when John mentioned, 8% to 10 millimeters of Mercury earlier, the primary was <unk> in.
and the AOBP measures. I think that 8 to 10 millimeter threshold, I just wanted to clarify a couple of things. Number one, you know, we do know that the half-life is a bit shorter.
Speaker Change: Their target East and trial and the primary in the launch trial is also a OBP. So in that trial, we expect things to be pretty comparable to eight to 10 now when you.
And, you know, with Loramstadt, so just trying to get a better characterization of how much you would anticipate that overnight average to change.
Speaker Change: Person with normal blood pressure control when you go to sleep you broad pressure goes down and so when you averaged 24 hours you end up with a lower value for blood pressure and a proportionately lower response the primary in the advanced trial is.
and how you're actually, you know, measuring blood pressure overnight. Is that a continuous monitor that you're using to average over time? And then when you've looked at other studies in terms of that comparison,
Speaker Change: 24 hour average a BPM and typically you will see about a one to one five millimeter lower.
You know, as you look at comparisons of the design of advance,
Speaker Change: Systolic blood pressure.
versus other programs.
Speaker Change: Change in trials when you compare the two.
Just trying to get a more complete understanding of what typically happens during that overnight period for placebo as well as for, you know, the full kind of long acting once a day.
Speaker Change: We also have the ability however to look at 24 hour daytime and that'll be closer to what you see with AB.
Speaker Change: Did that answer your.
Speaker Change: Your question.
you know, versus, you know, a program that has a shorter half-life in that regard. Thanks.
Speaker Change: Yes that was very helpful. Thank you.
As Shamans, I'll start and have Dave add some thoughts. And if we miss any of your points there, let me know. But I want to address the question on the half-flight, because the point I do want to reiterate from Target H-T and the primary endpoint was AOPP that was in office.
Speaker Change: Your next question comes from seamless Fernandez from Guggenheim Securities. Your line is now open.
Seamus Christopher Fernandez: Hey, guys. Thanks for the question so just wanted to clarify.
Seamus Christopher Fernandez: Dave.
Seamus Christopher Fernandez: A couple of those last points so.
And those measurements were taken in the morning before that day's dose. So we were looking at Nader within the office. And we actually saw that 8 to 10 millimeter mercury reduction that was also replicated within the 24-hour ABPM.
Seamus Christopher Fernandez: When we're thinking about the difference between 24 hour <unk>.
Seamus Christopher Fernandez: And the <unk> measures I think that that eight to 10 millimeter threshold I just wanted to clarify.
Seamus Christopher Fernandez: A couple of things number one we do know that the half life.
So we're very confident in the one's daily dose and we actually think it
Seamus Christopher Fernandez: <unk> is a bit shorter.
The 10 to 12 hour half life creates kind of an ideal mix of efficacy and safety. Basically, we'll continue to evaluate that. Now, to some of your deeper questions on the 24-hour monitoring, I'll have Dave address those.
Seamus Christopher Fernandez: And.
Seamus Christopher Fernandez: They are under stat, So just trying to get a.
Seamus Christopher Fernandez: Better.
Seamus Christopher Fernandez: Characterization of how much you would anticipate that overnight average to change.
Thank you, Seamus. We split a lot of thought into what pharmacology would be optimum. And as John mentioned, we like this idea of having a time for some release
Seamus Christopher Fernandez: And how you're actually measuring blood pressure overnight is that a continuous monitor that.
Seamus Christopher Fernandez: That youre using to average over time.
Seamus Christopher Fernandez: Then when you've looked at other studies in terms of that comparison.
in the sort of the pre-dawn hours so that ALDO can do its job in terms of excreting potassium.
Seamus Christopher Fernandez: As you as you look at comparisons of the design of advance versus other programs just trying to get a more complete understanding of what typically happens during that overnight period.
But if you think about the mechanism of action, this is a diuretic. It lowers your blood volume. And overnight, you don't really take on more volume. You're asleep. In the morning, when you get up, you take our drug, and within one hour, you've gotten rid of aldostrum.
Seamus Christopher Fernandez: For placebo as well as for.
Seamus Christopher Fernandez: The.
Seamus Christopher Fernandez: Full kind of long acting once a day.
And so essentially during the period of time when you need the sodium loss, the naturesis, you get it from our drug.
Seamus Christopher Fernandez: <unk>.
Seamus Christopher Fernandez: Versus.
Seamus Christopher Fernandez: A program that has a shorter half life in that regard.
Seamus Christopher Fernandez: As Seamus, so I'll start and have Dave add some thoughts if we miss any of your points there let me know.
During the amount of time when you can switch out and lose potassium, you get that window with our drug.
Seamus: But I want to address the question on the half life, because the point I do want to reiterate from target H T and the primary endpoint was <unk> that was in office.
And so the other thing that I'll mention is that when we measure aldosterone levels in blood, before the dose in the morning, the median value is a 70% reduction
Dave: And those measurements were taken in the morning before that days dose. So we were looking at Nader within the office.
Seamus Christopher Fernandez: And we actually saw that eight to 10 millimeter Mercury reduction that was also replicated within the 24 hour pm.
from the baseline.
value that you get without drug. So we still have a substantial reduction, even though we have the shorter half-life, it's just not zero. We get complete suppression of aldosterone an hour after a dose.
Seamus Christopher Fernandez: So we're very confident in the once daily dose and we actually think it.
Seamus Christopher Fernandez: 10 to 12 hour half life.
Seamus Christopher Fernandez: Creates kind of an ideal mix of efficacy and safety based on what we've seen and will continue to evaluate that.
70% in the morning. So don't think of it as a switch that's on and off. I like to think of it as restoring normal circadian rhythm.
Seamus Christopher Fernandez: Now on to some of our deeper questions on the 24 hour monitoring I'll have Dave address those.
This is what you should be doing. You know, you should have a lower aloe, which is what we produce, but it should be highest in the morning and then go down during the day, which is exactly what happens.
Dave: Thanks, Seamus, we slipped a lot of thought into.
Dave: What pharmacology would be optimum in as John mentioned, we like this idea of having a.
Dave: Time for some release.
Dave: In the sort of the pre dawn hours, so that Aldo can do its job in terms of excluding potassium, but if you think about the mechanism of action. This is a diuretic. It lowers your lead volume and overnight you don't really take on.
Thomas, did we get to your
All of your questions.
I think that covered a majority of it, but just as you look at other clinical studies and the performance of placebo versus an active,
You know, whether it be with an ACE or an ARB or mineralic corticoid, you know, targeted agents, MRAs, what do you typically see during that overnight period?
Dave: More volume Youre asleep in the morning, when you get up you take our drug and within one hour you have gotten rid of aldosterone and so essentially during the period of time when you need the sodium loss. The natural releases you get it from our drug during the amount of time, what you can.
Yeah, so good question. So let me start with the placebo piece.
So first of all, as I said, in our study, the first study, even with the relatively small numbers of 30 per arm, we saw a 2 millimeter of mercury placebo effect. And so that's de minimis.
Dave: <unk>.
Dave: Switch out and lose potassium you get.
Dave: That window with our drug.
Dave: So the other thing that I'll mention is that when we measure aldosterone levels in blood before.
it's not going to change over the course of the day because that's really not a treatment effect. That's just a measurement variability. And to answer your question that I completely forgot to answer,
Dave: The dose in the morning, the median value is a 70% reduction from the baseline.
Dave: Al you get without drug so we still have a substantial reduction even though we have the shorter half life. It's just not zero, we get complete suppression of aldosterone and hours after a dose 70% in the morning, So don't think of it as a switch on and off.
People wear a cuff and a recorder 24 hours.
whether they're awake or asleep. The only difference is we do measurements around every 20 minutes during the day and we space them out a little bit more at night because it can tend to disturb sleep a little bit, which can raise your blood pressure.
So that's how we do it. We don't expect to see a difference in placebo effect overnight. We do expect to see a reduction in blood pressure. In fact,
Dave: I'd like to think of it as restoring normal circadian rhythm. This is what you should be doing.
we will often see what's called restoration of nighttime dipping. So for you and I without sleep apnea, without untreated hypertension,
Our blood pressure will dip at night. It'll go down, as I mentioned. Hypertensive patients will first just lose the dipping, then get actually hypertensive overnight. So that's what we expect to see at night.
Great. And.
As we think about the, this is just my last question, you know, the importance of having
a diuretic on board like HCT, you know, as we think about the differences between, you know, your two programs, how do you expect
the, you know, sort of diuretics to come into play is that, you know, consistently baseline therapy across the board for all patients and then add on therapy from there in both trials, just trying to get a sense of how that sequencing is likely to incorporate, you know, a standard zyazide-based diuretics.
Dave: So that's de Minimis, it's not going to change over the course of the day, because that's really not a treatment effect, that's just a measurement.
Dave: The ability and to answer your question that I completely forgot to answer people, where a lot of cost and a recorder 24 hours, whether they are awake or asleep. The only differences. We do measurements around every 20 minutes during the day and we space them out a little bit more at night, because it can tend to disturbed sleep, a little bit which can.
Yeah, thanks for letting me clarify that. Everyone in both trials needs to be on a thiozide or a thiozide-like diuretic. And I'll mention also that in the United States at least,
Dave: Raise your blood pressure.
Dave: So that's how we do it we don't expect to see a difference in placebo effect overnight, we do expect to see.
The first line drug now is recommended to be a fixed dose combination between an ACE or an arm and a thiozyde diuretic. And so this mimics what
Dave: Reduction in blood pressure in fact.
guidelines would say you come in on two drugs, but they're in the same pill and there's always a thiozyde in that. So we're following to the letter the way we expect patients to show up in the doctor's office.
Dave: We will often see what's called restoration of nighttime dipping so for you and I without sleep apnea without untreated hypertension.
Dave: Our blood pressure will dip at night. It will go down as I mentioned hypertensive patients will first just lose the dipping then get actually hypertensive overnight. So thats, what we expect to see.
And therefore, when we give them guidelines and say, if they don't respond, if they're on that regimen, if they're obese,
You should think about our drug as a next step. Our data are going to exactly support that
Dave: At night.
sort of
Dave: Great.
practice pattern. In Chamis, as you're well aware, in Target H-10, you know, we had a little over half of the subjects on a diuretic, a little under half, not on a diuretic. And we saw a clear additive benefit of Lerunerstadt with the diuretic. So when we think about
Dave: As we think about the.
Dave: This is my last question the.
Dave: The importance of having.
Dave: A diuretic onboard like hcg.
Dave: As we think about the differences between.
what we hope to see from an effect size in advance and in launch of that 8 to 10 millimeter mercury, which is replicating target. That doesn't take into account the potential addativity of the diuretic, which, as Dave said, will be part of the background medication in both advance and launch HTN.
Dave: Your two programs how.
Dave: Do you expect.
Dave: The sort of diabetics to come into play is that consistently baseline therapy across the board for all patients and then add on therapy from there in both trials just trying to get a sense of how that that sequencing is likely to incur.
Great. Thanks so much, guys. Appreciate it.
James, good talking to you.
Dave: Incorporate.
Dave:
Your next question comes from Michael DeFiori from Evercore. Your line is now open.
Dave: Our standard size that based on diabetics.
Speaker Change: Yes, thanks for letting me clarify that everyone in both trials needs to be honest thiazide or a thiazide diuretic and I'll mentioned also that in the United States at least.
Bye. Bye.
Hey guys, thanks so much for taking my question. Just a general one from me. It's regarding just any preliminary thoughts you may share in how mineralis may proceed in cardio, renal, metabolic syndrome if the KD trial is successful. Just given that, you know, the people are starting to look at the CED field more holistically nowadays.
Speaker Change: The first line drug now is recommended to be a fixed dose combination between an ace or an arm and a size I diuretic and so this mimics what guidelines would say you come in on two drugs, but they are in the same pill and Theres always a fireside in that so we're following to the law.
Yeah, Mike, thanks for the question, appreciate it. I think you're right. We're seeing this
shift from treating hypertension and KD and heart failure and OSA is these independent standalone conditions, but really looking at the interplay between them,
Speaker Change: <unk> the way, we expect patients to show up in the Doctor's office.
Speaker Change: And therefore, when we give them guidelines and say if they don't respond if theyre on that regimen, if they're obese.
Can we find benefits from a single agent across that spectrum?
Speaker Change: You should think about our drug as a next step our data are going to exactly support that.
That's really kind of the basis of how we've been advancing for it. For us, hypertension is really kind of the beachhead indication. It's really, in a lot of ways, the genesis of these conditions. So you have hypertension that leads to CKD, heart disease, stroke.
Speaker Change: Sort of.
Speaker Change: Practice pattern in shipments as Youre, well aware and target age 10, we had a little over half of the subjects on a diuretic a little under half not on a diuretic and we saw a clear additive benefit of lower under staffed with the diuretic. So when we think about what we hope to see from an effect.
And so from our standpoint, the first step forward into that broader cardiorenal metabolic syndrome is the Explore-CKD study that's going to give us a perspective on not only addressing hypertension, but also the renal insufficiency within those patients.
Speaker Change: Size and advance San and launch of that eight to 10 millimeter Mercury, which is replicating target that doesn't take into account the potential add activity of the <unk>.
We also believe that that's a white space for us. There are a lot of agents for hypertension. There are a lot of agents for kidney disease, but to have a benefit on both is a little bit unique and distinct, and that's something that we think Larendorstack can point out.
Speaker Change: <unk>, which as Dave said, it will be part of the background medication and both advance and launch HTM.
Speaker Change: Great. Thanks, so much guys I appreciate it.
As we continue to learn more information about Lurundersat through our development program, we'll continue to contemplate where else can we extend the value of an aldosterone synthase inhibitor that has best-in-class selectivity like Lerunderset. And it could be some of these other areas that begin to get into heart disease, heart failure. There are a variety of places we can go.
Speaker Change: Payments good talking to you.
Speaker Change: Your next question comes from Michael <unk> from Evercore. Your line is now open.
Speaker Change: Yes.
Michael: Hey, guys. Thanks, so much for taking my question just a general one for me regarding.
Michael: Any preliminary thoughts you make sure and how <unk> may proceed in cardio renal metabolic syndrome. If the <unk> trial is successful just given that.
And I think as we're seeing a renaissance within research and in the pipelines right now, we're seeing more and more focus on aldostrum.
Speaker Change: People are starting to look at to see to feel more holistically nowadays.
which we believe is an important thing to do given the rising prevalence of disregulated aldosterone, which Mike you've heard to say before, we believe at least 25% of all hypertension patients are dealing with this, and that probably extends into full cardiorenal metabolic syndrome as well.
Speaker Change: Yes, Mike.
Mike: Thanks for the question appreciate it I think you're right.
Speaker Change: We're seeing this shift from treating hypertension and CTD in heart failure in OSA is these independent standalone conditions, but really looking at the interplay between them.
Very helpful. Thanks again.
Speaker Change: Can we find benefits from a single agent across that spectrum.
Thanks, Mike.
Speaker Change: That's really kind of the basis of how we've been advancing port for US hypertension is really kind of the beachhead indication. It's really in lot of ways. The Genesis of these conditions. So you have hypertension that leads to <unk> heart disease stroke and.
Ladies and gentlemen, as a reminder, should you have a question, please press star, followed by the number one. Your next question comes from Rami Katkuda from LifeSci Capital. Your line is now open.
Hey guys, thanks for taking my questions as well. I guess first, is there any risk that the three-week run-in period in advanced H-TN is not long enough to have patients get to stable blood pressure on the standardized background regimen?
Speaker Change: So from our standpoint, the first step forward into that broader cardio renal metabolic syndrome is the explore CTD study thats going to give us a perspective on not only addressing hypertension, but also the renal insufficiency within those patients.
So good question. Many of the people who come in will already be on most or not all components of that given
Speaker Change: We also believe that that's a white space for US there there are a lot of agents for hypertension. There are a lot of agents for kidney disease, but to have a benefit on both is a little bit unique and distinct and thats something that we think are understand can point out and as we continue to learn more information about <unk> through our development program, we will continue to come.
the type of patients we're screening for and screening out. And so I think the risk is relatively modest. It's taken care of, though, in the design because the placebo group stays on that regimen.
Speaker Change: Complaint where else can we extend the value of.
So let's just say over 12 weeks, in the running period, let's just say their blood pressure dropped by 8 millimeters of mercury.
Speaker Change: And I'll now turn the synthesis inhibitor that has best in class selectivity likely or understand it could be some of these other areas that begin to get into the heart disease heart failure.
but it drops another three from the
regimen over those 12 weeks. That will then be in the placebo effect, but it'll also be in the treatment arms and it'll just get subtracted out. So in the placebo adjusted, there's no risk.
Speaker Change: There are a variety of places we can go and I think as we're seeing a renaissance within research and in the pipelines right now, we're seeing more and more focus on aldosterone.
Speaker Change: We believe is an important thing to do given the rising prevalence of Dysregulation aldosterone, which Mike you've heard us say before we believe at least 25% of all hypertension patients are dealing with this and that probably extends into full cardio renal metabolic syndrome as well.
Got it. That makes a lot of sense. And then I guess with BIs, ASI, it was recently shown to have the selectivity of 250 to 1, but they still saw a number of cases of adrenal infefficiency in their KD study. I guess does this change your view at all on the selectivity threshold that's needed to kind of avoid the off-target suppression of cortisol?
Speaker Change: Great very helpful. Thanks again.
Speaker Change: Thanks, Mike.
Well, it's a really good question. I'm going to point out that
Speaker Change: Ladies and gentlemen, as a reminder, should you have a question. Please press star followed by the number one.
When we had LCI 699 at Novartis when I was there, that's essentially what killed the drug, and that's why it actually is sold now as a treatment for hyper-chortizolism, not hyper-aldosteroneism.
Rami Cutcuda: Your next question comes from Rami cut Cuda from lifestyle capital. Your line is now open.
Rami Cutcuda: Hey, guys. Thanks for taking my questions as well I guess first is there any risk that the three week run in period in advance HCN is not long enough to have patients get to stable blood pressure under standardized background regimen.
So the regulators are extremely, if not super sensitive about this issue.
When we do those selectivities, what we do is we take recombinant human enzyme and test it. But once you're in a patient, there are other variables. So I don't think I can answer your question and say we know an exact cutoff in vitro.
Rami Cuda: So good question many of the people who come in we will already be on most or not all components of that given.
Rami Cuda: Patients were screening for and screening out and so I think the risk is relatively modest it's taken care of though in a design because the placebo group stays on that regimen. So, let's just say over 12 weeks in the running period, let's just say their blood pressure dropped by eight melamine.
Truth is in humans. We haven't seen this so far and it hasn't been a close call for us, but we're continuing to look at that.
The YBI saw it, I can't
say we're very careful about not including people who've been using high strength
steroid creams or taking inhalers for asthma and things like that and confounding the data, we will look at that in profiling later because the real world is
Rami Cuda: The mercury, but it drops another three from the regimen over those 12 weeks that will then be in the placebo effect, but it will also be in the treatment arms and it'll just get subtracted out so in the placebo adjusted there is no risk.
people do that. So it's possible they're taking people who are predisposed and showing that their drug
you know, can suppress them. We're going to take that more carefully in our development programs so that when we eventually have guidance for physicians, they know exactly what our drug does and doesn't do.
Speaker Change: Got it that makes a lot of sense, and then I guess with ASI.
Speaker Change: ASI was recently shown tab cel activity at $2 50 to one but they still saw a number of cases of adrenal insufficiency and Theres TKD study.
Speaker Change: Does this change your view at all on the productivity threshold, that's needed to kind of avoid the off target suppression of cortisol.
Got it. Thanks so much.
Your next question comes from Rich Law from Goldman Sachs. Your line is now open.
Speaker Change: Well, it's a really good question Paul.
Speaker Change: Now that.
Speaker Change: When when we had <unk> 699 at Novartis when I was there that's essentially what killed the drag and that's why it actually is sold now as a treatment for hyper quarters holism not hyperaldosteronism. So the regulators are extremely if not 2%.
Hey guys, good to be back and congrats on the progress so far. For Advantage TN, can you discuss how the patients are enrolled and randomized due to three-week background sanitizing period since you're taking patients off to two to five meds and putting them on?
the background of two and two to three. How do you think that change in treatment from the sanitization could affect the results in the study? And then how do you mitigate against that?
Speaker Change: Ziv about this issue.
Speaker Change: When we do the selectivity is what we do is we take recombinant human enzyme and test it but once you're in a patient there are other variables. So I don't think I can answer your question and say, we know an exact cutoff in vitro proof is in humans, we havent seen this so far and it hasnt been a close.
Yeah, the rich, you know, the way advance is built is really to address the question of is somebody truly uncontrolled or truly resistant.
And we really have four main vectors that we address that during that run-in period before subjects ever get randomized to either placebo or active.
Speaker Change: Call for us, but we're continuing to look at that.
Speaker Change: While <unk> solid I can't.
Speaker Change: We're very careful about not including people who've been using high strength steel.
The first is following AHA prescribed guidelines for what subjects should be on. So if patients are on two meds,
Speaker Change: Ceroid creams are taking inhalers for asthma and things like that and confounding. The data we will look at that and profiling later, who is the real world is people do that so it's possible. They are taking people who are predisposed and showing that their drug.
coming into the trial, we take them off of those two meds and put them on Olminsartin an ARB and a diuretic. If they're on three, four, five meds, we put them on almost certain and diuretic and M. Lodapine, a calcium channel blocker. So we're putting them on the right drugs according to the AHA guidelines.
Speaker Change: Can suppress them we're.
Secondly, we ensure that they're on the proper dose of those medications. So in the case of Wellness Art, it's 40 milligrams. In the case of the diuretic, if it's in Dapmite, it's 2.5 milligrams. It's HCTZ. It's 25 NM load of penance 10 milligrams. So now we've got the right drugs at the right dose.
Speaker Change: We're going to take that more carefully and our development programs. So that when we eventually have guidance for physicians they know exactly what our drug doesn't hasn't been.
Speaker Change: Got it thanks, so much.
The third piece that we do is we ensure compliance. We know compliance is a factor in patients' inability to get to goal.
Speaker Change: Your next question comes from Rich law from Goldman Sachs. Your line is now open.
We're working with a firm called AI cure that's done, I think, up to 300 different registrational studies with this technology. And it's smartphone technology.
Jin Law: Hey, guys good to be back and congrats on the progress so far for advantage TN can you discuss how the patients are enrolled and randomized due to weak background standardizing periods since youre, taking patients after two to five minutes and then putting them on tobacco background with QM two to three.
that captures their consumption of these standardized medications during the run-end, and then we use it during the randomization period as well for background meds, as well as placebo inactive. But during that run-in period,
Jin Law: How do you think thats changed that changing treatment from the seven physician could affect our results in the study and then how do you mitigate against that.
This allows us to have daily confirmation that subjects have taken their medications
Speaker Change: Okay.
Speaker Change: Yes.
This is Bluetooth cloud enabled, so we get daily feedback, our subjects being compliant or not. It goes to the site, it goes to our CRO, and it comes to us as far as that information, and we're able to actively reach out to these subjects if they're missing doses.
Speaker Change: Rich.
Jin Law: The way advance has built is really to address the question of is somebody truly uncontrolled are truly resistant.
Jin Law: And we really have four main vectors that we addressed that during that run in period before subjects to ever get randomized to either placebo or active in the first is following haa prescribed guidelines for what subjects should be on so patients are on two meds coming into the trial, we take them off of those two meds and put them on.
and reinforce the importance of taking the study drug. So now we have them on the right drug at the right dose,
and we're ensuring they're compliant. And then at the end of that three-week period, which as you heard Dave said, when it is sufficient to get subjects to peak plasmine, probably maximal effect with that background regimen, we do 24-hour ambulatory blood pressure measurement.
Jin Law: Almost starting an arm and a diuretic if theyre on 345 meds, we put them on almost certain to diabetic and <unk> and calcium channel blocker. So we're putting them on the right drugs. According to the <unk> guidelines.
That's the gold standard measurement. As you heard Dave say earlier, it has a very de minimis placebo response. It takes out a lot of noise in what can sometimes be a noisy measurement in the office.
Jin Law: Secondly, we ensure that they are on the proper dose of those medications. So in the case of almost <unk> 40 milligrams in the case of the diabetics in depth minus two five milligrams of <unk>. It's 25 nm load opinions 10 milligrams. So now we've got the right drugs at the right dose.
If after that measurement, they continue to be hypertensive, so they have not achieved goal, then we randomize. If they do achieve goal, we don't randomize them, and they're not included in the study.
Jin Law: The third piece that we do is we ensure compliance we know compliance as a factor in patients and ability to get to goal. We're working with a firm called AI cure that's done I think up to 300 different <unk>.
Great. And then for patients who are treatment resistant on four or five met coming into the trial, and you take them down to three background med and then adding laryngeotone.
Jin Law: Registrational studies with this technology and its smartphone technology that captures their consumption of.
Do you think these patients are more difficult to treat compared to others since they are already treatment with them on four or five and then you pick them back down to four?
Jin Law: These standardized medications during the run in and then we use it during the randomization period as well for background meds as well as placebo and active.
Yeah, so this is Dave Robben. So traditionally, the definition of resistance is
Jin Law: That run in period.
Jin Law: This allows us to have daily confirmation that subjects have taken their medications.
having not reached goal on three medications, an acer and ARB, a thioside or a thyside like diuretic, and then either a beta blocker or a calcium channel blocker.
Jin Law: This is Bluetooth cloud enabled so we get daily feedback our subjects being compliant or not it goes to the site. It goes to our CRO when it comes to us as far as that information and we're able to actively reach out to these subjects if theyre missing doses.
And so there,
They may be on four or five drugs, but once you get to three without a drug like ours,
Jin Law: And reinforce the importance of taking this study drug so now we have them on the right drug at the right dose.
You can expect maybe a three or four or maybe a
best case 5 millimeter mercury fall with adding
Jin Law: And we're ensuring they're compliant and then at the end of that three week period, which as you heard Dave said, whether it is sufficient to get subjects.
any one of those as a fourth drug, but once you add, the more you add, the less the benefit generally. And the reason for that is you're not going after the main reason
Jin Law: Two peak plasma and probably maximal effect with that background regimen.
Jin Law: We do 24 hour 24 hour ambulatory blood pressure measurement.
that they have this problem. That's the reason why guidelines say go after aldosterone is your fourth line. The problem is there isn't a great drug to do that.
Jin Law: That's the gold standard measurement as you heard Dave say earlier and has a very de Minimis placebo response.
A pair of known just simply is too weak.
Jin Law: Makes a lot of noise.
Jin Law: What can sometimes be a noisy measurement in the office.
Spirone Lacto, you can't dose up to the maximum efficacious dose of 100 to 200 milligrams without running into problems.
Jin Law: After that measurement they continue to be hypertensive. So they have not achieved goal then we randomize if they do achieve goal, we don't randomize them and they are not included in this study.
And so the reason why we think we're actually going to be very effective
in that population where we cut them down to three is that we're going to be the first drug that really can get to go after that guideline of going after ALDO is fourth line because we can make dose up to maximum efficacious dose.
Speaker Change: Great and then for patients who are treatment resistant on four or five that coming into the trial and you took them down to three background Meds and then adding Lorenzo fab do you think these patients are more difficult to treat compared to others since they are already.
with our drug and get a robust blood pressure response. So I don't think it's a bug. I think it's a feature of cutting them down to three and then giving them the drug they really need, which is what we anticipate we're going to see.
Speaker Change: We system on four or five and then tick back down to before.
Jin Law: Yeah.
Jin Law: So this is Dave Rodman so traditionally.
David M. Rodman: The definition of resistant is.
I see. And one more question from me. So looking at the data you guys presented at ASN last year, where you show BMI versus the SBP reduction. And we see around like 20% of patients who did not respond to treatment across the BMI spectrum, meaning that their SBP entry went up in the study.
David M. Rodman: Having not reached go on three medications and Acer and our science side or if that is I'd like diabetic and then either a beta blocker or accounts in channel blocker and <unk>.
David M. Rodman: So.
David M. Rodman: They may be on four or five drugs, but once you get to three without a drug like ours.
Have you characterized these patients further on why they did not respond? And was there any difference of non-responder weight between the 50-Make and 100-Make dose in targeted QTN? And going forward, what do you expect is a non-responder way for your pivotal studies?
David M. Rodman: You can expect maybe at three or four.
Jin Law: It may be best case, five millimeter Mercury fall with adding.
Jin Law: Any one of those as a fourth drug but once you add the more you add the less the benefit generally and the reason for that is youre not going after the main reason that they have this problem. That's the reason why guidelines say go after aldosterone as your fourth line. The problem is there isn't a great drug.
Thanks.
So that's a really good question. What we actually, so I'm going to, I hope I don't give you a wonky answer because I'm a wonky guy. But when we do a frequency histogram and ask the question, what's the distribution?
On the right side of no response, it's a perfect
Jin Law: To do that.
It's nearly a perfect normal distribution. In other words, it's just statistics.
Jin Law: Apparel.
Jin Law: Simply as two week slowness around <unk>, you can dose up to the maximum efficacious dose of 100 to 200 milligrams without running into problems and so the reason why we think we're actually going to be very effective.
They didn't respond on that day, but they might respond a similar amount on the next time they're measured. It's just noise in the measurement when you do A-O-B-P.
On the left hand side, it's a left skewed distribution, meaning we see responders and we see super responders. And so we really...
Jin Law: In that population, where we cut them down to three is that we're going to be the first drug that really can go after that guideline of going after Aldo as sport line, because we can match those up to maximum efficacious dose with our drug and get a robust blood pressure response.
Don't think it's a confounder. Sure, there will be people in a general population
that don't respond to our drug more than an average drug.
Jin Law: So I don't think it is but I think it's a feature of cutting them down to three and then giving them the drug they really need which is what we anticipate we're going to see.
But it's not really responder, non-responder. It's really the normal distribution on the right-hand side. And this really interesting left skewed distribution, where we see people with 30 millimeter mercury falls and blood pressure.
Speaker Change: I see.
Speaker Change: One more question from me so looking at the data you guys presented at ASN last year, where you show BMI versus the SVP reduction.
The higher their blood pressure, the bigger the fall essentially, and that's because they're aldosterone dependent. So it's a really good question. It's easily controlled in our placebo-controlled design and the use of our statistics, so it doesn't introduce any kind of a confounder.
Speaker Change: And we see around like 20% of patients who did not respond to treatment across a BMI spectrum, meaning that their <unk> went up in the study have you characterize these patients further on why they did not respond and was there any difference of non responder of weight between the 50, making 100, Meg dolson target of KPN and going forward. What do you expect it to non fund away for your pivotal studies.
And Rich, I'll just add, and you're well aware of this, you know, our whole intent is to really identify those positive and negative predictors.
Speaker Change: Thanks.
Speaker Change: So that's a really good question one we actually.
for response to Lurunders stat. BMI clearly was a pre-specified analysis that we did in Target H-10. We saw a very tight correlation
Speaker Change: Going to accurately I don't give you a wonky answer because I'm a lucky guy.
Speaker Change: But when we do a frequency histogram and ask the question what's the distribution.
as far as response magnitude relative to BMI. That's something that we're going to continue to analyze in advance and launch H-TN. But as I noted in my opening comments, we're partnering with an AI firm to continue to really identify
Speaker Change: On the right side of no response, its a perfect.
Speaker Change: Nearly a perfect normal distribution in other words, it's just statistics a didn't respond on that day.
Speaker Change: Might respond as simple similar amount on the next time, they're measured it's just noise in the in the measurement when you do a BP.
those predictive values that would say this is the type of patient that's going to respond to Lerunderset very exquisitely. Dave made the point. The data is out there that as you get
Speaker Change: On the left hand side, it's a less skewed distribution, meaning we see responders and we see super responders and so.
into that resistant state where you're on three or more background meds, there is an enrichment of an aldosterone-dependent form of hypertension in that population because
Speaker Change: We really.
Speaker Change: We don't think its a founders.
Speaker Change: <unk> founders sure there will be people in a general population.
fundamentally those patients aren't being addressed with an aldosterine directed therapeutic. And so all of those I think are really going to enable us in this development program to come forward with a really clear toolkit of who should be on Lerunerostat and the kind of benefits that they can drive from it.
Speaker Change: Don't respond to our drug more than an average drug.
Speaker Change: It's not really responder non responder, it's really the normal distribution on the right hand side and this really.
Got it. And then just following up, based on what you guys said, is there like a certain percentage of patients who are just not elbow driven in that third and fourth line? Have you guys thought about there could be other drivers of hypertension?
Speaker Change: Interesting less skewed distribution, where we see people with 30 millimeter of Mercury falls in blood pressure the higher their blood pressure the bigger the fall essentially and that's because they're aldosterone dependent so it's a really good question, it's easily controlled in our placebo controlled design and the use of our statistics. So it does.
I think the literature would say that there are going to be other drivers. Our interest has always been on where Aldosterone's driving it.
Speaker Change: Introducing.
Speaker Change: And founder and rich I'll just add.
Speaker Change: You are well aware of this our whole intent is to really identify those positive and negative predictors for response to <unk>.
You know, hypertension is a multifactorial disease. We're not developing lorundersat as a monotherapy. We actually think an ideal combination would probably be an ARB, a diuretic, and lorostat for those patients who have aldosterindependent hypertension.
Speaker Change: BMI clearly was a pre specified analysis that we didn't target <unk>, we saw a very tight correlation.
So there are definitely other factors driving this condition, but that's where
Speaker Change: As far as response magnitude relative to BMI.
You know, frankly, we're taking advantage point of let's bring a level of precision to the treatment of hypertension and acknowledge those different variables. And in our case, very specifically, let's identify those subjects that have dysregulated aldosterone and will benefit extremely well from our understand.
Speaker Change: That's something that we're going to continue to analyze and advance and launch HTM, but as I noted in my opening comments, we're partnering with an AI firm to continue to really identify.
Speaker Change: Those predictive values that would say this is the type of patient that is going to respond or under set very exquisitely Dave made the point the data is out there that as you get.
That makes sense. And then just another final follow-up. And if you are you able to quantify how much of those patients are just not elder driven at that point and may not respond to an ASI?
Speaker Change: Into that resistant state, we're on three or more background meds. There is an enrichment of and aldosterone dependent form of hypertension in that population because fundamentally those patients aren't being addressed with and aldosterone directed therapeutic.
So it's a great question. Just to
embellished one statement that we've made. If you look at the classical teaching, the most common cause of hypertension beyond what we used to call essential hypertension or primary hypertension is too much aldostero.
Speaker Change: And so all of those I think are really going to enable us in this development program to come forward with a really clear toolkit of who should be on the <unk> and the kind of benefits that they can derive from it.
Speaker Change: Got it and then just following up based on what you guys said, it's sort of like a certain percentage of patients who are just not aldo driven in that fourth third and fourth line.
Previously, that was called hyperaldastronism and it had a very specific and complex
way of diagnosing it.
We now call it inappropriate aldosterone. The field recognizes that you can have a low aldosterone but the aldosterone dependent.
Speaker Change: You guys thought about there could be other drivers of hypotension.
Speaker Change: Well I think the literature would say that there are going to be other drivers.
And so while we will be measuring blood aldosterone, urinary aldosterone, at the end of the day, the gold standard is does your blood pressure go down when you reduce that aldosterone?
Speaker Change: Our interest has always been on where aldosterone is driving it.
Speaker Change: Hypertension is a multifactorial disease, we're not developing <unk> as a monotherapy, we actually think an ideal combination would probably be an arb, a diuretic and were under stat for those patients who have valdosta are independent of hypertension.
And so we'll be looking at that and saying, do we have people who didn't reduce their aldosterone? And is that why they didn't respond? And if that's the case.
Speaker Change: So there are definitely other factors driving this condition, but thats where.
We will see that in the 50 to 100 dose escalation arm of the trials.
Speaker Change: Frankly were taken advantage point of let's bring a level of precision in the treatment of hypertension and acknowledged those different variables and in our case very specifically, let's identify those subjects that have dysregulation aldosterone and will benefit extremely well from or understand.
Or are they truly, truly, truly resistant?
Aldo doesn't go down, blood pressure, Aldo does down, blood pressure doesn't. And then we'll be able to answer your question with data, and we'll have those data.
Speaker Change: Right that makes sense and then Jess.
Great. Thank you so much.
Speaker Change: Not our final follow up.
Speaker Change: And are you able to quantify.
Thanks, Rich.
Speaker Change: How much of those patients are just not alto driven at that point it may not respond to two two.
Your last question comes from Mohit Bonsal from West Fawar. Your line is now open.
Speaker Change: Two in ASI.
Thank you very much for taking my question.
Jess: So it's a great question.
And I have a passion regarding the future of these people.
Jess: <unk>.
Speaker Change: Embellish one statement that we've made if you look at the classical teaching the most common cause of hypertension beyond what we used to call a central hypertension, a primary hypertension is too much aldosterone.
conceptual so in Mohan? Can you hear me?
It was a little bit difficult to hear you. I just wondered if you could reorient the phone.
Can you hear me better now?
Thank you. Hello. So I just wanted to ask, yeah, sorry. Can you hit me?
Speaker Change: Previously that was called hyper aldosterone Ism and ahead of very specific and complex way of diagnosing it.
Yes.
Speaker Change: I'll call it.
Speaker Change: Inappropriate aldosterone. The field recognizes you can have a low aldosterone, but be aldosterone dependent and so while we will be measuring blood aldosterone urinary aldosterone at the end of the day.
given the shortened treatment period here, because I mean, I think in the past, you talked about IGLG2 inhibitors could have 30 to 40% improvement in proteinuria. So can you talk a little bit about that and how would you compare in contrast when the data come with what is out there and how would you make the Kono go-go decision here? Thank you.
Speaker Change: Gold standard is does your blood pressure go down when you reduce that aldosterone and so we'll be looking at that.
Speaker Change: And saying do we have people who didn't reduce their aldosterone and is that why they didn't respond and if that's the case.
Speaker Change: We will see that in the 50 to 100 dose escalation arm of the trials.
I think what we would anticipate, Mohead, and thank you for your question. You know, in Target H.TN, again, we saw the 8 to 10 millimeter mercury placebo adjusted drop in blood pressure with a really nice safety profile. The majority of that response was seen in about two weeks.
Speaker Change: Or are they truly truly truly resistant although it doesn't go down blood pressure.
Speaker Change: Dose blood pressure doesn't and then we'll be able to answer your question with data and we will have those data.
or with two weeks we saw the beginning of the drop and the majority of it was at four weeks. So I think we're comfortable that we'll see that level of drop.
Speaker Change: Great. Thank you so much.
Speaker Change: Thanks Rich.
Speaker Change: Your last question comes from Mohit Bansal from West West Fargo. Your line is now open.
within systolic BP. As far as the renal benefit, you know, I'd hate to extrapolate at this point in time. We know that the kidney benefit to a large degree is de-risk with an ASI based on what the Beringer-Engelheim data that was presented last fall.
Mohit Bansal: Well. Thank you very much for taking my question.
Mohit Bansal: The question regarding <unk>.
Mohit Bansal: So.
Mohit Bansal: Mohan.
Mohit Bansal: Can you hear me.
We wanted to confirm that we see the same benefit with Lurunderset. We think that that UACR effect is likely driven from the reduction in blood pressure. And so that's...
Mohan: It was a little bit difficult to hear you I'm just wondering if you could reorient the phone.
Speaker Change: Can you hear me better now.
Speaker Change: Thank you Hello.
Mohit Bansal: So I just wanted to ask yes, sorry can.
You know, what we anticipate seeing from a BP standpoint of 8 to 10, and then we'll be evaluating what we see from a UACR reduction standpoint. But again, our perspective is ASIs within CKD have been significantly de-risk based on some of the other work with the class.
Mohit Bansal: Can you hear me.
Mohit Bansal: Yes.
Mohit Bansal: Okay, sorry about that.
Mohit Bansal: I just wanted to ask about the kind of magnitude of benefit you want to see in the CBD proof of concept prize here.
Mohit Bansal: Uh huh.
Mohit Bansal: Okay.
John , can I just talk a little bit to that? Sure. Well, thanks for the question. It's really a good question. First of all, we made blood pressure the primary because we have a very effective blood pressure drug. And if you just treat
Mohit Bansal: Given the shorter treatment period here.
Mohit Bansal: Because I mean I think in the past you talked about <unk> two inhibitors could have 30% to 40% improvement in proteinuria. So can.
Mohit Bansal: Can you talk a little bit about that and how would you compare and contrast, when the data come.
John: The metabolic piece of this and you don't treat the hypertension piece of it, you're still going to lose your kidney.
Mohit Bansal: What is out there and how would you make the core mobile decision. Thank you.
And so you have to treat both. And we think our drug is going to be particularly effective there. But flipping over to your question about proteinuria, which is a UACR is what we're measuring. It leads through to decrease decline in GFR over a year or two, but you can't measure that in a short study. And your point is, well, can you really measure something in four weeks?
Speaker Change: And I think what we would anticipate mohit and thank you for your question.
Speaker Change: And target HCN again resolve aged 10 millimeter mercury placebo adjusted drop in.
Speaker Change: And blood pressure with a really nice safety profile. The majority of that response was seen in about two weeks.
Speaker Change: Or with two weeks, we saw the beginning of the drop of the majority of it was a four week. So I think we're comfortable that we will see that level of drop.
The answer is yes, we've talked to many experts about it. Will it be the maximum? It will be most of it. It won't be necessarily all of it, but enough. But I want to caution you
Speaker Change: Within systolic BP as far as the renal benefit.
Speaker Change: I'd hate to extrapolate at this point in time, we know that the.
Everybody's going to come out on SGLT2. This is going to be the benefit of our drug above SGLT 2.
Speaker Change: Kidney benefit to a large degree is de risked within ASI based on what the Boehringer Ingelheim data that was presented last fall.
We don't think we need to do a monotherapy trial anymore because that's already been questions been asked and answered by BI and also AC is doing that. And so we just want to know what's that increment above standard of care. So when you compare it, it's got to be apples to apples.
Speaker Change: We wanted to confirm that we see the same benefit with <unk>.
Speaker Change: Think that that UAC, our effect is likely driven.
Speaker Change: From the reduction in blood pressure.
Speaker Change: And so that's.
Speaker Change: What we anticipate seeing from a BD standpoint of eight to 10, and then we will be evaluating what we see from a UAC our reduction standpoint, but again our perspective is.
make sure it's not our addition of or understat compared to the combination product, say with BI or AZ, which starts from a lower baseline.
Speaker Change: Size within CTD have been significantly derisked based on some of the other work with the class.
It is only the comparison to what they get above the SGLT 2. And we expect to see a similar magnitude what they've reported in their prior trials for that increment.
Speaker Change: John can I, just got a little bit.
Speaker Change: Sure.
John: Well. Thanks for the question, it's really a good question first of all we may blood pressure that primary because we havent various active blood pressure drug and if you just treat the.
Got it. This is super helpful. If I may ask one more, I know I understand that you are approaching CKD or chronic kidney disease with hypertension angle, but there is a lot of activity in rare kidney disease space as well. And I mean, the relationship between hypertension and kidney diseases is
John: The metabolic piece of this and we don't treat the hypertension piece of it youre still going to lose your kidney and so you have to drag, but we think our drug is going to be particularly effective there.
John: Flipping over to your question about prudent area, which is a well UAC or is what we're measuring it reads through to decrease decline in GFR over a year or two but you can't measure that in a short study and your point is well can you really make sure something in four weeks. The answer is yes, we've talked to many.
very much intertwined. Is there an angle which a lot of the stat can play in those rare kidney diseases as well? Or I'm just too, like it's more of a visual thinking right now.
So that's a really good question. We've been excited to see, for instance, the IGA nephropathy data. That's a group of, it's often children. It's a bad disease and now it has multiple treatments.
John: Spurts about it will it be the maximum it will be most of that it won't be necessarily all of it but enough, but I want to caution you.
We expect we can play in that space, not against IGA. We do have some ideas right now. We're not at liberty to discuss them. But yes, the answer is I think there is an opportunity there for Lerunderset.
John: Everybody is going to comment on <unk>. Two this is going to be the benefit of our drug above <unk> soon.
John: I don't think we need to do a monotherapy trial anymore, because thats already been <unk>.
John: She has been asked and answered.
John: <unk> and also Acs is doing that and so we just want to know what's the increment above standard of care. So when you compare it it's got to be apples to apples.
Got it, helpful. More worth for us to do then. Thank you.
Thanks. Go ahead.
There are no further questions at this time, Mr. John Congelson. Please proceed with your closing remarks.
John: Make sure it's not.
John: Our addition of around <unk> compared to <unk>.
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 and advancing our clinical programs and remain enthusiastic about the upcoming milestones for the rest of the year.
John: The combination products say with by our AC which starts from a lower baseline.
John: It is only the comparison to what they get above the <unk>, two and we expect to see a similar magnitude.
We look forward to updating you as our pivotal program for Lurunderset continues to advance. With that, we'll close the call.
John: <unk> reported in their prior trials for that incremental.
Speaker Change: Got it does it super helpful. If I may ask one more.
Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.
Speaker Change: I understand that you either protein <unk> chronic kidney disease.
John: With hypertension angle.
John: Is a lot of activity in rare kidney disease space etcetera.
John: The relationship between hypertension kidney diseases is very much in decline.
John: Is there an angle, which allowed us that can play in those rare diseases are or I am just to make it more of a visual thinking right now.
John: Okay.
Speaker Change: So that's a really good question, we've been excited to see for instance, the Iga nephropathy data.
John: Group, it's often children.
John: A bad disease and now it has multiple treatments. We expect we can play in that space not against Iga. We do have some ideas right now were not at Liberty to discuss Bob but yes. The answer is I think there is an opportunity there for <unk>.
Speaker Change: Got it helpful Motor vessel after today. Thank you.
John: Okay.
Speaker Change: Thanks Mohit.
Speaker Change: There are no further questions at this time, Mr. John Carlton. Please proceed with your closing remarks.
John Carlton: 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 and advancing our clinical programs and remain enthusiastic about the upcoming milestones for the rest of the year we.
Speaker Change: We look forward to updating you as our pivotal program for Laura understand continues to advance with that.
Speaker Change: We will close the call.
Speaker Change: Ladies and gentlemen, this concludes today's conference call. Thank you for participating you may now disconnect.