Q4 2022 Mineralys Therapeutics Inc Earnings Call
Speaker 1: Greetings and welcome to the Minerellas fourth quarter and folio 2022 earnings calls. At this time, all participants are in a listen only mode. A brief question and answer session will follow the formal presentation. If anyone should require operator assistance during the conference, please press star zero on your telephone keypad.
Speaker 1: As a reminder, this conference is being recorded. It is now my pleasure to introduce your host, Dan Ferri of LifeSci Advisors. Please go ahead, sir.
Speaker 2: Thank you operator. Good afternoon everyone. Welcome to our fourth quarter and full year 2022 conference call.
Speaker 2: Today, after the market closed, we issued a press release providing our 4th quarter and full year 2022 financial results and business updates.
Speaker 2: A replay of today's call will be available on the investors section of our website approximately one hour after its completion.
Speaker 2: After our prepared remarks, we will open the call for Q&A.
Speaker 2: 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.
Speaker 2: These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings including our annual report on Form 10-K and subsequent filings.
Speaker 2: Please note that these forward looking statements reflect our opinions only as of today, March 15th. Except as required by law, we specifically disclaim any obligation to update or revise these forward looking statements in light of new information or future events.
Speaker 2: I would now like to turn the call over to John Cuggleton, Chief Executive Officer of Mineralis Therapeutics. John . John Cuggleton, Chief Executive Officer, Mineralis Therapeutics I'm John Cuggleton. I am here to talk to you about the
Speaker 3: Thank you, Dan. Good afternoon everyone and welcome to our first corporate update in Financial Results Conference call for.
Speaker 3: I'm joined today by Adam Levy, our Chief Financial Officer and Chief Business Officer, and Dr. David Rodman, our Chief Medical Officer.
Speaker 3: I'll begin with a brief overview of the business and recent milestones, followed by David, who will discuss our clinical programs, and then Adam will review our fourth quarter and full year financial results before we open up the call for your questions.
Speaker 3: The past few months have been a truly transformative period for mineralis, as we announced positive phase two proof of concept data for our product candidate, Lorunderstat, our proprietary, orally administered, highly selective aldosterone synthase inhibitor, that we are initially developing for the treatment of patients with uncontrolled hypertension or...
Speaker 3: Mar indication.
Speaker 3: The therapies currently available in the market.
Speaker 3: and the unmet need among patients failing to achieve their VP goals with current therapies.
Speaker 3: which should allow you to see why we're so excited about this opportunity in our clinical data today.
Speaker 3: To start, over 115 million patients in the US have sustained elevated blood pressure or hypertension, and over 30 million hypertensive patients in the United States are unable to achieve their BP goal despite treatment. And within this population, over 10 million patients suffer from resistant hypertension.
Speaker 3: defined as failing to achieve goal on three or more medications.
Speaker 3: Furthermore, obesity, particularly when associated with visceral adiposity, is a major cause of hypertension accounting for 65 to 75% of the risk.
Speaker 3: Uncontrolled hypertension is a serious medical condition. As patients with hypertension that persists, despite taking two or more medications, have a significantly elevated risk of developing heart disease, stroke, and kidney disease.
Speaker 3: For example, it is estimated that uncontrolled hypertension patients have a 1.8 times greater mortality risk due to cardiovascular disease.
Speaker 3: and a 2.5 times greater mortality risk due to stroke.
Speaker 3: Despite numerous options available to treat hypertension, including thiazide diuretics, ACE inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and mineral corticoid receptor antagonists,
Speaker 3: The majority of hypertension patients require multiple therapies to achieve their target blood pressure.
Speaker 3: Also worth noting is that many of these therapies designed to address hypertension were introduced several decades ago when the incidence of obesity was below 20 percent and abnormal aldosterone production affected less than 10 percent of the US population. As a result, these therapies failed to adequately address the shifting biology of hypertension.
Speaker 3: While first and second line treatment, often an ACE inhibitor or anti-attention receptor blocker plus diazide diuretic, have general efficacy, they are often unable to normalize blood pressure.
Speaker 3: And third line agents tend to produce only a 6 to 7 millimeter mercury improvement.
Speaker 3: However, this incremental reduction does not always adequately enable patients to reach their blood pressure goal. Therefore, many patients require three, four, or more antihypertensive agents in an attempt to achieve their target blood pressure.
Speaker 3: In addition, while hypertension is an asymptomatic disease, many of the currently available treatments have side effects and tolerability issues which may limit their use. Dr.
Speaker 3: For example, patients taking ACE inhibitors often develop a chronic cough.
Speaker 3: Men taking spironolactone often develop gynecomastia, otherwise known as breast enlargement.
Speaker 3: Notwithstanding this significant and growing unmet need, there's been a lack of U.S. FDA-approved novel therapies targeting hypertension, with no new class of antihypertensive treatment approved within the last 15 years.
Speaker 3: There's also a heavy cost beyond that of the health of the individual patient. As estimates show that hypertension and related to health issues resulted in an average economic burden of about $130 billion each year in the United States.
Speaker 3: This brings me to our late stage clinical candidate, Lorinderstaffe, a proprietary orally administered, highly selective aldosterone synthase inhibitor, designed to reduce aldosterone levels by inhibiting the enzyme CIP11-beta2, which is responsible for producing the hormone.
Speaker 3: our late stage clinical candidate, Lorinderstaff, a proprietary orally administered highly selective aldosterone synthase inhibitor designed to reduce aldosterone levels by inhibiting the enzyme CIP 11 beta 2 which is responsible for producing the hormone. We are targeting aldosterone.
Speaker 3: because abnormally elevated aldosterone levels are a key factor in driving hypertension in approximately 25% of hypertensive patients.
Speaker 3: Our goal is to emphasize a precision medicine approach in the development of Lourunderstat and identify predictors of enhanced response, a toolkit to inform when and how to use Lourunderstat in order to help patients achieve their goal of blood pressure.
Speaker 3: We began this journey of bringing targeted treatments to hypertension with our phase two proof of concept study, Target HTN, which was completed last year. Top line data from this study announced in November 2022 show that we demonstrated the clinically meaningful reduction in systolic blood pressure with 50 milligrams and...
Speaker 3: 12.9 millimeter mercury placebo adjusted reduction in systolic blood pressure with 50 milligrams once daily of lorunde staff.
Speaker 3: We also demonstrated that a body mass index greater than or equal to 30 predicted an even greater response with 50 milligrams once daily yielding a 16.7 millimeter mercury placebo-adjusted reduction in systolic blood pressure.
Speaker 3: Given the rising epidemic of obesity, its correlation to abnormal aldosterone levels, and the risk of uncontrolled hypertension, we believe our phase 2 data offer a critical finding that we will further investigate in our pivotal program.
Speaker 3: In summary, hypertension remains an area of significant unmet need with significant implications to long-term patient health. The clinically meaningful reduction demonstrated in Target HTN with Lorunderstaffe represents a substantial benefit to the millions of patients struggling to achieve their blood pressure goal.
Speaker 3: At Mineralis, our goal is to develop lorunderstaffe in a novel, targeted manner, with a toolkit to inform enhanced clinical response.
Speaker 3: Let me now turn the call over to Dr. David Rodman, Chief Medical Officer of Mineralis Therapeutics, who will offer a review of our clinical data and ongoing clinical program for the understand. Dr. David Rodman, Chief Medical Officer of Mineralis Therapeutics,
Speaker 4: Dave, thank you, John and good afternoon. Everyone. Today, I will provide an overview of trial results for the understand. Then provide an overview of the pivotal program that we're preparing to initiate. In the 1st, half of this year, as John touched on earlier target, HTN was a 200 subject.
Speaker 4: two-part phase two randomized double-blind placebo-controlled dose-ranging multi-center trial designed to evaluate the safety, efficacy, and tolerability of orally administered laryngostat for the treatment of uncontrolled and treatment-resistant hypertension.
Speaker 4: The study population was balanced for gender, age, body mass index, use of two versus three or more background antihypertensive medications and baseline blood pressure.
Speaker 4: which averaged approximately 142 millimeters of mercury systolic.
Speaker 4: There was good representation by the African American individuals. Part one of the trial explored the dose and exposure response characteristics of the run just at. In part two was designed to study the effect of the render stat in individuals with normal to high running levels.
Speaker 4: We were pleased to announce in November of 2022 that Target HTN successfully met its primary objective, reduction in systolic blood pressure, assessed by automated ossilometric blood pressure measurement in subjects dosed with Glorondrostat versus placebo for 8 weeks.
Speaker 4: Placebo-adjusted reduction of 9.6 millimeters of mercury and 7.8 millimeters of mercury in the 50 and 100 milligram once daily cohorts, with p-values of 0.01 and 0.04 respectively were observed.
Speaker 4: There was no advantage to splitting the 50 milligram dose to 25 milligrams twice daily.
Speaker 4: This supported our hypothesis that the observed 10-12 hour half-life of lorundristat was sufficient to achieve blood pressure reduction without a longer half-life that may have greater risk of sustained potassium elevation.
Speaker 4: Secondary endpoints such as diastolic blood pressure and 24-hour average nighttime and central blood pressure.
Speaker 4: were also reduced and supportive of the primary findings.
Speaker 4: Importantly, no observed effect on morning and stimulated cortisol levels was found, which is consistent with the 374-fold selectivity of lorundustat for aldosterone versus cortisol production.
Speaker 4: Larundra Stat was well tolerated with uncommon treatment emergent adverse events.
Speaker 4: Most frequently related to mild hyperkalemia. There was one treatment related adverse event of hyponatremia in the top dose cohort, which did not require special intervention and spontaneously resolved after discontinuation.
Speaker 4: of lorundrostat. In a planned analysis of factors associated with increased response to lorundrostat in part one of the trial, hypertensive subjects with obesity, defined as body mass index greater than 30 kilograms per meter squared, demonstrated significant reduction in placebo adjusted.
Speaker 4: systolic blood pressure of 16.7 millimeters of mercury in the 50 milligram once daily cohort, and 12.3 milligrams millimeters of mercury in the 100 milligram once daily cohort.
Speaker 4: The obesity findings supported our hypothesis that dysregulated systems biology associated with crosstalk between visceral adipocytes and the adrenal cortex links obesity to aldosterone mediated uncontrolled and treatment resistant hypertension.
Speaker 4: In contrast, there were no consistent differences in clinical response to lorundrostat based on gender, race, age, or the number of baseline antihypertensive medicines. Although use of a thiazide diuretic in either a two or three drug regimen was associated with greater blood pressure reduction.
Speaker 4: with a reduction in placebo adjusted systolic blood pressure of 12.9 millimeters of mercury in the 50 milligrams once daily cohort, and 10 millimeters of mercury in the 100 milligram once daily cohort.
Speaker 4: In November 2022, we held an end of phase 2 meeting with the Food and Drug Administration's Cardio Renal Division. To review our program, including the results of the target HTN trial. And discuss our planned pivotal program for lorundustat in hypertension.
Speaker 4: We have designed our pivotal program and overall drug development program based on FDA feedback at this meeting. As a result, we intend to initiate the pivotal program. For understand in the 1st, half of 2023. Starting with the advanced HTN trial.
Speaker 4: This is a randomized double blind placebo controlled pivotal trial in up to approximately 300 adult subjects. To further define the safety and efficacy of the understand. Prior to randomization subjects will be transitioned to a standardized background treatment regimen.
Speaker 4: consisting of an angiotensin receptor blocker, a thiazide-like diuretic, and if needed, a calcium channel blocker. If hypertension persists on the standardized regimen, subjects will be randomized to one of three cohorts and treated for 12 weeks.
Speaker 4: One third of subjects will be randomized to placebo, one third to laryngostat 50 milligrams once daily, and one third to laryngostat 50 milligrams once daily, and then increased at week four to 100 milligrams once daily if blood pressure goal has not yet been achieved.
Speaker 4: The primary endpoint of the trial will be change in systolic blood pressure as measured by 24 hours ambulatory monitoring at week 12 in the 2 active arms versus placebo. We anticipate having top line data from this trial in the 1st, half of 2024. Now, we also plan to initiate a randomized.
Speaker 4: double-blind, placebo-controlled three-arm, phase 3 pivotal trial in the second half of 2023.
Speaker 4: The proposed trial is expected to have a similar design as the advanced HTN trial, except subjects will remain on their previously prescribed background regimen of either two or more anti-hypertensives.
Speaker 4: including a diuretic maintained at the maximum efficacious or maximum tolerated dose level.
Speaker 4: Approximately 1,000 hypertensive adults will be randomized one to one to one to the same three regimens as in the advanced trial. And again, change in average 24 hour ambulatory systolic blood pressure will be the primary outcome measure.
Speaker 4: The top line data from this trial is expected in mid 2025.
Speaker 4: Subjects from both pivotal trials will be offered the opportunity to roll over into an open label extension.
Speaker 4: In addition to those trials, we plan on initiating a randomized double blind. Placebo controlled phase 2 trial in mid 2023. To evaluate the safety and efficacy of the understand. In subjects with chronic kidney disease.
Speaker 4: with top-line data expected in the first half of 2024.
Speaker 4: In summary, with the transition of lorundeustadt to pivotal trials, we have the opportunity to develop the first built for purpose precision therapy for hypertension.
Speaker 4: Following the science, we designed the target HTN trial to not only establish the benefit-risk and dose-responsive laryngostat, but also to test if inappropriate production of aldosterone was a significant driver of hypertension in obese individuals.
Speaker 4: We found that inhibiting the production of aldosterone in the study population as a whole, and particularly in the subset of individuals with obesity, led to what we feel is a substantial clinical benefit.
Speaker 4: Going forward, our intent is to confirm the observations from Target HTN and leverage the evolving science to allow us to implement a precision approach to the treatment of uncontrolled and resistant hypertension.
Speaker 4: I will now turn the call over to Adam who will provide a financial review for the 4th quarter and the full year ending 2022. Adam.
Speaker 4: Thank you, Dave. Good afternoon, everyone. Today I will discuss select portions of our fourth quarter and full year 2022 financial results.
Speaker 5: Additional details can be found in our Form 10-K , which will be filed with the FCC later today.
Speaker 5: R&D expenses for the three months ended December 31st, 2022, were $7.8 million compared with $6.6 million for the same period last year.
Speaker 5: R and D expenses were 26.3M dollars for the full year ended December 31st 2022. Compared with 16.3M dollars for the same period last year.
Speaker 5: The increase in full year R&D expenses was primarily due to increases of $7.4 million in pre-clinical and clinical costs related to the research and development of Lurunderstat.
Speaker 5: $1.7 million for the clinical supply, manufacturing, and regulatory costs, and $0.9 million in personnel expenses for additional employees to support the research and development.
Speaker 5: DNA expenses were $2.2 million for the 3 months end of December 31st, 2022, compared with $0.5 million for the same period last year.
Speaker 5: GNA expenses were $5.2 million for the full year ended December 31, 2022, compared with 2.4 million dollars for the same period last year.
Speaker 5: The increase in full year G&A expenses was primarily due to higher professional fees of 1.7 million dollars related to accounting, legal, and other support and personnel expenses of 1.1 million dollars associated with additional employees.
Speaker 5: Net loss was $29.8 million for the full year ended December 31, 2022, compared with $19.4 million for the same period last year. The increase was primarily attributable to the factors described earlier.
Speaker 5: Cash equivalents and marketable securities were $110.1 million as of December 31, 2022. Then, in February 2023, we completed an IPO of our common stock for net proceeds of approximately $202 million after deducting underwriting discounts, commissions, and estimated offering-related expenses.
Speaker 5: With that, I'll ask the operator to open the call for questions.
Speaker 5: ask the operator to open the call for questions. Operator.
Speaker 1: Thank you. We will now be conducting a question and answer session. If you would like to ask a question, please press Start 1 on your telephone keypad. A confirmation tone will indicate your line isn't the question cue.
Speaker 1: You may press start to if you'd like to remove your questions from the queue. For participants using speaker equipment, you may be necessary to pick up your handset before pressing this start case. Please hold while we pull for questions. Our first question comes from Greg Harrison, Bank of America.
Speaker 1: Thanks for taking the question and congratulations on the IPO and all the progress. Maybe first off, what are your thoughts on Laryngostat's future positioning in the market and how are you thinking about differentiation versus MRAs that could put Laryngostat ahead of them as a treatment option?
Speaker 3: Yeah, Greg, thanks for the kind words. Nice to connect.
Speaker 3: As we think about positioning for the Runderstadt, it matches to a large degree the clinical development strategy. We're looking to identify basically a toolkit that could help predict enhanced response to the Runderstadt and ideally in a third-line position. We've tested with the payers and physicians.
Speaker 3: that combination of utilization at third line with predictors of response, which based on the phase two data that Dave just walked you through, could be a BMI over 30, that's gonna give you an even more enhanced response than we saw at the top line data.
Speaker 3: And it's why it's important to bear in mind what meta analysis would indicate. As far as what a third agent can provide in blood pressure reduction of 6 to 7 millimeters of Mercury. If we can provide that double digit reduction as a third line agent, we think that becomes very compelling based on the work we've done with payers and we've done with physicians and testing that target product profile.
Speaker 3: Why we also think the MRAs will not be competitive in that space is frankly sporonal act on which is the predominant MRA used has been around for 60 years. I think the market as it relates to hypertension has largely voted against the utilization. We know that in national market share data it's about 2.6% of the high pretention. .
Speaker 3: that with the data that we're generating, the approach that we're taking, bringing a targeted approach, really enables us to bring a safe and highly efficacious drug into third line treatment where we think can really resonate and meet a lot of the unmet need as far as helping patients get the goal.
Speaker 1: Great, that's super helpful. Maybe just one more. What steps are you taking to maximize your chances of repeating the impressive data you've shown to date when you run your Pivotal programs? Yeah, Greg, really good question. I want to hand it over to Dave, but I first want to give him.
Speaker 4: Sure thing. Thanks, Greg. So first of all, we were quite gratified that the effort we put into the target HTN trial resulted in very precise measurements. We had a placebo effect of four millimeters of mercury with the automated osmometric blood pressure and close to zero.
Speaker 4: with 24-hour ambulatory blood pressure.
Speaker 4: So, for the next trials, we're going to use 24 hour ambulatory blood pressure. As the primary outcome measure that's been a trend in other trials, and it was discussed with the FDA at our end of phase 2 meeting and we got agreement that that was the proper. Endpoint.
Speaker 4: I will say one other thing that we're implementing is to have very good data on adherence. So compliance with both the background regimen and the experimental therapy. We're using...
Speaker 4: some technology advances that are fairly recent that are gonna allow us to know in quite good detail on a real time basis if the subjects take their pills and what time of day so that we can immediately intervene. And so I think those two things, compliance and a more precise way to measure it are gonna be, are gonna be, are gonna be, are gonna be.
Speaker 4: Lead to an even more precise. Point estimate of blood pressure response and I'm confident that that trial will deliver. Very appropriate and accurate results in the first half of 2024.
Speaker 5: Great, thanks again. Thanks, Greg. Thank you. Our next question comes from Umar Raffid with Evercore ISI.
Speaker 2: Hi guys, thanks for taking my question. I have two very quick ones here if I may. First, I saw you guys posted a new trial today. I don't know why I thought the primary endpoint would be SBP and I know that it's ABPM which is obviously a more robust endpoint but I was curious if a, how you thought about that and b, should we expect ABPM?
Speaker 2: to be the primary endpoint you guys are on with in future trials, including pivotal ones as well. Thank you very much.
Speaker 4: Well, why don't I take that question to a good question. We had discussions with our
Speaker 4: The principal investigators at the Cleveland Clinic or. Clinical advisory board, and then took that to the FDA. To get a consensus on this, and it was clear that the consensus. Was that while either AOBP.
Speaker 4: So, office, systolic blood pressure or ABPM can be used to register drugs that the preferred one in 2023 is to use 24-hour average ambulatory blood pressure. And so, for that reason, we chose it for this study as well as future studies that we've got plans to initiate later in the year.
Speaker 6: Thank you very much.
Speaker 1: Thank you. Our next question comes from Annabelle Semime with CIFIL.
Speaker 7: Hi guys, thanks for taking my question. Just to follow up on a couple things that you mentioned. First, when you talk about the tool kit that you're going to be using to be able to identify the right patients to...
Speaker 7: Is this strictly going to be, I guess, a clinical assessment based on weight or resistance level, or are they actually going to be testing for aldosterone? So what are the types of things you might put in this toolkit?...
Speaker 7: I guess that's the first question. And just to follow up on the ABPM, I know you mentioned it, but can you just remind us the difference between the in-office measurement that you conducted and the ABPM that you conducted, what's the magnitude of difference that you saw between those two measurements just for us to sort of have a frame of reference. The rest of the ASM has them again. So we won't have them within their level in science.
Speaker 3: Yeah, Annabelle, good to hear from you. I'll go first and I'll actually take the second question, then I'll have Dave speak to the first one. We really saw pretty concordant data, Annabelle, between the AOBP, which was the in-office measurement, and the 24-hour average reduction.
Speaker 3: both were in the double digit neighborhood. You know with the 50 milligrams in the AOBP, we saw about a 9.6 millimeter mercury placebo adjusted reduction, and we saw about a 10 millimeter mercury placebo adjusted reduction in the 24-hour average that was replicated in the central BP as well as the nighttime benefit. So that's why we were...
Speaker 3: I was really thrilled that the team had the forethought to do both measurements. It was very supportive, very concordant, and it gives us a good sense of what to expect going into the pivotal program, having done it in the Phase II proof of concept. But let me turn it over to Dave to give you some thoughts on the toolkit and what we know so far and what we're looking to continue to gather.
Speaker 4: Yeah, so great question. In terms of a hierarchy, because we had such a strong signal when we used obesity as a categorical variable. In other words, we just said, if you're obese with a BMI over 30, what's your response if you're non-obese?
Speaker 4: What's your response? And we saw fairly dichotomous results. Now that doesn't, so there was a very high response rate with a robust reduction in blood pressure in the obese patients.
Speaker 4: In the non-obese patients,
Speaker 4: there were some individuals who responded, but most had a modest response or no response. So your question is very interesting. First of all, as a clinician, knowing that obese patients are hard to treat,
Having just a predictor like obesity and we'll expand it to waist to hip ratio, which is more directly a measure of visceral adipocytes. But that by itself will be an extremely useful. Precision tool, it sounds low tech. But, in fact, it's going to deliver great benefit. With a highly enriched responder population.
But we aren't going to stop there. And your question about aldosterone is an interesting one. We looked at spot measurements of aldosterone. And like everyone else, we found that they were extremely variable and somewhat difficult to use. And so we're going to be implementing 24-hour urine measurements of aldosterone going forward in the next trials.
and we'll explore that question you asked. One important issue to remember, though, is that there are inter-individual and ethnic differences in the response, the sensitivity to aldosterone, so it's not just the aldosterone level. And so I think we'll see something there, but I don't know that it will be predictive enough.
We are also going to explore other biomarkers related to the abnormal positive feedback loop that's generated between visceral adipocytes and the adrenal gland. One of the important ones is leptin, which has been shown to increase aldosterone production, and we anticipate that increased leptin will be associated with an increased response.
To therapy, but we'll be looking at many other potential find additional measures that could be useful, particularly in the subjects who are no beast. But might benefit from the drug.
And if I could just squeeze in one more, as you're thinking about the trial in the CKD population, this is a CKD population that has uncontrolled hypertension. Is this meant to be a proof of concept to move into other cardioreal indications or is it just to specifically look at the CKD population? The specific hypertensive population of CKD? Of course, right in the depth of your brain it's just to define itsCongroicon. And yes, if I could, feel that degeneration kicking into my eyes because every time I can feel that it's just water I go oh, I can grab my paper Europeans that's exactly the same. That is the complete description of what that means.
Yeah, and about we wanted to get a sense from a profiling standpoint, what the Laryundra Stat would do in a population with a more compromised renal function. We'll be looking at the EGFR 30-45. The two pivotal studies will be going down to an EGFR of 45.
And we anticipate a study getting started mid year, so we'll be able to provide. Updates on that study in more detail, probably at the May earnings call.
a study getting started mid-year. So we'll be able to provide updates on that study in more detail probably at the May earnings call. Great, thank you. Yeah.
Thank you. Our next question comes from Rich Law with Credit Suisse. Please go ahead. Hey, guys. Congrats on the IPO from me as well. A couple of questions for you. Can you give more information about that CKD profiling study, what's the study size and what is the power to show?
And it's this study, pivotal, and if so, like what does it add to your potential indication or label that you wouldn't be able to otherwise? And then I have a couple more follow-up questions. Yeah, Rich, thanks. Thanks for the kind words. As I noted to Annabelle's final question, we'll have more details in May. The predominant goal of that study is to get a characterized response in a special population dependation.
And that's with reduced kidney function, again, in that 30 to 45 milliliter per minute for 1.753 meters squared measurement. You know, we'll talk about size in May as we finalize that. You ask, is it pivotal? I think it's probably part of the package.
to be able to provide additional data, again, in a patient with more compromised renal function. But again, we'll provide more data, more details in May.
Okay, great. And then the other question is, given the mixed results that we saw in the non-obesity patients, and I think David mentioned it a little earlier as well, why not just use obesity as an enrollment criteria instead of a pre-specified analysis? And then if not, like, would you expect a non-obesity patient to perform better?
So, excluding obese patients from the trial would, first of all, preclude us from doing that and quite honestly, the FDA just wouldn't allow that kind of a design. And so, instead what we can do is
in a larger trial, like a phase three trial, we can get really into the granularity. So for instance, when we say that non-obese patients don't respond, that's not true. It's a continuous variable. And if you have a BMI of 29.5, you can see that the
or you have a BMI of 30.5, those two people are going to have a similar response. But it's going to be less than somebody with a BMI of 40 and more than somebody with a BMI of 20. And so by going into a much larger group, we can look at that as a continuous variable as well.
as well as look at our toolkit which includes potential biomarkers, to get to a point maybe where what we could tell a clinician, and this is just hypothetical, is yes, if you have an obese patient who's failed two drugs, then you should probably think about using this drug.
because it's likely to have a very good response. On the other hand, we can also say if you have a patient with a BMI less than 30, who's also having difficulty with blood pressure control, then you can try the drug and we'd like to have it be better than empiric.
In other words, just give them and see if it works. So we're going to continue to explore other biomarkers largely, as I mentioned with an idea towards pulling out those people who have super responses, but they're not. Clinically obese, they are just physiologically obese.
Got it. That makes a lot of sense. If you may, I'm just going to squeeze in one more question. Can you, for your studies, will you include any cardiac imaging or structural related endpoints? Thank you.
Yeah, so great question. Right now we don't have plans to do that. We're open to the idea of a sub study to look at that and we'll be talking with external experts on whether there is a proper plan.
to do it that way or to do it simply as a small standalone trial. But there's no plans to do that at this point.
You have been mentioning the drug really works better among obese patients. So the way we think about it, it's possible that this drug may have some usage in other lines of therapy as well if it can be shown that there is a subset of patients who benefit more than others.
So, in that context, what would it take for physicians to use this drug among obese patients more and maybe in earlier lines? Do you have to run additional trials or subgroup data enough? I mean, how do you convince the doctor that this is a subset where you need to use?
this work earlier than anything else.
Yeah, Mohit, this is John . I appreciate your question. I think our view is
Based on the market need, based on just the dynamics of a highly genericized space and the multifactorial nature of hypertension.
that a launch profile for LaryundraStat as third line with an informed toolkit of where to really predict enhanced response is the way to enter the market.
that a launch profile for Laryundra Stat as third line with an informed toolkit of where to really predict enhanced response is the way to enter the market. Thank you for that.
doesn't mean that there may not be an opportunity for second line use or maybe even first line use. But I think that's gonna be part of the stage development for lorundristat. I think we've got a clear signal coming out of target HTN that there is a segment of patients that can have a very clinically substantial response to lorundristat on the backbone of St. Asar and we clearly saw an interaction with the diuretic.
And so we're looking to move into the pivotal program informed by that proof of concept study, giving us a sense of de-risking moving into a replicate population in the phase two pivotal with a standardized background of an ARV and a diuretic, and in some cases, a calcium channel blocker.
and with their existing background in the phase three. And so that's our view of entering the market. It doesn't mean this drug will not work earlier. We just think that's gonna be part of the life cycle development of this program as we advance it.
Got it. And if I can squeeze one more in. So in your trials, you are combining the uncontrolled and resistant hypertension patient population. Is there any difference in terms of the physiology of these patients where you know.
a drug like yours could work better among uncontrolled or it is easier to show benefit among uncontrolled versus resistant or vice versa.
Okay, so that's a really interesting question. Now, looking at the Target HTN Study, we certainly didn't see any major difference between whether the subject was on two drugs or three drugs. It was a much, obesity and use of thiazide were much bigger predictors.
We will be diving into that though in much more detail. We had a 50-50 split in those kinds of subjects, two versus three or more in Target HTM which gave us great visibility into your question. And we're going to be...
looking at that in more detail in these larger studies, I think what we'll find is that it doesn't matter but
it's probably quite reasonable to say that after you've failed to be controlled on an ASARB and a thiazide, that if you put all of the generics in a row in our drug, it's much more likely.
based on our data you'll respond to our drug. And so it's a matter of saying that right now the guidelines tell you it's totally empiric, essentially what we call an N of one office experiment in each individual, which is a very, very, very, very, very
poor way to do it because blood pressure is quite variable. And so we think that by giving them a toolkit we will be able to get through that hurdle of the sort of randomness of empiric treatment and the really transformational potential for precision medicine.
I think I just add one point to that, as we've had dialogues with the FDA, they don't really view the world as uncontrolled or resistant. It's for the treatment of hypertension. And from our standpoint, we want to make sure we respect the medical community that wants to know what drugs do in resistant hypertension. That's why those groups are in our intended populations. But we're really interested in the biology, in trying to understand where aldosterone is in a dysregulated state and can exquisitely respond to a highly selective aldosterone synthase inhibitor like Lorendorstat.
regardless of whether they're failing to get to go on two or three or more background meds. This is super helpful. Thank you very much. Appreciate it.
regardless of whether they're failing to get to go on two or three or more background meds. This is super helpful. Thank you very much. Appreciate it.
Thank you. There are no further questions at this time. I would now like to turn the floor back over to John and Colton for closing comments. Thank you, operator, and thank you to everyone for joining us today. We're very excited about the progress we've made over the last year, and we're enthusiastic about the upcoming milestones for 2023.
We look forward to updating you as our pivotal program for the L'Oréndez that continues to advance. With that, we'll close the call. Thank you. That does conclude today's teleconference. You may disconnect your lines at this time. Thank you for your participation.