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spk08: Greetings and welcome to Minor List First Quarter 2023 Earnings Conference Call. At this time, all participants are on a listen-only mode. A 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. As a reminder, this conference is being recorded. It is now my pleasure to turn the conference over to your host, Dan Ferry. Thank you. You may begin.
spk00: Thank you, Operator. Good afternoon, everyone, and welcome to our first quarter 2023 conference call. Today, after the market closed, we issued a press release providing our first quarter 2023 financial results and business updates. A replay of today's call will be available on the investor section of our website approximately one hour after its completion. After our prepared remarks, we will open up the call for Q&A. Before we begin, I would like to remind everyone that this comments call and webcast will contain forward-looking statements about the company. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our annual report on Form 10-K and subsequent filings. Please note that these forward-looking statements reflect our opinions only as of today, May 15. 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. I would now like to turn the call over to John Congleton, Chief Executive Officer of Mineralis Therapeutics. John?
spk05: Thank you, Dan. Good afternoon, everyone. and welcome to our first quarter 2023 financial results and corporate update conference call. I'm joined today by Adam Levy, our Chief Financial Officer and Chief Business Officer, and Dr. David Rodman, our Chief Medical Officer. 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 first quarter financial results before we open up the call for your questions. Thus far in 2023, we've continued to make significant progress advancing our clinical development program for lorundrastat, a proprietary, orally administered, highly selective aldosterone synthase inhibitor. We're initially developing lorundrastat for the treatment of patients with uncontrolled hypertension or resistant hypertension, with the goal of expanding to other cardiorenal diseases. Building off the positive data from our target HTN Phase II study that were presented at the end of last year, We recently announced the dosing of the first patient in the pivotal trial named Advanced HTN. As David will discuss in detail momentarily, this is the first trial in our pivotal program to evaluate the safety and efficacy of lorundrastat for the treatment of uncontrolled or treatment-resistant hypertension. It is notable that many of the sites from the target HTN study are already active or slated to participate in the Advanced HTN study and are familiar with lorundrastat. This is an exciting milestone for the company as we continue to execute our strategy, and we continue to expect to read out top-line data from the trial in the first half of 2024. In addition, under the Pivotal program, we also plan to initiate a second Pivotal trial named Launch HTN in the second half of 2023, which is expected to read out top-line data in mid-2025. The open-label extension trial for our long-term safety data set should begin enrollment in the middle of 2023. We're also on track to begin our chronic kidney disease, or CKD, profiling study, extending the use of lorundrastat to individuals with stage 3b CKD during the middle of 2023, with expected data readout in the first half of 2024. The PIVOTL program is designed to provide additional data supporting our belief that normalizing aldosterone levels can provide an effective and more targeted approach for the control of hypertension. As with target HTN study, the PIVOTL program is specifically addressing patients with uncontrolled hypertension, which we believe represents a significant unmet need as over 50% of treated patients fail to achieve their goals. And it's worth noting that these patients have a substantial risk of developing heart disease, stroke, and kidney disease. We believe that a lack of innovation in new therapies is at least partially to blame, as many of the currently approved therapies for hypertension were introduced several decades ago. When the incidence of obesity was below 20%, and abnormal aldosterone production affected less than 10% of the hypertension population. As a result, we believe these therapies failed to adequately address the shifting biology of hypertension, as the obesity rate has skyrocketed to over 40% of U.S. adults, and abnormal aldosterone production is thought to be prevalent in at least 25% of all hypertension patients. The shift in the underlying biology of hypertension requires new innovations, like Larunderstat, to provide hope for patients struggling to control their blood pressure, particularly in the obese population. We look forward to providing updates on the progress of our Pivotal Program through the course of 2023. 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 La Runderstadt. Dave, the floor is yours.
spk07: Well, thanks, John, and good afternoon, everyone. Today, I'll provide an overview of the Pivotal Clinical Program for La Runderstadt, that, as John touched on earlier, has now commenced enrollment. We're pleased to announce sites have started dosing patients in the advanced HTN trial, and site initiation and trial enrollment are currently on track. This is the first of two core trials in our registration program for lorundrastat. The advanced HTN trial is a randomized, double-blind, placebo-controlled pivotal trial. We plan to enroll up to approximately 300 adult subjects with uncontrolled or resistant hypertension, defined as patients failing to achieve their blood pressure goal on two to five antihypertensive medications, in order to further define the safety and efficacy of lorunderstat. Prior to randomization, subjects will be transitioned to a standardized background regimen consisting of an angiotensin receptor blocker, omasartan, a thiazide-like diuretic, indapamide, And if they entered the trial on three to five medications, a calcium channel blocker and Lodipine will be added. Subjects will be separately randomized by the number of background medications that they were on, two medications versus three or more. If hypertension persists on the standardized regimen, subjects will be randomized to one of three cohorts and treated for 12 weeks. One-third of the subjects will be randomized to placebo, one-third to lorundrastat 50 milligrams once daily, and the final third to lorundrastat 50 milligrams once daily and then increased at week four to 100 milligrams daily if blood pressure goal has not yet been achieved and if they meet certain safety criteria. The primary endpoint of the trial will be change in systolic blood pressure as measured by 24-hour ambulatory monitoring at week 12 in the two active arms versus placebo. We anticipate having top-line data from this trial in the first half of 2024. Now, the second part of our pivotal program for lorundrastat includes initiation of the larger LAUNCH-HTN trial in the second half of 2023. This randomized, double-blind, placebo-controlled three-arm trial is planned to have a similar design as the advanced HTN pivotal trial, except subjects will remain on their previously prescribed background regimen of two to five antihypertensives, including a thiazide or thiazide-like diuretic, maintained at the maximum efficacious or maximum tolerated dose. In the launch HTN trial, randomization will be stratified by body mass index less than 30 kilograms per meter squared versus greater than 30 milligrams per meter squared or obese. Approximately 1,000 hypertensive adults will be randomized one to one to one to the same three regimens as in the advanced HTN trial. And again, change in average 24-hour ambulatory systolic blood pressure will be the primary outcome measure. The top-line data from LAUNCH-HTN are expected in mid-2025. In addition, subjects from both pivotal trials will be offered the opportunity to roll over into an open-label extension trial. In mid-2023, we plan to initiate a randomized, double-blind, placebo-controlled Phase II trial to evaluate the safety and efficacy of lorundrastat for the treatment of untreated, I mean uncontrolled or resistant hypertension in a chronic kidney disease population. Topline data from this trial is expected in the first half of 2024. This is really a truly exciting time in our company's history as we advance the development of the first built-for-purpose targeted therapy for hypertension. The data we've collected to date show 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 will be a substantial clinical benefit. We look forward to seeing initial results of the confirmatory pivotal program next year, moving our strategy to implement a targeted approach to the treatment of uncontrolled or treatment-resistant hypertension forward. I want to thank our cross-functional team members, the equally important teams at our trial sites, and most importantly, study subjects who anxiously wait for a new approach to treating their hypertension. We look forward to keeping you appraised of the status of our pivotal program as progress on our journey to transform the antihypertension landscape unfolds. I'll now turn the call over to Adam, who will provide a financial review for the first quarter of 2023. Adam?
spk06: Thank you, Dave. Good afternoon, everyone. Today, I will discuss select portions of our first quarter 2023 financial results. Additional details can be found in our Form 10-Q, which will be filed with the SEC later today. R&D expenses were $12.3 million for the three months ended March 31st, 2023, compared to $6.8 million for the same period last year. The increase was primarily due to increases of $4 million in licensing fees under the license agreement with Mitsubishi Tanabe upon achieving a development milestone of Lurendra Stat in March 2023, $0.9 million in higher compensation expenses as a result of additions to headcount, $0.7 million in clinical supply, manufacturing, and regulatory costs, and $0.5 million in other research and development expenses, which were partially offset by a decrease of $0.6 million in preclinical and clinical costs, driven by the timing of research and development activities and clinical trials of lorundrastat in each quarter. G&A expenses were $2.6 million for the three months ended March 31, 2023, compared to $0.8 million for the same period last year. The increase was primarily due to $0.8 million in higher compensation expense as a result of additions to headcount, $0.5 million in higher professional fees associated with operating as a public company, $0.4 million in higher other administrative expenses, and $0.2 million associated with new director and officer insurance policies. Net loss was $12.6 million for the quarter ended March 31, 2023, compared to $7.6 million for the same period last year. The increase was primarily attributable to the factors described earlier, cash, Cash equivalents and investments were $301.8 million as of March 31st, 2023. This includes the net proceeds from our IPO completed in February 2023. We believe our cash, cash equivalents, and investments will fund the planned activities and our operations through mid-2025. With that, I'll ask the operator to open the call for questions. Operator?
spk08: Thank you. At this time, we'll be conducting a question and answer session. If you'd like to ask a question, please press star 1 on your telephone keypad. A confirmation tone will indicate your line is in the question queue. You may press star 2 if you'd like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we poll for questions.
spk11: Our first question comes from Omer Rafat with Evercore.
spk08: Please proceed with your question.
spk12: Hi, guys. This is Mike DeFiore in for Omer. Congrats on all the progress, and thanks so much for taking my questions. Two for me. Number one, what's the likelihood or probability that patients would actually need to titrate up to the 100 milligram dose at four weeks in the pivotal trials? I see that based on the phase two target hypertension trial, Aside from reducing nighttime systolic blood pressure, it seems as if 100 milligrams offers limited benefit, if anything, beyond 50 milligrams. My second question is just regarding the design, again, of the current Phase II advanced hypertension trial. How should we think about the risk of having patients switch to a standardized regimen of background meds, which it seems as if they exclude the use of ACE inhibitors and non-thiazide diuretics? Should we expect any different results from and if patients would remain on their random two to five baseline background meds. Thank you.
spk05: Hey, Mike. This is John. Just a couple of thoughts, and then I'll turn it over to Dave. You know, I think the thing that we learned from target HTN, as you alluded to, is that the 50 and the 100 milligram once daily provided a really robust and well-tolerated clinical profile. We think from the Exposure response analysis that we did, the 100 milligrams for select patients, is going to provide value. But as you recall, target HTN was not a titrated study. We feel that those patients that maybe had more incidence of that mild hyperkalemia that we saw with 100 milligrams probably would have sufficed at the 50 milligrams. And that's why we built in the titration schedule that we've done. But to give you a sense for the probability, which is going to be a bit of a guess, I'll turn it over to Dave. And I'd also like to have him, as he speaks about the risk that you pointed out of switching, also talk about some of the other risks that we think we've mitigated and managed within this study. Dave?
spk07: Sure. So, thanks for the question. I guess, should I just answer the second question then?
spk05: Go ahead if you've got a thought on probability, Dave. I mean, it's hard to guess at this point.
spk07: Yeah. So you made a really good point that if you look at the group, 50 milligrams had about the same effect as 100, and it was extremely well tolerated with a low potassium increase. But that's the group level. And what we know is that some people absorb the drug better than others. And so our thought is that if you have people who are low absorbers, then they may not respond to 50, not because it's not a good dose, but because their levels are too low. And so it's only in those people we expect to advance to 100 milligrams. The important point about that is that we'd expect them to have the response and the safety of a 50 milligram dose in that subset of patients. We're not going to measure blood levels but we can tell from the increase in potassium whether that's what's going on if I had to guess based on the data we saw you know all things considered it might be 10 to 20 percent so any other questions about that one before I move on to your second no that's fine thank you okay so really good questions about what happens when you change to that standardized regimen, good and bad? And let me discuss that a little bit, and I'll come to your question, which is, is there a risk? The, you know, spoiler alert on that, we think the benefits are really manifest, and the risks are quite well managed to go into that. Now, the point here is that we wanted to design that trial to be tier one evidence for activity of our drug as an aldosterone synthase inhibitor. To do that, you need a very well controlled study with very few variables other than the patient and the drug. Now, for instance, we know that things like lack of adherence to the background regimen, lack of adherence to the, you know, the drug itself, can really drive variability, and we've seen that recently in other trials. We also know that white coat hypertension, in other words, people that have hypertension when they come to the office, but if you do 24-hour ambulatory blood pressure, you see that, in fact, they don't have hypertension, is something that can also confound things, because those are uninformative patients, and about 20% of patients in our trial the target HTN had that. So, with our design, which is that you have to have hypertension by ABPM, we get rid of white coat hypertension. By using an AI-trained adherence monitor where the subjects take a picture of their drug every day and we know exactly what they took and when they took it, we control completely for adherence, will get rid of much of the placebo effect. And those things together mean that changing people over to this new regimen will simply mean that everyone who passes that screening and still has hard-to-control hypertension will be informative. That's a really powerful thing. That's why we can do a 300-patient study instead of 1,000. to get, you know, highly precise data. Now, I want to mention one more thing that we do as part of our operational excellence plan, and that's to look at serum potassium. Because as you know, that's the reason why people don't use MRAs much. And we learned a lot in our trial. And what we're doing is four things. The first is, when possible, we're going to have subjects come in on an empty stomach. If you come in after a meal, particularly one with things like bananas and apricots and so on, you'll increase your serum potassium by 0.2 or 0.3 and that's uncontrolled noise. The second thing is a tight tourniquet and fist pumping causes muscle to release pet potassium, which artificially raises your serum potassium. So we're going to be retraining the phlebotomist. The third thing, is we're going to cap the inclusion serum potassium at 4.8 millimole per liter. That's been done with drugs like thanarinone, and it gives you a better safety margin than capping it at 5.1, the top of the normal range. And finally, we're going to be doing local blood draw, because what happens is if you use a central lab, that tube ends up traveling by courier, going somewhere else, And that tends to introduce artifacts like red cell breakdown. So, we're going to do just the potassiums locally, try to get those results back during the visit. And if the results show that the potassium has gone above the normal range, they'll be repeated that day so that we know exactly what the potassium was. So, that three-pronged approach, getting rid of white coat hypertension, monitoring adherence, and making sure that potassiums are completely accurate, we think is going to transfer a ton of operational excellence. And we've controlled for the challenge of changing people to that new regimen by planning for a slightly higher screen failure rate with the number of sites and the ability of those sites to recruit their subjects.
spk11: Very helpful. Thank you. Thanks, Mike.
spk08: Our next question is from Greg Harrison with Bank of America. Please proceed with your question.
spk10: Hey, good afternoon. Congrats on the progress and thanks for taking the questions. How are you thinking about the opportunity in hypertension in the CKD population? And how would you characterize the overlap between these patients and your targeted initial population? And then what level of response would you say is meaningful here compared to the trials you're running currently and will be running in hypertension?
spk05: Greg, this is John. Good to connect. Hopefully I got those three questions in sequence here. The opportunity from a hypertension CKD standpoint, we know there's pretty significant overlap. Our perspective is There's a significant unmet need in the hypertension space as it relates to number of patients not getting the goal being 50%, the growing prevalence of abnormal aldosterone biology, and the clear linkage between that uncontrolled hypertension and the development of CKD. So from our standpoint, there's significant overlap, there's significant unmet need, and there's significant opportunity. The profiling study that will get underway mid-year 2023 is a step in that journey to fully understand the profile of lorundrastat in that overlap population that then could lead us to further study within CKD itself. From a targeted approach, I think that's what we've been about from day one. As you and I spoke about it at the B of A conference last week, Greg, we believe that target HTN not only highlighted the efficacy of lorundrastat and hypertension, but further solidified the selectivity of lorundrastat to effectively inhibit and lower aldosterone levels to the clinical benefit of hypertension patients. And we're going to continue to take that targeted approach, particularly as what we found in target age 10 with the obese population, and continue to look at that as we look at other cardiorenal disorders. As far as level of response, you heard Dave speak very clearly about some of the operational learnings that we had from Target HTN as well as other contemporaneous studies to try to manage and mitigate risk moving from the phase two into the pivotal program. We continue to look for a double-digit reduction in systolic BP. That continues to be our goal, and certainly we're going to continue to look at predictors of enhanced response. looking to potentially confirm obesity as well as be open to other indicators of response that could form an endophenotype of a responding population to understand.
spk07: John, can I jump in here as well? So really interesting question, and if I can just rephrase it, you're asking how does it differ, the patients we're going to be looking at here versus our target trial, and let me start with that. So, in target HTN, we kept the EGFR, which is related to creatinine, let's say, at above 60. Sixty, basically, you have no problems. You don't have a problem with fluids. You don't have a problem with potassium. If you could just stabilize people at 60, they would do great forever. In our next two trials, we're going down to 45. And the same thing's true there. If you stabilize somebody's GFR between 45 and 60, they'll stay there and they won't progress on to end stage renal disease. The issue is when you get below that, say 45 down to say 25, there's no real good drugs on the market that will prevent you from progressing on to dialysis unless they're really highly effective. And as John mentioned, these patients are sorely in need of that. A lot of these patients have diabetes and hypertension, so a double hit that's going to push them into dialysis. And so we'll be looking for mainly do they reach goal, because any amount of hypertension is a problem. So while we look for 10 or 15, millimeter mercury falls, if somebody in this group has a blood pressure of 125, then getting them down to 120 is going to be a big benefit. And so it's more a matter of where they start and trying to get everybody to goal. So I hope that kind of answers your question, not just about the opportunity, but the rationale and the level of response we're looking for.
spk09: Yeah, that's exactly what I was hoping to learn. So thanks for taking the question. Super helpful.
spk11: Thanks, Greg.
spk08: Our next question is from Rich Law with Credit Suisse. Please proceed with your question.
spk03: Hey, guys. Congrats on the progress, and thanks for taking my question. A couple questions from me. So you guys mentioned about developing a toolkit along with a rental set. Can you discuss your vision on what this toolkit looks like? and how it will work in terms of providing practice guidance for providers and payers. Is this more or less a marketing document, or is it something that the FDA will also need to review? And then I have a couple of follow-up questions.
spk05: All right. Rich, good to connect. Let me turn it over to Dave to really kind of articulate how the toolkit really fits what we're trying to do, and that is bring a targeted approach to the treatment of hypertension, which we understand. Thank you.
spk07: Yeah. So it's a great question, and it's a work in progress, right? So what we're looking for is to explore different things, looking at phenotype, looking at lab tests, looking at ways to follow response to therapy that can all together be put together in a package that'll be helpful to clinicians in deciding when to use a drug like this and what, you know, and in whom. We think that this drug used in the right patients is going to be a really helpful drug as third line. But to do that, you have to really know who to treat. You can't just put it in everybody because many of them will respond to other third line drugs that are conventionally used now. So who are they going to be? Well, the first thing was we did an exploratory study and we saw this dramatic difference in obese patients versus non-obese patients. Well, that may seem simple, maybe even obvious. Very few of those patients are on a mineralocorticoid receptor antagonist. And it's because those drugs are not built for purpose. Spironolactone, for instance, was launched in 1959. It has a half-life of its active metabolites of a day and a half. So if you get hyperkalemia, it's going to be there a long time. In addition, all those drugs really raise your aldosterone. So our toolkit basically is if you have an obese patient, You don't need to measure urinary aldosterone. It will be high. And they will often escape from an ACE or an ARB because the leptin produced by adipocytes in the abdomen is independently driving the production of aldosterone. So one of the things we're looking at now is the predictive value of leptin in the serum? I don't have an answer for you, but that's part of our approach to trying to develop a toolkit. The obesity, though, looks very promising, and we'll be measuring that effect, especially in the 301 trial, where we randomize people in a balanced way for obesity. I could go on, but those are some of the key aspects of it. Looking at tests, looking at phenotype
spk05: and looking at response to therapy. Yeah, Rich, let me add just one thing. We know from the discussions, I think we've conveyed this before, but from discussions with the FDA, that really won't inform the indication. In other words, Lurander stat would still be indicated for the treatment of hypertension. But if that toolkit continues to play out, if we see that confirmation of the effect within, say, an obese population, that's the kind of data that could go into Section 14, which is the clinical section of the label, that would then inform how we could promote and communicate both the data as well as the direction and how to use that quote-unquote toolkit. So, good question. You said you had a follow-up?
spk03: Yeah. Before I go to that, I just want to have some clarity over the toolkit. Is it like some sort of flow diagram, like a flow chart where patients here, and then you test with A and B, and then if A, then you do this, B, you do something else?
spk05: No, I think the way, yeah, I think it's more in the context of having the clinical data in a pre-specified manner and targeting third or fourth line, but third line is where we want to target basically indicators of enhanced response. And so it's, You know, if it's a flowchart, I think at the end of the day, it's if the patient's failing on an ACE or an ARB and a diuretic, and they match certain criteria that our pivotal program would direct that enhanced response to, that would be indicative of where a clinician could basically insert lorundum stat within their clinical practice. And it, frankly, could be part of what payers can incorporate into their treatment algorithms. Okay, got it.
spk03: And then the other question I have is that your phase two and phase three pivotal studies are different in terms of size and the background therapies being either standardized or non-standardized. Are there other differences that we should be aware of between these two different studies? And also, how do you envision the results to differ between these two studies?
spk05: The main, you've highlighted the main differences. You know, advanced HTN is going to be up to 300 patients. Launch HTN is going to be up to 1,000. Advanced HTN, as we've articulated, is going to have a standardized background regimen that, as Dave alluded to, gives us Class I evidence in support of hypertension guideline committee review. And launch HTN will be preexisting antihypertensive treatment, similar to what we saw within the target HTN trial. Dave, do you want to make any comment on where there may be some distinction as far as response between the two?
spk07: Right. So the other thing is, remember, we have an obligation to have a certain size of safety database for people that are treated for at least 48 weeks. And so the sum of the two, plus other studies we're doing, adds up to the several thousand people that you need for that, or between 1,500 and a little more, and so we decided not to do a standard pharma approach, which is to do two replicate studies like 301, but rather to do the advanced study design, which is really state of the art and gives you extremely precise feeling about the treatment effect in people who really can't be controlled. And we thought that would be really useful for practitioners, including hypertension specialists, to really know when to pull this out and use it. And as I said, in that trial, we're stratifying by two versus three drugs because it worked in both populations. So if we get a good point estimate for the effect size in people on two drugs, that provides the evidence for third-line treatment, which I think otherwise would be a challenge for somebody just using a design like our LAUNCH trial. Now, LAUNCH gives us a very different important deliverable, which is it's stratified on BMI, comparing obese and non-obese, matched to placebo, as well as drug across all the arms. That was our pre-specified hypothesis in TARGET that looked very strong. We'd like to confirm that. because that's a game changer, game changer for people who struggle with obesity-related hypertension. And even with all the exciting developments in weight loss drugs, the amount of weight loss for many of these people is not going to resolve their cardiovascular risk and their hypertension. It may make it better, but most of these people are going to remain overweight and some, many of them are going to be obese still.
spk03: Okay, got it. Just a final comment on what you said. So basically what I can see is that maybe the phase two study could generate better results due to less variability from the standardized background. Is that true? Or how do you think?
spk07: Yeah. Let's think of them both as pivotal trials. You know, phase two, phase three isn't necessarily the way we refer to it. We refer to them as pivotal, smaller and larger pivotal trials. So the question is, yes, we'll have 100%, we think, informative subjects in the advanced trial, and the launch trial will be much more standard, where maybe 20% of people won't. But we are going to exclude white coat hypertension, and we are going to look at adherence in both trials. So the main difference is the background regimen, and we think it's very important to have a big database on the way clinicians actually treat patients. Clinicians have their own biases. They don't usually follow closely the guidelines for the treatment of hypertension. That's something that specialty centers do once people are referred to them. And so we wanted to have a really big, robust database for those clinicians to be able to relate from the way they treat patients to the data we have. That's why we think it's kind of a perfect pairing of two different but related designs.
spk11: Okay, got it. Very helpful. Thanks. Thanks, Rich.
spk08: Our next question comes from Seamus Fernandez with Guggenheim. Please proceed with your question.
spk01: Oh, thanks. So just a couple of quick ones, and congrats on the progress. So maybe you can just first, you know, help us understand in the first study to read out, the study that reads out next year, the ability to differentiate the potential BMI benefits. I know you're stratifying by the line of therapy, but hoping to understand how you're going to look at BMI in that data set to inform the larger follow-on study. And then Separately, can you just remind us your conversations with payers, particularly as it relates to some investor concerns that are raised about spironolactone and perhaps even a clarinone as a potential step-through agent? I know that they are very infrequently used, and so I remain a little perplexed by some of those questions. Thanks.
spk05: Yeah, thanks, Seamus. On the The first question, as far as the BMI within the 202 study, you're right, we'll be stratifying on background meds, but we will be doing a pre-specified analysis on BMI within the advanced HTN study. Dave, just looking at you to confirm that.
spk07: Yeah, so our statistical plan is to use a mixed effects model with repeated measures to, that's the preferred way to do your statistics for the primary, which is change in systolic pressure. at 12 weeks. And so, essentially, it's like doing an analysis of covariance. We'll be able to do just what we did, but at a much bigger set of data to get much more precise point estimates. We'll also be able to, you know, in that case, compare across the doses, et cetera. It'll be a robust analysis. Because of the 100 subjects in an arm, it's very unlikely that we'll have major imbalance in the proportion that are obese versus not. That's the only way you can get into real trouble is if let's just say 80% of the people in placebo are obese and 20% in the treatment are obese, you wouldn't be able to interpret the data. But it was about 50-50 in the target trial and it was pretty well distributed across all the arms. So I think that risk is very small and obviously it's mitigated by the data from three, the launch trial.
spk05: Thanks, Dave. And, Seamus, to your second question about payers and will there be a step through to either Spiro or Aplirinone, we've done three separate payer research projects in the United States. And where we've positioned the drug, LaRondra, is that as third line in the targeted manner has resonated with the payers. We have not received feedback that a step through an MRA would be required. In fact, I think one of the payer quotes was, why would I have patients step through a drug that's not being used right now? And that's part of the issue, is if you look at the macro market share data, the MRAs collectively have about 2.6 percent market share in the hypertension indication. Of that 2.6, the vast majority is spiral. And we know there are issues with hyperkalemia with off-target effects. And as Dave noted, and has always seen an elevation of aldosterone within that population. So there's a lot of reasons that spironolactone, which is the leading MRA, is not used. And I think that leads to why the payers, frankly, don't look at the MRAs as a step-through. The feedback that we get is the patients will need to step through an ACE or an ARB, which is the majority of their antihypertensive business. And our positioning presumes that a patient will be on an ACE or an ARB and, frankly, a diuretic. And so we think the third line is the ideal place to bring a targeted approach. It acknowledges that the hypertension space will continue to be initially prescribed generics, but at some point we have to bring the treatment of hypertension into the 21st century and begin to target what is truly driving a patient's underlying disease And we think, to a large degree, that's going to be aldosterone. And we think we'll be able to build the toolkit, such as obesity, to inform that.
spk11: Great. Thank you. Thanks, Seamus.
spk08: Our next question is from Annabel Sammy with Stiefel. Please proceed with your question.
spk04: Hi. Thanks for taking my question. So, I apologize if any of you have been asked. I just got onto the call. As you're starting to enroll these sites for the PIVIL studies, have you received any questions or feedback from KOL regarding whether these patients who are on two or three ACEs or other therapies, they don't need to identify them as a patient with hyperaldosteronism. It's enough to just know that they're unresponsive or uncontrolled or refractory on these two or three agents, like they're not doing anything in terms of like identifying through obesity or weight to hip to weight ratio yet. They're just looking at that very specific metric. So I just want to make sure I'm understanding how these patients are being rolled. Is it just by the background therapies or is there any other, you know, metric they're looking at?
spk05: Yeah, right now, Annabelle, and thanks for the question, we're really you know, frankly, largely focused on that large bolus of patients that are uncontrolled. You know, we're going to be looking at patients on two to five background meds, both in advance and in launch HTN. And if their hypertension is uncontrolled as measured by both AOBP in the clinic as well as 24-hour ambulatory, they will, in the case of launch, the larger study, be randomized into the study. In the case of advanced, if they're uncontrolled, we'll then put them into the standardized background regimen that Dave alluded to for a three-week placebo run-in, confirm that they remain uncontrolled from a hypertension standpoint, and if they are, then randomized. So there will be no use of either aldosterone or BMI or hip-to-waist ratio or other criteria. as a means of identifying are they specifically aldo-driven hypertension.
spk04: Okay, got it. And if I could just follow up on one other question. You know, as you're talking to these KOLs, have you heard any concerns on how to manage hyperkalemia? Or do you feel that you've sort of got a good idea of, you know, keeping them on a diuretic will, you know, address this and keep them within the range that you identify is going to be able to, you know, I guess reduce the risk of potential, you know, risk of hyperkalemia.
spk05: I'll let Dave add some comments. I think hyperkalemia is an area of focus for prescribers, whether it's ACEs, ARBs, certainly it's been probably one of the rate limiters for MRAs. But I think what we've seen in target HTN to date, specifically with the 50 milligrams QD, is well within the acceptable range of potassium elevation. We think that's the route of titration to the 100 milligrams, as Dave articulated earlier in the call, is a means to further manage that for patients based on their own exposure. But Dave, if you've got any other comments from your discussions with KOL.
spk07: Well, John, thanks. I think you covered it really well. I do want to make a point again that I made earlier. This drug is designed with its short half-life to make hyperkalemia, even if it occurs, less of a problem. And what we've built into the target trial was we had a point of overlap with twice daily versus once daily, 25 milligrams twice a day versus 50 milligrams once a day. We saw very little hyperkalemia at 50 milligrams once a day, which leaves you probably seven or eight hours where you have enough aldosterone to make sure you get rid of potassium. And yet your blood pressure doesn't go up because you're not ingesting sodium. And with 25 milligrams BID, it was not as good. And that's a model for longer half-life drugs, whether it's spironolactone or other drugs in the ASI class that have longer half-life. It shows that that theory that we have an escape window from the ASI seems to give you a better benefit risk than the drugs that have longer half-life. And so that doesn't completely answer your question, but it gives you a you know, a reason why I think you're going to see it just behave much more safely than other drugs in this class or MRAs.
spk11: Okay, perfect. Thank you. Thanks, Annabelle.
spk08: Our next question is from Alhit Bonzel with Wells Fargo. Please proceed with your question.
spk02: Sure. Thank you very much for taking my question. So I have a couple of them. So first one is, I don't know whether you have explained it, but is there a mechanistical rationale for an aldosterone synthase inhibitor working better in combination with diuretic agent? So that's the first one. And the second one is that with your CKD trial, so CKD patients do have an underlying risk of higher hyperkalemia or potassium increase. How are you managing that in your trial scenario? I mean, is that the reason you have a lower dose to start with? If you could help us understand how you're managing the risk among the patients.
spk05: Yeah, Mohit, thank you for that. And I'll have Dave provide some of the background to it. We did, within target HTN, not only see an enhanced response in the obese population, but we saw an enhanced response within the patients taking a diuretic versus those not taking a diuretic. And I think that's a An interesting point to make as we think about the pivotal program, both advanced HTN and launch HTN, those patients will be required, one by design with a standardized background and one by background written by their prescriber, will be required to have a diuretic as part of their background medication. So I think that's you know, just another part of the risk management going into this Pivotal Program as we transition from the proof of concept into the Pivotal Program. But I'll have Dave just add some final thoughts to that as well as some thoughts about CKD and the underlying risk and how our approach to that fits this kind of halo of safety that we've had on the development of La Runder stat from the very beginning. Dave.
spk07: Okay, thanks. I'm going to just spend a minute on your first question and then focus on the second one. So hyperaldosteronism or obesity-related increase in aldo is a volume-related hypertension. So the people who respond to drugs like calcium channel blockers have a vasoconstrictive remodeling phenotype primarily. The people who are volume-related, like obese patients, benefit from diuretics of any kind. What's a little unique about the thiazide is that the receptor for non-genomic signaling for aldosterone resides on the cells that have this thiazide-related transporter. And so you get sort of a double hit on a mechanism that is otherwise driven by the increase in aldo from the MRAs. So it's sort of a theoretical reason why thiazides would be better than, say, Lasix. If I can pivot, though, over to your question, which is the risk of hyperkalemia in chronic kidney disease, the rationale for why we're doing our trial the way we're doing it. So, first of all, we think that people with more advanced disease, like stage 3B or 4, should be cared for by specialist nephrologists who are comfortable in dealing with an increase in potassium. You're right. They have bigger risk. We have really good potassium binders that they can use, and they're very well trained to do it. The reason why we're advancing from 25 up to 50 milligrams is exactly as you said. Let's see what the benefit-risk is in this population that might be more likely to get hyperkalemia and see if there's a window, say, at 25 milligrams, or see if we need to give guidelines nephrologists on how to decide who should be on a potassium binder. So it's an important profiling study of a special population. It doesn't really extend to people with estimated GFRs over 45. They won't have this kind of risk. And so it's really just to give those specialists a little bit more information that they'll need to treat these patients.
spk11: Got it. Super helpful. Thank you very much for that. Thanks, Mohit.
spk08: We have reached the end of the question and answer session. I'd now like to turn the call back over to John Cogleton for closing comments.
spk05: 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 2023 and are enthusiastic about the upcoming milestones for the rest of the year. We look forward to updating you as our pivotal program for La Runderstad continues to advance. With that, we'll close the call.
spk08: This concludes today's conference. You may disconnect your lines at this time, and we thank you for your participation.
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