Biodesix Q1 2023 Earnings Call Transcript

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Provided by Quartr
May 15, 2023

There are 11 speakers on the call.

Operator

Greetings, and welcome to Minerless First Quarter 2023 Earnings Conference Call. At this time, all participants are in a listen only mode. A question and answer session will follow the formal presentation. As a reminder, this conference is being recorded. It is now my pleasure to turn the conference over to your host, Dan Ferry.

Operator

Thank you. You may begin.

Speaker 1

Thank you, operator. Good afternoon, everyone, and welcome to our Q1 2023 conference call. Today, after the market closed, we issued a press release providing our Q1 2023 financial results and business updates. A replay of today's call will be available on the Investors section of our website approximately 1 hour after its completion. After our prepared remarks, we will open up the call for Q and A.

Speaker 1

Before we begin, I would like to remind everyone that this conference call and webcast will contain Forward looking statements about the company. Actual results could differ materially from those stated or implied by these forward looking statements due to risks and uncertainties associated with the company's business. These forward looking statements are qualified by the cautionary statements contained in today's press release and our SEC filings, including our Annual Report on Form 10 ks 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.

Speaker 1

I would now like to turn the call over to John Congleton, Chief Executive Officer of Mineralis Therapeutics. John?

Speaker 2

Thank you, Dan. Good afternoon, everyone, and welcome to our Q1 2023 financial results and corporate update conference call. I'm joined today by Adam Levy, our Chief Financial Officer and Chief Business Officer and Doctor. 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 Q1 financial results advancing our clinical development program for lorondrastat, our proprietary, orally administered, highly selective aldosterone synthase inhibitor.

Speaker 2

We're initially developing lorondrastat for the treatment of patients with uncontrolled hypertension or resistant hypertension with a goal of expanding to other cardiorenal diseases. Building off the positive data from our target HTN Phase 2 study that were presented at the end of last year, we recently announced the dosing of the first patient in 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 lorondrastat 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 lorondrastat. 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 in the first half of twenty twenty four.

Speaker 2

In addition, under the pivotal program, we also plan to initiate a second pivotal trial named LAUNCH HTN in the second half of twenty twenty three, which is expected to readout top line data in mid-twenty 25. 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 lorondristat to individuals with Stage 3b CKD during the middle of 2023 with expected data readout in the first half of twenty twenty four. The pivotal 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 pivotal 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 goal.

Speaker 2

It is worth noting that these patients have a substantial risk at 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.

Speaker 2

The shift in the underlying biology of hypertension requires new innovations like lorunderstat 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 Doctor. David Rodman, Chief Medical Officer of Mineralis Therapeutics, who will offer for a review of our clinical data and ongoing clinical program for lorondristat. Dave, floor is yours.

Speaker 3

Thanks, John, and good afternoon, everyone. Today, I'll provide an overview of the pivotal clinical program for lirondrastat That, as John touched on earlier, has now commenced enrollment. We're pleased to announce sites have started Dosing patients in the ADVANCE HTN trial and site initiation and trial enrollment are currently on track. This is the first of 2 core trials in our registration program for lorongestat. The ADVANCE HTN trial is a randomized, Double blind placebo controlled pivotal trial.

Speaker 3

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 2 to 5 antihypertensive medications. In order to further define the safety and efficacy of lirunderstat, prior to randomization subjects will Transition to a standardized background regimen consisting of an angiotensin receptor blocker, omesartan, Athiazide like diuretic engapamide and if they entered the trial on 3 to 5 medications, A calcium channel blocker amlodipine will be added. Subjects will be separately randomized by the number of background medications that they were on 2 medications versus 3 or more. If hypertension persists on the standardized regimen, Subjects will be randomized to 1 of 3 cohorts and treated for 12 weeks. 1 third of the subjects will be randomized to placebo, 1 third to lirondrastat 50 milligrams once daily and the final third to lirondrastat 50 milligrams once daily And then increased at week 4 to 100 milligrams daily of blood pressure goal has not yet been achieved and if they meet certain Safety criteria.

Speaker 3

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 2 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 lorongestat includes initiation of the larger launch HTN trial the second half of twenty twenty three. This randomized double blind placebo controlled 3 arm trial It's planned to have a similar design as the advanced HTN pivotal trial, except subjects will remain on their previously prescribed background regimen of 2 to 5 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 1 to 1 to 1 to the same three regimens as in the ADVANCE HTN trial and again change in average 24 hour ambulatory systolic blood pressure will be the primary outcome measure.

Speaker 3

The top line data from LAUNCH HTN are expected in mid-twenty 25. In addition, subjects from both pivotal trials will be offered In mid-twenty 23, we plan to initiate a randomized Double blind, placebo controlled Phase II trial to evaluate the safety and efficacy of lorondrastat for the treatment of untreated I mean uncontrolled 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 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.

Speaker 3

I'll now turn the call over to Adam, He'll provide a financial review for the Q1 of 2023. Adam?

Speaker 4

Thank you, Dave. Good afternoon, everyone. Today, I will discuss select portions of our Q1 2023 financial results. Additional details can be found in our Form 10 Q, which will be filed with the SEC later today. R and D expenses were $12,300,000 for the 3 months ended March 31, 2023, compared to $6,800,000 for the same period last year.

Speaker 4

The increase was primarily due to increases of $4,000,000 in licensing fees under the license agreement with Mitsubishi Tanabe Upon achieving a development milestone of lorondrastat in March 2023, dollars 900,000 in higher compensation expenses as a result of additions to headcount, dollars 700,000 in clinical supply, manufacturing and regulatory costs And $500,000 in other research and development expenses, which were partially offset by increase of $600,000 in preclinical and clinical costs driven by the timing of research and development activities and clinical trials of lirondrastat in each quarter. G and A expenses were $2,600,000 for the 3 months ended March 31, primarily due to $800,000 in higher compensation expense as a result of additions to headcount, $500,000 in higher professional fees associated with operating as a public company, 0 point $4,000,000 in higher other administrative expenses and $200,000 associated with new director and officer insurance policies. Net loss was $12,600,000 for the quarter ended March 31, 2023 compared to $7,600,000 for the same period last year. The increase was primarily attributable to the factors described earlier. Cash, cash equivalents and investments were $301,800,000 as of March 31, 2023.

Speaker 4

This includes the net Proceeds from our IPO completed in February 2023. We believe our cash, cash equivalents and investments We'll fund the planned clinical activities and our operations through mid-twenty 25. With that, I'll ask the operator to open the call for questions. Operator?

Operator

Thank you. From the queue. One moment please while we poll for questions. Our first question comes from Umer Raffat with Evercore. Please proceed with your question.

Speaker 5

Hi, guys. This is Mike DeFiori in for Umer. Congrats on all the progress and thanks so much for taking my questions. 2 for me. Number 1, what's the likelihood or probability that patients would actually need to titrate up to the 100 milligram dose at 4 weeks in the pivotal trials?

Speaker 5

I see that based on the Phase 2 target hypertension trial, aside from reducing nighttime systolic blood pressure, it seems as if 100 milligrams offers limited benefit, if anything beyond 50 milligram. My second question is just regarding the design again of the current Phase 2 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

Speaker 6

Thank you.

Speaker 2

Hey, Mike. This is John. Just a couple of thoughts and then I'll turn it over to Dave. I think the thing that we learned from target h10 as you alluded to is that the 15 to 100 milligram once daily provided Really robust and well tolerated clinical profile. We think from the exposure response analysis that we did, the 100 milligrams Select patients is going to provide value, but as you recall, target HTN was not a titrated study.

Speaker 2

We feel that Those patients that maybe had more incidence of that mild hyperkalemia that we saw with the 100 milligrams probably It's advised 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. So I'll turn it over to Dave. And I'd also like to have him as he speaks about the risk But you pointed out of switching also talk about some of the other risks that we

Speaker 3

think we've mitigated and managed within this study. Dave? Sure. So, thanks for the question. So, I guess, should I just answer the Go ahead if you've got a

Speaker 2

thought on probability, Dave. I mean, it's hard to guess at this point, but Yes.

Speaker 3

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.

Speaker 3

The important point about that is 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, all things considered, it might be 10% to 20%. So any other questions about that one before I move on to your second?

Speaker 5

No, that's fine. Thank you.

Speaker 3

Okay. So, really good questions about the state 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 spoiler alert on that, we think the benefits are really manifest and the risks are quite well managed So you're going to that. Now the point here is that we wanted to design that trial to be Tier 1 evidence For activity of our drug as an aldosterone synthase inhibitor.

Speaker 3

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 drug itself can really 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 It's 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 you have to have hypertension by ABPM, We get rid of white coat hypotension by using a 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, which will get rid of much of the placebo effect.

Speaker 3

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 a 1,000 to get 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.

Speaker 3

And we learned a lot in our trial and what we're doing It's 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 potassium, which Artificially raises your serum potassium. So we're going to be retraining the phlebotomists.

Speaker 3

The third thing We're going to cap the inclusion serum potassium at 4.8 millimole per liter. That's been done with drugs like finerenone. And it gives you a better safety margin than capping it at 5.1%, the top of the normal range. And finally,

Speaker 2

we're going to

Speaker 3

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 3 pronged approach, getting rid of white coat hypertension, monitoring adherence and making sure that potassiums are completely accurate, We think it's 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 Fair subjects.

Speaker 6

Very helpful. Thank you.

Speaker 3

Thanks, Mike.

Operator

Our next question is from Greg Harrison with Bank of America. Please proceed with your question.

Speaker 7

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.

Speaker 2

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.

Speaker 2

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 lorondestat 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 1. As you and I spoke about it at the BofA Conference last week, Greg, We believe the target HTN not only highlighted the efficacy of lorondrastat in hypertension, but further solidified the selectivity of lorondrastat To effectively inhibit and lower aldosterone levels to the clinical benefit of hypertension patients. We're going to continue to take that targeted approach, particularly as what we found in target H10 with the obese population and continue to look at that As we look at other cardio renal 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 contemporary and studies To try to manage and mitigate risk moving from the Phase 2 into the pivotal program, we continue to look for Double digit reduction in systolic BP, that continues to be our goal.

Speaker 2

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 a Runderstand.

Speaker 3

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.

Speaker 3

60, basically, you have no problems, you don't have problem with fluids, you don't have 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 is true there. If you stabilize somebody's GFR between 4560, 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.

Speaker 3

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 millimeter 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.

Speaker 3

And so it's more a matter of where they start and trying to get everybody It's a 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.

Speaker 7

Yes, that's exactly what I was hoping to learn. So thanks for taking the questions. Super helpful.

Speaker 2

Thanks, Greg.

Operator

Our next question is from Rich Law with Credit Suisse. Please proceed with your question.

Speaker 6

Hey, guys. Congrats on the progress and thanks for taking my question. A couple of questions from me. So you guys mentioned about developing a toolkit along with Orendelstat, 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?

Speaker 6

And then I have a couple of follow-up questions.

Speaker 2

All right. Rich, good to connect. Let me turn it over to Dave to really kind of articulate how the toolkit It fits what we're trying to do and that is bring a targeted approach to the treatment of hypertension with veranda statin. Thank you. Yes.

Speaker 3

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 altogether be put together In a package that will be helpful to clinicians in deciding when to use a drug like this and what 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.

Speaker 3

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. Add a 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.

Speaker 3

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.

Speaker 3

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 try and to develop a toolkit. The obesity though looks very promising and we'll be measuring that effect, Especially in the 301 trial where we randomized 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 and looking at response to therapy.

Speaker 2

And Rich, let me add just one thing. From a 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, lorondristat 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 Sanofi's 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 on how to use that toolkit. So good question.

Speaker 2

You said you had a follow-up? Yes. Before I

Speaker 6

go to that, I just want to have some clarity over the toolkit. Is it like some sort of flow diagram, like a flowchart where Patients here and then you test with A and B and then if A then B do this, B do something else? No, I think the way

Speaker 2

Yes. I think it's more in the context of having the clinical data in a pre specified manner And targeting 3rd or 4th line, but 3rd line is where we want to target, Basically, indicators of enhanced response. And so it's if it's a flowchart, I think at the end of the day, it's if a patient's failing on an ACE 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 lirondristat within their clinical practice. And it Frankly, it could be part of what payers can incorporate into their treatment algorithms.

Speaker 6

Okay, got it. And then the other question I have is that your Phase II and Phase III pivotal studies are different in terms of size and the 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 results to differ between these two studies?

Speaker 2

The main you've highlighted the main 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 1 evidence in support of Hypertension Guideline Committee review and launch HTN will be pre existing 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 2?

Speaker 3

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 2 plus other studies we're doing, Adds up to the several 1,000 people that you need for that and or between 1500 and a little more. And so we decided not to do a standard pharma approach, which is to do 2 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.

Speaker 3

And as I said, in that trial, we're stratifying by 2 versus 3 drugs because it worked in both populations. So if we get a good, point estimate for the effect size in people on 2 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 Match 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 you are going to be obese still.

Speaker 6

Okay, got it. Just a final comment on what you said. Basically what I can see is that maybe the Phase 2 study could generate better results due to less variability from the standardized background. Is that true? Or how do you think

Speaker 3

Yes. Let's Think of them both as pivotal trials. Phase II, Phase III 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 ADVANCE 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.

Speaker 3

So the main difference is on 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 These 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 The way they treat patients to the data we have.

Speaker 3

That's why we think it's kind of a perfect pairing of 2 different but related designs.

Operator

Our next question comes from Seamus Fernandez with Guggenheim. Please proceed with your question.

Speaker 8

Thanks. So just a couple of quick ones, and congrats on the progress. So maybe you can just First, help us understand, in your 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 aplaridone As potential step through agents, I know that they are very infrequently used and so I remain a

Operator

little perplexed by some of those questions. Thanks.

Speaker 2

Yes. Thanks, Seamus. On The first question is 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 ADVANCE HTN study. Dave, just looking you to confirm that.

Speaker 3

Yes. So our statistical plan is to use a mixed effects model with repeated measures So 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 So 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, in that case, compare across the doses, etcetera. 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.

Speaker 3

That's the only way you can get into real trouble Is it, 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 fifty-fifty in the target trial and it was pretty well distributed across all the arms. I think that risk is very small and obviously it's mitigated by the data from the LAUNCH trial.

Speaker 2

Thanks, Dave. And Seamus, to your second question about payers and will there be a step through to either Spiro or aplarone. We've done 3 separate payer research projects in the United States and where we position the drug Lirondrastat, 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% market share in the hypertension indication.

Speaker 2

Of that 2.6, the vast majority is spiro and we know there are issues with hyperkalemia with off target effects. And as Dave noted, and as always seeing 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 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 3rd line is the ideal place to bring a targeted approach and 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 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.

Speaker 3

Great. Thank you.

Speaker 2

Thanks, Seamus.

Operator

Our next question is from Annabel Samimy with Stifel. Please proceed with your question.

Speaker 9

Hi. Thanks for taking my question. So I apologize if any of you have been asked, I just got on to the call. But as you're starting to enroll these sites for the pivotal studies, have you received any questions or feedbacks from KOL regarding Whether these patients who are on 2 or 3 ACEs or R, which are 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 2 or 3 agents, Like they're not doing anything in terms of like identifying through obesity or weight to hip to weight ratio yet.

Speaker 9

They're just looking at that very specific measure. 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 Metric you're looking at?

Speaker 2

Yes. Right now, Annabel, and thanks for the question. We're really, frankly, largely focused on That large bolus of patients that are uncontrolled. We're going to be looking at patients on 2 to 5 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 24 hour ambulatory, they will in the case of launch, the larger study, be randomized into the study. In the case Advance, if they're uncontrolled, we'll then put them into the standardized background regimen That Dave alluded to, for a 3 week placebo run-in confirmed that they remain uncontrolled from a hypertension standpoint and if They are then randomized.

Speaker 2

So there will be no use of either aldosterone or BMI or hip Waste ratio or other criteria as a means of identifying are they specifically alto driven hypertension.

Speaker 9

Okay, got it. And if I could just follow-up on one other question. As you're talking to these KOLs, have you heard any concerns on how to manage hyperklemia? Or do you feel that you've sort of got a good idea of keeping them on a diuretic will Address this and keep them within the range that you identify is going to be able to, I guess, reduce the risk of potential Risk of hyperkalemia?

Speaker 2

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?

Speaker 3

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 be less to make hyperkalemia even if it occurs less of a problem. And what we've built into the target trial Was our we had a point of overlap with twice daily versus once daily, 25 milligrams twice a day versus 50 milligrams once a day.

Speaker 3

We saw very little hyperkalemia at 50 milligrams once a day, which leaves you Probably 7 or 8 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 reason why I think you're going to see it just behave much more safely than Other drugs in this class are MRAs.

Speaker 9

Okay, perfect. Thank you.

Speaker 2

Thanks, Annabel.

Operator

Our next question is from Mohit Bansal with Wells Fargo. Please proceed with your question.

Speaker 10

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 mechanistic rationale for And Aldosterone Synthesia inhibitor working better in combination with diuretic agent. So that's the first one.

Speaker 10

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? I mean, is there is that the reason you have a lower dose to start with? If you could help us understand how you're managing the risk from other patients?

Speaker 2

Yes. Mohit, thank you for that. And I'll have Dave provide some of the background to it. We did within target HTN Not only seeing enhanced response in the obese population, but we saw an enhanced response within the patients taking a diuretic versus those not taking the diuretic. And I think that's an interesting point to make as we think about the pivotal program, Both advanced HTN and launch HTN, those patients will be required 1 by design with a standardized background and 1 by Background written by their prescriber will be required to have a diuretic as part of their background medication.

Speaker 2

So I think that's 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 loranderstat from the very beginning.

Speaker 3

Okay. Thanks. I'm going to just spend a minute on your first question and then focus on the second one. So, if you 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.

Speaker 3

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 thiazide would be better than say Lasix. Now, 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.

Speaker 3

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 to nephrologists On how to decide who should be on a potassium binder.

Speaker 3

So it's an important profiling study of a special population. It doesn't really extend to people with GFR it's estimated GFR is 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.

Speaker 10

Got it. Super helpful. Thank you very much for this.

Speaker 2

Thanks, Mohit.

Operator

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.

Speaker 2

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 are enthusiastic about the upcoming milestones for the rest of the year. We look forward to updating you as our pivotal program for lorondristat continues to advance. With that, We'll close the call.

Operator

This concludes today's conference. You may disconnect your lines at this time. And we thank you for

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Earnings Conference Call
Biodesix Q1 2023
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