Kardigan, Inc. (KARD) Earnings Call Transcript & Summary

Good morning. We're going to get started right and early. I appreciate everybody coming today. I'm going to talk a little bit about Aortic Stenosis. Thanks for meeting us here in Chicago. For those of you who don't know me, my name is Tassos Gianakakos, I'm CEO of Kardigan, and I'm really glad to be here with you today and with leading cardiologists to talk about Kardigan's mission in Aortic Stenosis. Before we begin, let me give you guys the most exciting news of the day here, I'd like to remind you that certain statements made during the call may include forward-looking statements, including those relating but not limited to the therapeutic potential and safety of Ataciguat and our expectations regarding the design end points timing and outcome of our current and future clinical trials, including KATALYST-AV. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors including those set forth in our most recent quarterly report on Form 10-Q filed with the SEC a caution not to place any undue reliance on these forward-looking statements, and Kardigan disclaims any obligation to update such statements unless required by law. All right. So we'll start with the news on KATALYST-AV, our Phase II study of Ataciguat in Aortic Stenosis, it's fully enrolled. So this is big news for us. It's a foundational milestone for the program at Kardigan, but it's also a really important one for people living with Aortic Stenosis. Today, we're going to share what we've learned along the way from one of the largest real-world data sets that has been ever analyzed in Aortic Stenosis and from our KATALYST-AV baseline data as well. Those insights have told us much more clearly, which patients progress fast and they directly shape how we are going to plan our development program or registrational Phase III trials. Today, you're going to hear from members of our team who are in the audience, some that you see here up on the screen as well and from thought leaders in Aortic Stenosis. First up after me will be Dr. Sreek Vemulapalli of Duke University School of Medicine. And then you'll hear from Professor Philippe Pibarot, of the Quebec Heart & Lung Institute on how we measure the valve and the heart, and he'll share his thoughts as well on the KATALYST-AV baseline data. And finally, you're going to hear from our Cheryl Abbas. She's our Global Program Head for Ataciguat. She'll share specific impact of all of this on our KATALYST-AV program, and we'll have some time at the end to open it up for questions. So hopefully, you guys will have a few for us, and we'll be ready to take them. All right. So four things to start first that have really shaped how we are developing Ataciguat. First, there is no approved medicine for Aortic Stenosis. Patients wait until the valve is bad enough to replace, a therapy that slows progression would really change that and revolutionize this space. Second, patients don't all progress at the same pace, a subset moves much faster, and they're the ones who end up needing valve replacement and end up in the hospital with heart failure. Third, this is one disease with two linked pathways, the valve and the heart muscle. Damage to the heart can begin well before the valve is severe. And fourth, Ataciguat has the potential to act on both of these pathways on the valve and directly on the heart muscle. So here's why this matters. With enrollment now complete, our baseline data and the real-world analysis they are done and they point to potential markers of rapid progression. This is what we set out to learn. This is intentional. And so what you really hope for in the clinical program, particularly one that affects so many people. And now that we have that we set out to learn about this on day 1 of the program, and it's really going to be very helpful. Based on the analysis that we're going to share, we're now able to sharpen how we select patients for Phase III, what the right endpoints are to measure and how long we need to treat to see a meaningful benefit. So Cheryl is going to get into many more of the details and what it means for KATALYST-AV in just a little bit. So let's look a little bit at what we knew coming into today's analysis. So we're looking here at a meta analysis of published data, and they point to an important finding a meaningful subset of patients with Aortic Stenosis progress rapidly. And these patients have worse outcomes. On average, valve area declines by about 0.08 square centimeters a year. So fast progressors can lose more than twice that. So if you look at the chart, if you're starting from a moderate disease state, a fast progressor can reach a severe Aortic Stenosis in under 3 years, while a typical patient is still moderate at 5. So in moderate AS, about 30% of patients are fast progressors. It is not a small segment. And they have more than 3x the rate of valve replacement and a higher risk of death. So these findings by the way, have been independently corroborated right around the same time here a couple of weeks ago from the [ Progressa ] study as well, and we can get into that a little bit later. So the question for us looking at this data was simple. How do these patients progress? What drives their worst outcome? They're worsening outcomes. What defines a fast progressor. And importantly, can we identify them in advance. And that's what we set out to understand and inform our Ataciguat program, and I'm really happy that we've been able to do that. So to answer those specific questions and start getting us into the nitty gritty, we went to one of the largest real-world data sets to assess Aortic Stenosis. There's more than 45,000 patients in that data set. Here to walk us through it is Dr. Sreekanth Vemulapalli, Associate Professor of Medicine and Medical Director of the Echo Lab at Duke. Sreek, I'm going to hand it over to you.

So I want to walk you through what we did here. And again, to reinforce something that Tassos has said, we really have two different pathways and mechanisms going on here. We have the valve, of course. And even within the valve, there are a couple of different things happening here. We often think about the fibrocalcific process that's going on. I'll say that again, fibrocalcific process, not just classification. We also have aortic valve area. And these two things are somewhat related, but not exactly the same thing. Patients often go through a progression of going from sclerosis to mild AS to moderate AS to severe S. But in the real world, they often sort of jump between mild to severe because they don't get checked in between. Now independently of that, but again, somewhat related is cardiac function or dysfunction, so there are other changes going on besides the valve that include the ventricle. So we have LV mass index. So the mass of the ventricle gets larger. We get diastolic dysfunction. This means when the ventricle is relaxing, it's not relaxing appropriately. Then we get enlargement of various portions of the heart, including the left atrium. And finally, we get a reduction in the actual output of the myocardium. So it's important to keep these two pathways in mind. They are distinct, but related, and these things result in heart failure events, aortic valve replacement and death. So what we did was we looked at multiple health systems, and we tried to define a population of patients with mild and moderate Aortic Stenosis. So we started with about 160,000 patients with Aortic Stenosis as identified by natural language processing and ICD-10 codes got down to an analysis population of about 45,000 patients with mild and moderate disease and discordant disease. And then of those 20,000 patients actually had enough information with multiple echocardiograms within a 2-year period to look at annual progression. And we defined fast progression based on accepted values within the literature, so aortic valve area change of 0.1 centimeter square per year or more or a jet velocity gain of 0.3 meters per second per year or more. So what did we find here? The key takeaway from this point is almost one in four patients with mild to moderate AS are fast progressors. You can see there, 27%. And in fact, it's not just that we saw one and four fast progressors. But in fact, the progression that they had is faster than what we saw in the previously published literature, you can see what we found was a change of about 0.12 centimeter square per year as opposed to what's in the literature of 0.08 and in fact, our normal progressors averaged around 0.08 in this analysis. So what does that actually mean? Okay, we defined about one in four fast progressors. Well, it's as you would expect, these fast progressors have worse outcomes. So valve replacement or repair 3.1x risk for that for fast progression. Acute all-cause hospitalization, 1.5x risk. Worsening heart failure. So this is heart failure hospitalization plus heart failure events, outpatient events that required an intervention in terms of medication, that's 1.3x, all cause death 1.2x. And these are substantial event rates. Take a look at the all-cost hospitalization. That's 35 out of 100 patient years, so substantial rates. Okay. In parallel to looking at fast progression of the valve as defined by AVA or peak velocity, we were looking at myocardium. This is really important. There's a growing literature to suggest that amongst patients, at least with severe AS, that myocardial damage is directly associated with outcomes. Now it's less well known, whether that's true in mild or moderate AS. And so we're going to show you that data. And just to remind you, again, we're looking at LV mass index, we're looking at left atrial volume index, we're looking at stroke volume index as well and then measures of diastolic functions such as e-prime or EoE-Prime. So what do we find four in five patients, just about 80% of patients in this cohort of mild or moderate AS actually have cardiac dysfunction as we define it. And that's very much in line with what's in the literature, which is between 75% and 80%. So then the next key point is that fast progression is more prevalent in patients with cardiac damage. Take a look at the graph on the right. 28% have cardiac damage versus 19% without cardiac damage. So more prevalent there. What does that mean? Well, patients with cardiac damage have worse outcomes. And here, look at the red dots here in the forest plot valve replacement or repair more likely with cardiac damage, all-cause hospitalization, worsening heart failure, all-cause death and heart for hospitalization, all worse with cardiac damage. So some of you may be thinking at this point. You've spent some time talking about AVA. You've spent some time talking about the myocardium, but we've all been told that Aortic Valve Calcification is the thing. Why aren't you talking about that? While I think this data is really important. Two points here. Number one, between fast progressors and normal progressors, the aortic valve calcification values in this cohort were not substantially different. Okay? And we already just showed you that fast progression is a marker of bad outcomes. But here, aortic valve calcification, not different. Also look at the actual values. Here's a distribution in this plot. But the red values are the fast progressors and the gray values are the normal progressors. Notice the aortic valve classifications are at least numerically lower in the fast progressors than in the normal progressors. So this is actually the opposite of what you'd want to see if you thought that aortic valve calcification was the most important thing in terms of figuring out outcomes, all right? So it may not be about the aortic valve calcification. So in summary, one in four patients with mild or are fast progressors, 27% actually. AVA in this analysis was the strongest predictor of outcomes, not aortic valve calcification. The rates of events amongst those with fast progression, you saw them. They're all substantially higher in fast progression and cardiac damage than in normal progressors. And there's a 3x rate in terms of the rate of valve replacement. And really, the key takeaway here from this analysis is it's not just the valve, the valve and the myocardia matter. And I really want to highlight this because really, the world changed on Monday morning as far as this world. On Monday morning, the progress trial at TCT was presented. And what the progress trial was a trial of patients with moderate AS with risk factors. And most of those risk factors were myocardial damage. And what we saw was in that patient population those who have these risk factors may benefit from therapy on their valve, right? So it really brings into play a new concept in Aortic Stenosis, which is that it's the valve and the myocardium that determine outcomes. So I'm going to pass this along now to Dr. Philippe Pibarot, Philippe is a friend and an expert both in echocardiography as well as Aortic Stenosis from University of Laval. And he's going to be talking a little bit about the baseline factors from Catalyst AV as well as some of the echo parameters that you've seen us mention.

So let's move to the next topic and how to interpret the echocardiographic measures of [ tabel ] and cardiac function in Aortic Stenosis. So this slide illustrates potential scenarios of physical effect related to a drug and how the different echocardiographic measures of the ventricular and valve function would behave. So the first scenario that we could consider is a drug that would have an effect only on the valve, will reduce the pull on traction. Of course, the LV [ telesystem ] function, may not change, the flow remain unchanged. And so what you will see with the [ big counting jet velocity ] and main gradient that are often used as endpoint in the pharmacotherapy trial in AS is that this parameter will decrease, so that would improve and to show you the benefit of the drug on the back. If you look at the [ Vavaria ], the [ Alivaria ] and C Index, they will also improve, that would increase with this positive effect of the [indiscernible]. And the [ AliCloud ] customer core that is measured by city will decrease. So all parameters, all imaging parameters are showing you the benefit of the drug on the [indiscernible]. Now let's consider another scenario where you have a drug that only target the vantage so that leads to an improvement in myotonic function. So of course, here, the [ vitobstruction ] remained unchanged. The [ RV ] systolic and diastolic function improved the flowing increase. And so here, the big velocity and migrated will actually because they are highly flow-dependent and because they increase with flow. There were worsen, and so they will mimic, if you will, the progression of the Aortic Stenosis, whereas there is no change. The [ article and opacity ] Index on the other hand, they also are flow-dependent, but to a lesser extent. And they improve, so they increase with flow. So at least, they're showing you the benefit, the positive benefit of the drug on the [indiscernible]. So this eventual benefit is reflected by parameters such as the [ altivar and labels ] index, but not by the big radiant, the [ big velocity and migrate ]. Now let's come consider a scenario where you have a drug with a dual effect, positive effect on the valve and positive effect on the ventricle concomitantly. In such case, while the time obstruction would be reduced, the [ RV ] systemic anti improve and the flow increases. And so with the [ meridian and big velocity ], what you will see is minimal or no change because the increase in flow and so the worsening of the parameters will mask the positive effect on the [indiscernible]. With the [ fabry and davos ] index here, this timer will improve -- would increase with both the effect of the valve and the effect on the [ myelo ]. So this dual effect of the drug on the valve and recon is adequately reflected by the [ vavaria and ablate ] index, but not by the [ panvelocity and midi ]. So that's why when you select an endpoint, an imaging endpoint for the pharma cuttings. It is important to select a time to caster or the top level of the index, especially if you have a drug that get both the and the manager. So let's discuss now the baseline characteristic obtained in catalyst AV trial. So as you know, Ataciguat is an investigational an activator of the soluble [indiscernible] class. And that may act on both the valve and ventilate Aortic Stenosis. So Ataciguat is actually activate the oxidized form of the solidness and therefore, increase the [ DMP ] and this may have potential effects on the optical. So this may, according to the results that have been obtained so far, in the Phase II trial conducted at the Mayo clinic. So this may lead to reduced activation of the [ deck ] and reduced osteogenic signaling as well as reducing fibrotic remodeling at the [indiscernible]. And subsequently, after some time, this may also have a secondary positive effect on the bench LV remodeling and function. Also, there are some data suggesting that we may also have potential direct effects on the [ ventricle ] and that Ataciguat may reduce [indiscernible] fibrosis and stiffening. So we have some direct immediate effect on the ventricle. So eventually Ataciguat would be in the category of drugs that have a dual effect on the valve. And so the [ Ataciguat ] would be the best parameter to follow its positive effects. So this is the baseline customer burden according to the bar area. And as you see, the [ customer burden ] the [indiscernible] that we measure by City does not predict the [ Artifarea ] that we ensure by echo in patients with moderate AS but actually across the range of [ urticaria ] in this trial. You see that the [ Altice ] as score varies widely. And patient with a similar area can have more different to customer [ burden ], both in men and women actually. So the [ Altia ] area is the co-parameters that best predict the AS progression rate and also defined disease severity, obviously, but it does not predict the baseline of techops, which is an independent marker of the risk of adverse clinical tests. So here, you have the baseline of the valve customers core. And according to the echocardiographic measures of function, and you see that while these two parameters actually have limited concordance, there is an important overlap in the range of outing focuses in a different category of geometry and function, you see that beside [ apotrophy ] versus done with no hypertrophy as a huge overlap in terms of our class CASE score, same for left at enlargement for low flow state, [indiscernible] side index and elevated set pressure. So the [ Altice ] [indiscernible] is an independent marker of the risk of clinical events and launched more changes across both optical and vans measures are actually more informative when assessed together.

So we thank Professor Philippe Pibarot, who has been an outstanding leader in the KATALYST-AV trial, and thank you, Dr. Vemulapalli for being here and presenting on the real-world analyses. So today, I'm going to kind of concise this and make sense of what it means for us as it pertains to the KATALYST-AV program. But first, I want to say, we're thrilled to share that this trial is enrolled. And thanks to that, we're able to learn. Specifically about this patient population in a way in which nobody has done so before. Based upon this baseline data and the real-world analyses, I'll walk you through why this means that the assessment of aortic valve calcium as the primary endpoint should be read at week 48 rather than that at week 24, and in particular, what it means in terms of how we would interpret a read-through for our Phase III registrational trial. With the shift in the primary endpoint, the baseline demographics really allowed us to characterize this patient population. We'll walk more through what that means, what we learned. And essentially, week 24 now becomes a planned interim analysis. We are still able to learn and evaluate the mechanistic trends of Ataciguat on aortic valve calcium, aortic valve area and on the myocardium, on the heart itself as we've discussed. So top line data at week 48 will be in the second half of 2027, and these changes were made under blinded conditions. So the study has not been unblinded. This is not based upon any efficacy terms. And really now, we have two inflection points to adapt and change our Phase III trial. First, at the week 24 end points as well as at the week 48. So what do we really learn from the baseline data? If we start from the left, it's really two things. The first is related to this patient population. Aortic Stenosis specifically moderate Aortic Stenosis comprises a very heterogeneous patient population. Aortic valve calcium spans greater than sixfold the range across a narrow valve area. What that means is two patients with the same valve area can have two very different calcium burdens. We heard from Sreek earlier that one would have predicted that a higher calcium burden would mean a more narrow valve. That is not really what we see here. So it points to the fact, as Philippe said, that aortic valve calcium is an independent predictor of risk. Its baseline value assesses a disease severity on the risk continuum, but it does not ascertain the pace of progression. That is really what aortic valve area predicts. Similarly, we see the range of aortic valve calcium is very wide across cardiac damage. Again, one would predict that more calcium on the valve would essentially mean that you would have a sticker ventricle. Here, we're learning that a sticker ventricle can actually precede the level of calcium and maybe even precede the stenosis of the valve. Again, we heard from Sreek two distinct pathways, but related. So if we put it together with what we see on the right, what this means is when we assess the rate of progression of disease, and we want to understand how Ataciguat modifies that rate. We have to interpret calcium, its mechanistic target alongside the valve, aortic valve area and alongside the ventricle. 24 weeks does not allow for that appropriate rate of progression, in particular, on aortic valve area to contextualize that information clinically. So by moving it to week 48, we're able to do that better and interpret how does this drug modify the disease at the valve, at the ventricle and overall along its continuum. So you may be asking, why is aortic valve calcium, low your primary endpoint in the Phase IIb trial? Well, it is still the mechanistic target. I want to remind you what we're looking at today is a snapshot in time. It's a baseline value of calcium. What we're really trying to understand mechanistically is how does Ataciguat modify the fibrocalcific process, which is a change in calcium. That's what we will see at week 48. And we need to understand that as it pertains to how the change in calcium now relates to the change in aortic valve area and how it relates to improvements in the ventricle, which is, as Philippe said, what we observed in the Phase IIb study in the Phase II study conducted by the Mayo Clinic. So now at week 48, the change in ABC has read alongside the change in valve area. It read alongside the changes in the ventricle, so we can better understand how Ataciguat is modifying this disease overall. The study has not changed. The design has not changed. None of the statistical assumptions have changed. The observation window has increased. The study is still powered for the same effect side in aortic valve calcium. And we expect that the placebo arm will progress from baseline to week 48 at about a rate of 20%. So a 20% increase in aortic valve calcium should be observed, which is consistent with the literature. So we are lucky that we have a drug that potentially affects both the valve and the ventricle. And we're even luck here that we -- well, this is by design. But we are quite lucky that this trial will be -- will provide us with the evidence needed to ascertain this dual mechanism. What we've learned and what progress, as Sreek has said, really showed is that the ventricle carries just as much risk as the valve. The ventricle can be severe in disease even before the valve is. We have a drug that may modify both. And so what that means is that week 48, even a modest change in the aortic valve calcium could still be red alongside a clinical preservation in aortic valve area and even improvements in the ventricle. So with these changes, we have even greater confidence in KATALYST-AV in providing the evidence needed to hopefully deliver the very first pharmacological therapy in Aortic Stenosis. We are thrilled to share that KATALYST-AV is fully enrolled. Now we have a trial that really is conducive to the mechanism of this drug that will allow us to ascertain how Ataciguat modifies the valve and the ventricle. And this data in the Phase IIb trial will directly inform our Phase III registrational study. As I mentioned, the design has not changed. KATALYST-AV is still powered for the same effect size or the change in the artic valve calcium at week 48. And of which the top line data will be in the second half of 2027. We've learned a lot about the real-world data. We also should mention that there was an additional publication and the [ IGNITE ] registry that also was presented after the progress trial that further corroborates these findings. So the world is really learning about the prevalence of cardiac damage in this patient population, which is highly significant. And that is equally important to understand how a drug like Ataciguat modifies the ventricle and the valve as it pertains to disease progression. And so we will share more about our Phase III registrational trial early or the first half of 2027. So with that, I will invite my colleagues up for Q&A.

This is Roana from Leerink Partners. A couple of questions for you guys. Really interesting presentation. It's out to me that AVA was really clear predictor progression from the real-world data. So could you help us understand how to think about the AVA result in the longer-term Phase IIb results, how should we frame that with ABC and then how it reads to the Phase III?

Yes. So AVA is a key secondary endpoint in the Phase IIb trial. It's not powered -- a powered trial for AVA would be substantially larger, but that you can think of AVA as a potential future registrational endpoint. So when you read it alongside calcium, what we're essentially looking at is how does the fibro calcification process impact valve area. But what we also heard from Sreek is it's not just about calcium. It's also about the ventricle and the disease may be modified at the valve quite differently. So a change in AVA could still be read along a modest reduction in aortic valve calcium. So we still may see that there's a clinical decline in the progression of aortic valve area with Ataciguat versus that of placebo, regardless of what the reduction in calcium is. Then we look at the ventricle. And so then we may see improvements in the ventricle that also then contribute to potential improvements in the valve area. And that's what Professor Pibarot was saying, is one that really contextualizes the venture and the valves. And so we have to kind of read it independent, but then contextualize both in the context of the ventricle and in the context of aortic golf calcium.

And maybe one for the KOL as well. Given what you saw in the real world data and thinking about Aortic Stenosis patients and a little bit of the variability in ABC, I mean, in the fast progressors versus the normal progressors. What does that tell us about the modern and Aortic Stenosis population? Like are things changing? Is there anything in the background happening? Like how should we think about that going forward?

Yes. I'm not sure that necessarily the population is changing, but certainly, our understanding of this is changing rapidly. So a couple of things. One is I really want to emphasize fibrocalcific. We know that this disease process looks different between men and women just as one example. And it really is highly fibrotic in women and more calcific in men. And this is generally considered a spectrum. We're going from fibrosis first to calcium. And once we get to calcium, it becomes a little bit more difficult to change the amount of calcium. So that's one thing. And then the second thing I would say is that our understanding of the interplay between the ventricle and the valve I mean, really has exploded just in the last year and with progress. And Cheryl made this point in that other [ IGNITE ] analysis. Some almost 80% of patients with moderate AS have one of these risk factors that show ventricular damage.

Great. And then last one for me. Just digging ahead to the Phase III of the adaptations that you could do based off of your Phase II analysis, like how much could change? I guess how should we think about the future there?

So the way I would contextualize it is the data will really help inform the strategy of the endpoint and the patient population. So we can -- there are ways clearly now that we can enrich potentially this population relative to cardiac damage, particularly if we see that this drug improves aspects of ventricular function that we know also precipitates risk. So there's a patient selection component there. There's a powering component of how long it takes the drug to modify the overall rate of progression, both at the valve and the ventricle. And then there's the endpoints piece. But we'll share more in the first half of 2027 on Phase III.

I think what is maybe noteworthy as you think about our company more broadly, is this is yet another example in an area which may be a priority is less obvious. Than, let's say, dilated cardiomyopathy of genetic nature, where we are clearly matching the drug mechanism to disease mechanism. And when you look at an area or a disease area as broad as Aortic Stenosis, right, the third largest area, right, after hypertension and coronary disease. You think about precision medicine like never, right? So now it's changing. And we have markers that allow us to enrich. So all of this is what you want. You want this as a sponsor of clinical trials, where you can start to really have thoughtful data-driven modelable right assumptions that are based in a pretty robust real-world data set to help you design duration, endpoints, power. And we have two shots at it. right? We have two shots at week 24, which we're going to look at internally, and we'll do all the analysis and then at week 48 before we have to lock into a statistical analysis plan with the regulators. And by the way, some of you who have been kind of connected to us for a while. I might remember, the FDA is totally cool with AVA as an endpoint as well as functional improvements like PVO2. So we've got some options as we assess the data to really zone in on what makes the most sense.

Ritu Baral, TD Cowen. I want to dig in on what Dr. Vemulapalli, you said about the fibrocalcific process and the decoupling with the calcium score. So that implies that there's more to the fibrosis component. Is that something that you can independently monitor for? Is there a biomarker where you realize that, that becomes the second variable in the second order process of stenosis? .

Yes, that's -- there's not a specific biomarker that's routinely checked in clinical practice that can tell us what's going on there. But remember, Ataciguat's was mechanism is smack dab in the middle of that transition between fibrosis and calcification. And so it makes sense that when you're looking at trying to prevent progression, do you want to impact that transition process between fibrosis and calcification. The marker that we have is just that end point. We can see how much calcium is there. We can't quite tell how much...

So there is nothing like either stiffness or genetic risk for fibrotic [indiscernible].

Not in the valve.

Not in the valve. What about systemically, Cheryl, are you -- are there things that you're mining in the database that will be useful to look at week 24.

Not as I would say, it pertains to fibrosis in particular because -- and then Sri can comment to this. There's really not much you can do that with correlate to the valve. There's things you can do that correlate to the ventricle which we'll look at. Yes. But it's really -- the issue with the [ VIX ] and I think maybe to go a little bit deep to where you're going into I want to be clear that Ataciguat as he said, works central to that. So the pathway is essentially activate the [ VIX ] are both fibro and calcific. So I don't want to imply that it means that the drug is only working on calcium, right? It's working along the full continuum of that process. We just only have a mechanistic marker in calcium as more of the downstream component.

So Cheryl, I guess, and [ Jay ], what are you looking for at 24 weeks? I understand it's going to be an internal look now. But what are you looking for now in the 24 week? And how could that impact potential modification of what you will show at 48 weeks and potential optimization of the Phase III? And I will book one last question. .

Yes. So at week 24, we're going to look at mechanistic trends. I would contextualize it around how does the change in calcium look relative to the change in valve area, what's the rate of that change at week 24. So we're able to predict what we would see at week 48. And then do we see early signs of ventricular improvement like we did in the Mayo Phase II? That allows us to not only predict what we would see at week 48, right? Because we know the AVA decline is linear. So that gives us intel into -- as we kind of stratify the population between rapid progressors, potential rapid progressors and normal, you can predict what the change in AVA would be at week 48. And so we would be able to understand how is the drug modifying it at that inflection point? Do we see the same effect at week 48 and then that allows you to adequately power for your Phase III?

And last question, [indiscernible], you brought this up. So the AVA and peak [ VO2 ] is a potential endpoint. Does anything that we are seeing here impact how you believe the pivotal endpoint could end up evolving and just given all the changes in the FDA over the last couple of years since your last go around this. Any comments on how we should think about their viewpoint.

Well, I mean, the FDA is, from our perspective, has been really consistent and has been very constructive. So -- and that's been my experience with the [ cardiorenal ] division like before Kardigan. So it's been great. And you could imagine across three of our programs, there's a lot of interaction with these people across these programs, and so a lot of consistency. So they've been great partners so far. As it relates to the end point, we have choices. And that's a good thing. Ultimately, when you listen to folks like Sreek and Professor Pibarot, there is a lot deeper understanding and contextualization of AVA in this patient population relative to peak [ VO2 ]. But that, for us, peak [ VO2 ] wasn't necessarily something that the HCM community knew about, right, et cetera. So we'll do what makes the most sense and it's nice to have options like that. AVA is going to feature. There's no way around it in this patient population. It has to, right? And AVA has as Cheryl mentioned, is linear against progression. It is, as you heard today from both Sreek and from Professor Pibarot, it's something that is very relevant to the mechanism, both on the valve and the myocardium. So I would expect that we'll work together with you and the investor community to really educate around AVA. You guys have a vibe for peak [ VO2 ], I think, at this point. But AVA is sound to get familiar with that.

Alice Nettleton from UBS. So firstly, I was wondering if you could clarify the catalyst path from here because previously, we're expecting three readouts in the first half. So in terms of the interim, I'm guessing we shouldn't expect any indicators from you as to how that's going. And then if you could clarify the other two readouts timing, if that's possible?

Yes, for sure. I think you shouldn't expect data at week 24, but we will update think of qualitatively some of the things that Cheryl was talking about. Remember in the background, we are in study kind of formation start-up mode for a registrational program. And so we'll want to let you know how all of that is interplaying and what are we doing, right? And so I think you'll see some, for lack of a better word, some qualitative kind of updates at week 24 and just know that we are looking at it and we're analyzing the things that Cheryl said as well. And the other programs are tracking. We'll have updates on our earnings that are coming up here as well on those, but we're super pleased with the progress so far on the [ captive ] side on the sites are up and rolling, and we're enrolling in that program as well. So stay tuned.

And then for you, Dr. How are you thinking about the addressable population and how that may change as well over time?

Yes. Well, my comments around the world changing this week, I think, are apropos here. So in addition to progress at the same time, there was a paper that Cheryl has mentioned out of the Ignite database. So this is a real-world database multiple institutions in the United States. And this was the burning question. How many patients are there really that look like they have cardiac damage and moderate Aortic Stenosis who might benefit in this program. And again, it's up to 80% of patients with moderate Aortic Stenosis who have evidence of cardiac damage. So I think clinically speaking, there are a lot of patients with mild and moderate AS out there. You saw that in our real-world analysis in terms of the percentage of our population [ 160,000 ]. We got down to about 45,000, so roughly 1/4 there. And then amongst those, taking into account this other paper, 80% of those look like they're going to have cardiac damage. So there's a very large addressable population here. And if we can slow progression of disease, that's really very, very clinically useful. The issue that patients end up facing is if and when they get to severe and they need an aortic valve replacement if there's 60 when that happens, the rest of their life and the choice of how they get that aortic valve replacement is very different than if they're 80. So there's a lot of value to being able to slow disease even if you're not curing it.

Can I add one thing, Sreek, if I may. The analysis that we conducted also was across mild, right? So I want to stress that because the night analysis was specific to the progress patient population. So it was specific to modern AS. We looked at it across mild and moderate as Sreek went through. And that's important because a little as I think, still known about the mild patient population. And we still found approximately 80% of mild AS still has evidence of cardiac damage. So a very large addressable patient population that we need to learn more about.

Justin Kim from Tara Capital. I just had a question, maybe that's kind of for both sides. In terms of -- as you think about a pivotal design and the insights that you're going to gather from Phase IIb, how do you think about the treatment paradigm shifting potentially given that maybe moderate to severe treatment might look more like moderate with the insights on AVA in terms of the risk benefit kind of shifting where some of these more moderate patients might get more benefit and may be worth the risk of more severe treatments? And how you think about enrollment sort of and what you're going to be looking at in terms of who you enroll in these future trials. I guess you talked a little bit about how there are mild patients potentially who could benefit for this type of treatment. Are there cohorts that you're thinking about in terms of like gathering those insights to potentially say these could be mild patients we incorporate into a pivotal design?

I mean on the last question, the answer is yes, definitely. But I think it's an interesting question for you, Sreek, in terms of -- what -- how do you see what we're learning here impact clinical practice, right? Because in some ways, like I'm the new guy to the story, certainly relative to you, but it does feel like this taxonomy that we have had for the last couple of decades of mild, moderate, severe is sort of on its last legs and is changing. And that will affect practice and, of course, your program.

Yes. I mean I think that's exactly right. Implicit in the terms mild, moderate and severe is mild, don't have to do anything, moderate, don't have to do anything severe, okay, we should start talking. That's just wrong now, right? We know that, that's wrong. And the paradigm is going to change substantially where as soon as you have the diagnosis, there's going to be a discussion about what can we do to slow this disease process. right, maybe prevent you from ever needing a valve replacement or at least delaying it substantially. . So that's why when I say the world is changing. I mean the timing for this kind of analysis and this kind of set of trials is perfect, because of this change in paradigm how we're going to approach these patients. We're going to be having these discussions now from day one.