TCT TAVR and TMTT Investor Q&A - EDWARDS LIFESCIENCES CORP

welcome everyone and thank you for being here before I turn it over to Bernard to make some opening remarks please take some time a moment to familiarize yourself with our cautionary statement you guys all know this it's an important slide behind me during today's event we may be making forward-looking statements and it is possible our actual results can differ from our expectations So here is the agenda for today's session. We'll spend the first 20 minutes on TMTT, discussing the results of the CLASP2-TR, and then we will move to TAVR and talk more about the long-awaited results of the PROGRESS trial. We are very privileged to have the physicians with us here today, so please try as you might to focus the questions on the trial results and what the physicians will focus on. With that, I'll turn it over to Bernard for a few opening remarks. Good evening, everyone, and thanks for being here. It is obviously a very exciting day for Edwards, and more importantly, you know, for the many patients we serve and the many patient, you know, we are going to benefit from, you know, the result of today, you know, in Tricuspid and TAVR. And I like to always, you know, start with a quick reminder that this is, you know, truly the result of our unique innovation strategy as a company. You know, we are committed to bring, you know. Breakthrough innovation across, you know, the portfolio, TAVR, Mitral, Tricaspid, And we are also laying the foundation for AR and structural health failure later, but also our commitment to world-class evidence. It's not easy to do that. It takes courage, years of investment, years OF belief, having a vision. And I want also to recognize our field organization, which is very unique at Edwards, where every day they take care of patients, one patient at a time, to make sure that physicians can have the best patient outcome. At the end of the day, when Edwards leads, everyone benefits. The patients receive the best therapy, great outcome. Physicians have access to breakthrough technologies. In many of the cases, even like today, we are enabling a change of practice and evolving medicine, but also providing economic benefit to the entire healthcare ecosystem. So I'm very proud about what we do, what the 17,000 employees across the world are doing, ensuring this kind of impact. So let me now introduce the first session. The first session will be focusing on WAD therapy, PASCAL, in our TMTT portfolio. What we are going to talk about is mainly about CLASP2TR, a little bit also, Charlie Davidson will be able to talk a little about that, but also Ted, about TRIC-HF, which is also a study that has been presented a little earlier this year, important data for tracheal speed patients. So we are joined by Charlie Davidson, he's a chief of cardiology and medical director of the Bloom Cardiovascular Institute. He's deeply involved in trial leadership across TMTT portfolio for many years, including serving as a global co-PI of a class 2 TR trial. Also on stage with me, please, Devin, Ted, and Dr. Davidson, please join me. So also on stage, with me is Devin Chopra, our leader of the TMTT business. Devin joined us about eight years ago and has deep expertise in MedTech and at the company. He has overseen the TMTT success over the last several years as we have introduced in the portfolio. Finally, someone that everybody knows, Dr. Ted Feldman, he's our Senior Vice President of Medical Affairs of TMTT. Ted has been the brain behind many of our clinical evidence initiatives. And before it was, he has been a pioneer, a global leader, a researcher, and innovator. So again, thanks from the panelists here, and I'm going to turn to Charlie for a quick overview of the data, and then we will take questions. Charlie, back to you. My pleasure. Thanks. Thanks for having me here this evening. I'm just going to take you through a few of these slides. Many of you probably were at the presentation today, so you've already seen this. This isn't recording. Oh, sorry. me go back here. You already saw the whole presentation. Can you get me back to the first slide? Thank you. There we go. Okay. So this is the presentation that Suzanne and I made earlier today. So I'm going to bring you right to the primary endpoint, which was a six-month analysis. So the study was started in 2020. So the first patient was enrolled right at the month of COVID started in March, and it was originally designed to be a two-year endpoint on this trial. Through the course of the first four years, it stayed that way as people then became other devices approved. We had TTVR approved, Evoque. We had Triclip approved, and what we found was there was attrition in the control group, and that started in 2024, October, when FDA approval came for that. And so at that point, it was moved back to a one-year endpoint. And following that, a year later, we had CMS approval for coverage for those devices, and there was further attrition and went back to our six-month endpoint. So we're presenting six- month data here. We have one- year data that we presented. You saw that today. These patients are going to be followed annually out to five years. There will be more data to come behind this. But just to understand how we got to the evolution of a six- month endpoint. The six-month endpoint was a composite endpoint of mortality, RVAD or heart transplant, tricuspid intervention, number of heart failure, hospitalizations, and KCCQ improvement. This is fairly similar to what you've seen in other tricusped trials in Tricin-2, Triluminate, Trichy-HF, which I'll speak to later, is slightly different. But what you're seeing here that the main driver of the endpoint, as again it is in almost all these trials is the marked improvement in KCCQ, which I'll give it into a little more detail here. In this trial, there was also some attrition. Remember, this is at six months, so this is before we started seeing attrition from the control group to a treatment arm. But with all of that, the main win ratio was 1.98. That means that people are twice as likely to get the benefit of this device, that if they receive that compared to optimal medical therapy, and optimal medical therapy. And this trial included things like SGLT2 inhibitors, which were not routinely used in some of the earlier tricuspid trials. So better medical therapy in this trial than what we've seen. Tricky HF, again, I'll speak to, also had very good medical therapy. So I'm going to move to the next slide. And This is basically showing the KCCQ improvement. As you can see here, 57% of those that received the device had a large to moderate improvement, whereas 25% of those that stayed in the control group got worse. Now remember the control group included people that moved over and we had 20 patients that moved from the control group to an attrition to a treatment arm. So they stay in the control group in the analysis because we do it by a modified intention to treat analysis. They're still counted in the control group even though they've been treated. And with that there's still 25% that got worse and with this we had 57% that got better. So the conclusions from this trial, and then I'm happy to answer a lot of questions, is it met its six-month primary endpoint, demonstrated superior of the system with medical therapy compared to medical therapy alone, and patients that had severe or greater tricuspid regurgitation, and that was primarily driven by KCCQ and somewhat by TVI. There was no difference in mortality or heart failure hospitalization between the two groups. And I'm more than happy to speak to mortality. It was non-significantly different. And why you saw a very low mortality rate in this trial, which in the control group, which was 4%, is an interesting that we've not seen in any of the tricuspid trials to date. Some of that I think is due to medical therapy, but there's also that attrition in the TVI group in this population that accounts for that. The treatment in the Pascal system resulted in significant TR reduction in 80% of patients, achieving less than or equal to moderate TR at one year compared to 30% in the control group, which was significant. And there was substantial improvement in patient-reported health care outcomes, fully evident by 30 days, and really was persisted out to one year. And this trial demonstrates the safety and efficacy of the Pascal System to improve health status in symptomatic patients with TR. And I can tell you, as someone that's been treating patients with TR for now eight or nine years with different devices, I can say the number one thing people want is to feel better. We want to have them live longer, don't get me wrong. A six-month trial is no way powered to determine a mortality difference. And I think the enrichment that we saw from Tricky HF, which I want to get into here, is a trial that would really look at hard endpoints, and that's one of the things we've been lacking in the tricuspid trials is to show that we can impact heart failure, hospitalization, and potentially mortality. And what York Hausleiter did, a good friend and colleague, which was really a brilliant design, which is he took and enhanced the patients that were enrolled in the trial. Remember, we've taken all comers that are symptomatic with CRTR. He took particularly patients that had cardiorenal, so they had impaired kidney disease, CKD, and had TR, or they had hepatorenal. So they had evidence of hepatic dysfunction and had severe TR, or they had a previous heart failure hospitalization. And what he also did was to allow these people that once they presented for their next heart failure hospitalisation to then get treated. So it was really a terrific design to really enhance outcomes and enhance, excuse me, events to show heart outcome differences. And what we did in show this was that he was able to show a difference in death and heart failure hospitalisations, as you can see in panel A. Panel C shows freedom from hospitalization for heart failure. And I think this was a very important trial. Now, I think they followed out the three years, which is another piece of this. They don't have complete three-year follow-up at this point, but at least there is a suggestion there that there is a potential mortality benefit. And when you think about going back to some of the other trials, those of you who are familiar with the COAP trial, that was a trial that was done in people with functional mitral regurgitation and it randomized medical therapy to edge-to-edge repair for mitral valve disease. That trial did not get positive for a hard endpoint of mortality until three years. And if that trial had stopped at one year or two years, we'd still be sitting here not treating patients with FMR with devices. And so I think we need more of this if we really want hard endpoints, but quite frankly, I really believe most of the patients want to get better, and they'll take the hard end point if they get it. And with that, I'm going to stop, and hopefully I'll have some more provocative questions. Thank you. All right, we will open up for questions. We'll be able to take a few questions. Hey, thank you. Mike Pollark, Wolf Research. On the topic of clinical evidence in the tricuspid space, Trichy HF seems to have breathed some energy in on the hard endpoint differentiation. What are you looking forward to what's happening now in trial land that could further the more you know, persuasive endpoint claims for T-tier? I mean, I spoke there a little bit. I mean would we like more trials showing hard endpoints? Yes, but I honestly feel like at this point we've at least showed strong benefit with the therapy. I think our biggest question now is who to treat and when to treat probably the thing I'd like to learn more about I mean we're it's not that I can't make them better at what point in their disease process should we be intervening because right now most of us are still waiting for symptoms unless they have severe RV dimensional changes or dysfunction and do we want to make sure we're not missing people on the back end so we're on the front end that we need to go and we're in the back and I think the timing of intervention and who to be offering this to is important. I think the other piece that's a big gap is that we're still highly underdiagnosing tricuspid regurgitation, both at the general cardiology level and in the echocardiography laboratories where often patients are not being diagnosed early or then not being referred on. So when you think about the journey with aortic stenosis, which is fairly easy, anyone can measure a gradient. And even with that, it took us a while to raise awareness and to do some of the great work that philippe's been doing with early early tavern now with progress i think in the journey with tricuspid we're really just scratching the surface on what the true population is here to treat and i mean i've seen a huge acceleration in referrals in the last eight nine years i mean basically we were digging them out of charge finding people now they are coming in that's not that means we're not still doing that and i think think we need to get better at being able to get those people diagnosed early and get them treated when they become symptomatic. Peter. Peter, Chikrin, Deutsche Bank. You know, when you talk to the general cardiologists, you know, the referral sources, you know, one of the biggest debates we keep having, you know, from them is the quality of life indicators versus sort of these primary endpoints in order to change the treatment paradigm. kind of what is your view around saying which of those sort of starts changing actually the the before sources behavior well I I think most general cardiologists and even internists want their patients to feel well right like you we do hip replacements and knee replacements not because they're going to live longer we do that because the patients want to feel while and they have a better quality of life as we're moving on so I I don't think it's a problem in getting them to refer for that I think it is a problem and being able to recognize the disease. It's not an easy murmur to hear. The echo maybe gets one view and may not get to all the information. And many of the patients don't even get to that. So if they're seeing patients with edema or ascites, their shortness of breath, the symptoms are also indolent. They're a little bit shortness or breath fatigue. There's not clear symptoms on these. So educating both patients and physicians on what signs are, signals are to get additional testing and then potentially refer on I think that's to me we need to move I don't feel like anyone is going to deny someone a nice part about these treatments and particularly tears it's very safe therapy all the trials show very low event rates early on and throughout that so I think it's important to realize that and what's nice is now with replacement we have a larger portfolio which is very important for us because unfortunately you know tear is great when you can apply it but it's not for everyone and same thing with replacement and we can get into the details of one or the other but I think that's you know still evolving but it's nice to have both of those technologies available in order to have the full complement of therapies for patients that's Rick Just jumping off of that exact point, where do your mind is the latest debate on repair versus replace? How do you think that's evolved recently, and does the data presented at this stage change how you think about that referral pathway? I just wanted to make sure I asked the question correctly. When do we decide whether to repair or replace? Exactly. Is that what you're asking? Yeah. Well, that's a complex question. Well, I'll start to begin on how we think about this. So I think you have to look at clinical characteristics of the patient, and then there's the anatomic ones. And the clinical may be looking at things like bleeding risk and anticoagulation, and it may also be looking att, you know, what's the right ventricular function look like, and then what does the anatomy of the tricuspid valve look like. And if everything being equal, I'd rather repair than replace. uh, in patients. Um, I think it's very safe. Uh, you don't, at least some of the bleeding risks that we've seen with replacement, and I think its mainly not because of the replacement, it's because of population, but you don�t have to deal with that, and the pacemaker risk is a little bit less. So all of those things become good reasons to want to repair, but having said that, the majority of patients I treat, I end up replacing because their anatomy is such that they're not going to be getting a good result. And a good result has changed over time when we started this trial everyone was moderate or less that's great that's what we want to go for and that's why we behaved through most of this trial but as data has evolved as times about we realize we want to get them out or less so now we have scores one of which we develop the glide score to help decide can people get to mild or less and I think those are types of things you need to be thinking about if I can get them the mild I want to repair them if I cant and those are a larger proportion of what we see today let's go ahead and replacing that first we eliminate TR I don't know if that answers your question but the first step on it Bernard one more question last one um thanks Dave rescat with with Barrett um I wanted to ask about a little bit of a follow-up on the prior question or one of the prior questions when you think about how evidence kind of makes its way out into the field. I think we saw some data yesterday from the, I think it was the NIDA, an EDA database about how the mortality rates in some of these tricuspid patients is more significant than what you assume. So when you think about how data comes out, how that impacts the adoption of some of the transcatheter tricuspir interventions, is it something where you expect more data to is solely progressed on that solely increases the interest in utilizing these types of technologies, or would you assume something like these mortality benefits arising at three years being something that really creates a more flipping point behind the adoption curve here? Well, you've heard the forgotten valve a hundred times or a thousand times. Until nine years ago, no one even thought about treating anything mechanically on the tricuspid side. It's diuretic therapy. That's all that's in the guidelines right now in the U.S., So really there was no medical therapy, there's no transcatheter therapies, and so people just kind of shrugged their shoulders if they found it. And I think that needs to evolve to understand that there's a mortality price to pay, there's also a tax on morbidity, and now we have safe and effective therapies that can augment whatever medical therapy comes along to help these patients have better quality of life. And if it also has a mortality benefit, wonderful. But I don't think that's going to necessarily impact our ability to treat these patients. People want to get better, and their physicians want them to feel better. And that's, to me, where the focus could be. Would I like more mortality trials? Absolutely. Do we need them? No. I'd rather understand better when to treat, and then does it cause a mortality benefit or a hospitalization benefit? I mean, I'll take that, but I don' t think that' s the number one question in my mind. Great. Thank you. well thank you for the questions we'll now transition to bernard dr davidson thank you so much you know ted vin um thank you you know for the great panel here uh so let me uh briefly summarize here you know what i heard and what we know we have um we have a growing body of evidence um who have established this foundation of life-changing benefits to patients for tricuspid patients. A quick reminder, 10 years ago, it was a vision. And our sizable investment in the space, in technology, in science, our deep commitment to serve many patients in need has now resulted in TMTT having a full portfolio. And we have this full portfolio of repair and replacement for mitral and tracheal speed in both Europe for some time and now in the U.S. So all of this was possible with obviously the many patients who participated in this trial, physicians, TMTT employees who trusted us from the beginning. We are visionary. We learn together. And today we are partnering with physicians to change patient lives. So again, thank you so much, Dr. Davidson, Salmon, and Devine. We are now going to transition to TAVR, the long-awaited and important result of a PROGRESS trial. And who better to provide you with this additional perspective of what you heard in the last eight minutes that Philippe was on the podium about the trial results. So who better than the two pioneers in TAVR therapy? So Dr. Philip General, co-director of a structural health program at Morristown Medical Center, and Dr. Marty Leon, professor of medicine at Columbia, director of cardiology at New York University. Both, Dr. General and Dr., you know, Leon, have impacted the field in such a profound manner and saved millions of patient lives around the world. So they will be joined by, with Dan Lippis also, leader of TAVR. dan has deep medtech leadership you know globally more than 16 years at edwards in a very significant role across you know the company much of his time in tavern so now let me turn to philip who is going to go into the progress trial but also activate and i don't know if you have seen activate you know yet philips thank you so much all right hi everyone good to see you um thanks for the invite um don't like this timer already all right you can turn off the timer I get a PTSD here so um we're going to talk about the progress trial that was just thank you so much I feel better now so we're gonna talk about a progress style here that we just were presenting investigating the role of TAVR or clinical surveillance as you know and I was published in a New England Journal of Medicine and if you have a little QR code you see we have a QR code, you can download the New England on the right you also have on your card I believe and truly a transformative trial this is truly I would say a turning point like Dr. Leon like to call I call it a revolution because I'm French but I guess you can say a turning point. Just to clarify what is the progress for Alouage, we enrolled patients with moderate aortic stenosis and the definition of moderate was very rigorous by the ACCHA guideline and we want to identify patients that want to be we're known to be at risk or to develop either heart failure to or to progress fast and we know that there's seven at risk feature that were previously published and those patients were known to be at rest to progress faster to develop heart failure or to die and those risk feature you have them here symptoms diastolic dysfunction increase in calcium score, LVEF, drop of less than 60, NT, proBNP, AFib, and Stroke-Bolem index. And just to give you an idea, those features are very readily available for a cardiologist. They're easy to collect. They're not very difficult. Symptoms, AFIB, and low EF. This is something a cardiologists has every day in his office. Okay, this is not complex. No surprise, the symptoms were the first one to pop up, 96.4%. So most of the patients in progress were symptomatic. 44% patient had the dastleg dysfunction and you can see the rest interestingly 72% of those patients had at least two at-risk feature and 40% at least three really pointing out that this patient population were very sick at comorbidities and they were 78 years old it was an all-comer population only 45% with lower risk so 55% with high intermediates or high risk and that's important for the results section so these are the right risk feature that are easy to get and we enroll this trial in 18 months just to give you an idea we enroll early TAVR in five years okay just to give you how eager the physician or the patient are to be treated how easy it is to actually screen and enroll those patients that's obviously the first role is to show is it safe to do TAVR and moderate AS we never been there before Is there enough calcium to incur the valve? Are we going to embolize the valve or are we going to leak it? Actually, it was definitely safe. And as a matter of fact, it's probably the safest time point to do a TAVR for a patient, 0% mortality and 0% disabling stroke. So we never saw that before. So primary endpoint of safety at 30-day outcome was met, and we had a margin of inferiority, and we exceed the margin of superiority for this endpoint so this is the main findings so you can see the TAVR strategy of TAVR compared to clinical surveillance significantly reduced by 33% risk reduction the risk of death or heart failure event with or without hospitalization at two years with a number needed to treat of 14 patients so it is very compelling and you can see that there's early separation of the curve okay so moderate is not a benign condition and clearly there's heart failure event that happened quickly and importantly to say with this is was mainly driven by a reduction in heart failure stabilization there is the benefit of Stavr and this is a very important site was consistent across all subgroups and and including subgroup we will have thought that maybe early intervention or awaiting was better for example there is no interaction for the severity of the aortic valve so whether you have a severity of AV of less than 1.2 or more than 1 point 2 TAVR was superior same thing for the presence of biomarkers such as of heart failure BMP elevated or not we were the TAVR it was good for both type of patient and also the calcium score so elevated or so there was no interaction there's no subgroup where waiting was better and all the subgroup benefit from an early intervention in the trial in terms of death and a heart failure event and this is a very important slide because some people say that our federal event may be soft or not clinically significant but the main benefit of progress can be summarized in one line there's a 52% reduction in heart failure hospitalization and we know that our hospitalization is associated with subsequent mortality all the trial and heart failure if you get hospitalized one or twice then you're going to die from infection acute kidney injury et cetera et cetera so heart cell hospitalization fifty two percent reduction is very significant for a patient also will needs known to be associated with mortality in the future one learning of the progress trial is really about the natural history of moderate or stenosis we didn't have good perspective data on our patient with moderate evolved through time we have registry from the 1980s order 2000 but we don't have a good prospective trial so the progression to severe is actually was very frequent and unpredictable you can see among the 371 patient enrolled in surveillance 204 actually underwent AVR within two years with 27% at one year and 57% at two years and among the patient that underwent an AVR 80% so 81.4% crossed to severe aortic stenosis with a class one indication for AVR and that's very important because this is a curve you're going to see in all the textbook of medicine what is the progression of moderate to severe this is this okay in a very well control environment where you follow patient carefully this is one of the most important slide in my opinion when you look at the 30-day outcome how did we do with a VR in general when the patient need a VR we did well the ball group was good lower rate in both but when you look at their rate of 30-days post ever in the tower group this is where I get chills because you have 0% mortality and 0% disabling stroke to be able to say to a patient that I'm confident I'm going to do a procedure with 0% mortality and the percent is ending stroke is very powerful and reassured a patient and you can see if you wait to for severe as for example the stroke rate go to 2.5 percent so stroke is the most fear complication when you do procedure both for the family the patient and the operator to see those result of 0% is it being stroke don't underestimate that or very powerful to convince people that this is the right thing to do and I truly believe that this difference is probably triggered by the calcium score the new level of the aortic valve and we can discuss during the discussion why this low rate of stroke stroke compared to the waiting but is there's a physiopathology of this which is the amount of calcium on the valve pacemaker was 13 percent and 10 percent in book group was similar the other improvement was really the improvement in quality of life you can see when we do a TAVR immediately patient immediately feel better 15 points no surprise we fix the aortic stenosis and this is very important because that means that the symptoms of the patient was having was valve related some some people that like to write editorial will say that the symptom were not related to valves well this is the proof that when you do the valve you improve by 15 point significant improvement the key CCQ score and immediately on the other end people will say you can wait but if you wait you're gonna you're going to have a tatter at one year in two years there's no doubt but you can have a little decline in your quality of life a significant drop up to 10 and sometime up to 20 so and then of course you're gonna have a TAVR it's gonna be great you're going to improve your quality a lot after that but you're never going to go as high as the other group so yes TAVR improve quality of live immediately and prevent meaningful decline in health status so this is important for patient no stroke and no disabling stroke no mortality improve immediate improvement which actually validate the fact that we did something right for the patient and this is really the the conclusion where you can see that model a s with that risk feature on parallel safety is your percent mortality is your person stroke there's a being stroke we show security at two years for the primary point of death or heart failure and anyway reduce heart failure failure of position by 52 percent and we increase improve quality of life and I think that's really validate the fact that TAVR could be a great treatment strategy for patient with moderate aortic stenosis with that procedure this is on the right the most important slide that I didn't have the chance to present this morning and I'm going to take my time because every line is important because it's about the patient's clinical implication for the patient is that moderate AS is not benign when someone talked about moderate AS you think this is we can wait we just showed it's not benigne and I am going to show you data are even more powerful that is not benign and base patient will benefit from earlier referral to a valve clinic for more comprehensive evaluation to establish the optimal medical management strategy and I think we did we established that rather than waiting to severe progress support staffer for patient with moderate without risk feature this is a paper that I elected to do in parallel to the New England the progress trial is called the activate study and there's all the little QR code as well it is a Jack publication that was online at 2 50 today p.m. this is a real large a real-world large analysis of 15 million patients in 50 centers in other state to identify what is the proportion of severe what is a proportion of moderate and what is the proportion of Mariette with at risk feature in the real world and what the impact what we show from 54,000 patients with moderate to severe AAS 35% were severe 65% were moderate two-fold bigger population with moderate in the moderate group what is the percentage of patients with at-risk feature 80% had at least one at- risk feature if you remove symptoms because you think the symptoms are enough because of the valve we go down to 70% So in the real world, to have one moderate S with at-risk feature, you can see the mortality, the two years mortality when you have moderate S with at risk feature is almost the same as severe. And it's two-fold higher compared to moderate with no at- risk feature. Same finding for heart fetal excretion in real world. It's almost the same as Severe with two- fold increase compared to not having at- feature. So not only moderate AS is two times more frequent and severe, not only at risk feature is 80% of the moderate AS patient, but it's associated with increased mortality. And then you're going to look at the mortality curve, 20% mortality in progress, we have 7%. How is the difference? Because in a clinical trial we do better, both groups do better. It's very hard to show a benefit of mortality in a trial where everybody is followed like Hawk, by the clinical nurse, the research nurse that follows the patient every six months, that calls the patient to know why it feels it's not real world this is ritual so moderate is for is frequent is bad and it's especially bad in in a real-world patient so I guess I'm going to stop here and we're happy to take questions Larry? Thank you. Larry Bigelson, Wells Fargo. Can you hear me okay? Philippe and Marty, congratulations. Marty, I lost track of how many New England Journal publications you have on TAVR, but it's a lot. So, you know, I was, the two-part question, so of the data you just showed, Dr. Gennaro, the 23.5% versus the 20% for mortality for the severe and moderate but you didn't show a mortality benefit in progress so what's the difference severe why would you we saw mortality benefit in the severe trials with TAVR but not today in moderate and second you had the 80% with at-risk features the editorial everybody here read and you know the first message I got was it wasn't very positive but there was one statement that stood out which was you know it said something to the effect clearly TAVR is not appropriate for most patients with moderate AS, I'm going by memory. So what's the disconnect there, the editorial versus what you showed today? Thank you. Yeah. I think Catherine O'Toole didn't read my paper yet, so maybe she will change her mind. But I will say the first, the mortality question. The mortality question, very similar to early TAVR, we are in a clinical trial setting. Those patients are followed very, very carefully, which is not at all representative of what is in the real world. So that's the first difference, and you can see the difference in mortality, 20% roughly in the Real World compared to 7%, 8% for the PROGRESS trial. Second, we didn't power the trial to have a benefit of mortality. We power the trial based on the safety, and also we expect 30% to 15% difference in heart failure mainly driven at trial. The third point I will say, if you refer to early TAVR trial, early TAVAR trial was a mean follow-up of 3.8 years. We have two years. Every one is a two-year here. And when we do a landmark analysis of early TAVA, we see the difference in mortality and stroke start to happen beyond two years, Two years is very short in a lifetime of a patient with moderate AS. There's still 40% patient that didn't convert it. But beyond two years in early TAVR, we see the curve, which actually is exactly parallel at two years, and sometimes a little bit worse with TAVR. And then start to, beyond two year, two, three, four, five, to spread in earlyTAVR. So I'm expecting, and I'm speculating, but I'm expect the same phenomenon will happen, especially with the 40% patients that remain untreated. life will not be rosy for them it's not going to be better than being trained earlier so I'm not surprised and I was not expecting neither the mortality but the fact that we have 52% reduction in heart failure risk realization in spite of the quintessential follow-up trials like from a trial setting is unremarkable and that's the thing that moderate AS is not benign the second part of your question you think that modern is is a niche disease and most of the patients should not be treated strongly disagree I would say that we randomized this trial in 18 months in a record time with a lot of enthusiasts second activate data or the Jack paper completely I would contradict the statement when you have patient in the trial that most of it and what I believe that dr. Otto referred to is most of my patient with moderate as don't have those features she's referred to the 1.4 the 1 point 5 out area that actually were probably mild of course those patients are not the same they're mild we have one one one two one three a little bit of one for me mainly when you truly moderate as so I think that there's a matter of definition what she's thinking and and I think people don't realize yet because they maybe you don't pay attention so yeah Rob yeah that's let me just to go forward a little bit with this I haven't read the editorial yet me neither I haven t either but I know Catherine Otto very well in Catherine Otto is is an echocardiographer who works at University of Washington and rarely travels outside of Seattle she was also responsible for many of the guidelines and she's a very very strong academic she's not really what I would describe as a clinical cardiologist and nor does she refer many patients for TAVR although she does read a lot of echoes and she's got strong opinions and those are somewhat ossified in terms of new therapies for any form of alveolar heart disease let alone aortic stenosis so I'm not so surprised that she would come to that conclusion but it's an ill-advised conclusion and it's not just the the activate study that that Philippe discussed in a real-world population in the United States almost a decade ago the neither trial from Australia an echo based trial just looking at the prevalence of different forms of aortic valve disease demonstrated that moderate aortic stenosis occurred at at least two to three fold a higher frequency than severe aortic sthenosis and that the mortality was different only by a couple of percent untreated so what activate showed really was confirmed with a quarter of a million patient echo registry that was reported more than a decade ago and got us thinking about the importance of moderate AS and we did a whole bunch of studies trying to define the at-risk features that were then incorporated into the progress trial we did another trial called the unload trial which was a moderate AS study in patients with reduced ejection fraction and clinical heart failure because those patients had a 50% mortality untreated in the first two years. So this is a prevalent disease, at least twice as prevalent as severe aortic stenosis. The frequency of at-risk characteristics as defined in this study is the majority of these patients, at last in a U.S. population. And we can see, at least from ACTIVATE, untreated, they had a two-year mortality and heart failure hospitalization, which is unacceptable and worse than most subgroups of patients with severe symptomatic aortic stenosis. So I just totally dismiss some of the conclusions and some of the comments that were made in an editorial capacity by someone who really doesn't take care of patients and who really does know the data. Now, why didn't we see a mortality difference? the first clinical trial we did was partner 1b it's the only other randomized trial we did where we compared the current standard therapy which was surveillance in patients that were not surgical candidates and yes these were the sickest of the sick patients these patients had STS scores above 10 and the untreated one year mortality was 50 percent And we showed with the earliest version of a TAVR device, and we weren't sure what we were going to show, but the primary endpoint was a head count. It was all-cause mortality. We had an absolute difference of 20% in the first year in reducing all-course mortality in that population. And yes, that was historic. But we're not in that era anymore, and we don't treat many of those patients anymore. This is a very different era. now we have a therapy that doesn't have the kinds of complications and the kinds of burdens that we did in the earliest days of TAVR we have a therapy we can apply with a one day hospitalization and in this population had zero mortality at a month and no disabling strokes at a months we've never seen that in any population so this is I would argue this is no riskier than having a colonoscopy in terms of the therapy and its safety as demonstrated in a huge number of sites, broadly applied, not just in the U.S., but elsewhere. So I think the safety, and when you look at risk-benefit, you've got to always think of the risk. And the risk of the theory, the therapy, does it negate the potential benefit that might be achieved? And in this case, the risk is de minimis. So that, I think, needs to be put to rest. And Philippe's point, which is, this may be the best population to treat with TAVR. We can fully expand the valve. We've got the lowest complications. They can get out of the hospital literally overnight. And we think that the hemodynamics, by the way, achieved with this therapy in these patients were better than in any subset population that we've ever treated with balloon expandable TAVR We had mean valve areas of greater than two. So that's going to translate, especially with resilient tissue, into long-term durability. So I think everything about this from the standpoint of safety and the quality of the result is as good, in fact, was beyond what we had expected. When you look at a population like this and you do close surveillance, which is what we did, this wasn't real-world surveillance. In the real world, 20% to 30% of patients who have moderate AS don't get an echo within two years of the diagnosis. We were following these patients every six months. They had intense scrutiny, the kind of oversight that you'd like to see. And if there's anything that comes out of this study, it is if you have moderate AS, you better not just sit in somebody's office. You better get your butt to a valve center to have what we call extensive investigation and what would be what we believe is optimized therapy, not what we've been doing before, which is just waiting for these patients to present ultra-sick, too late, and not achieving the kind of clinical benefit that we can achieve. So I think that that emphasis that we've now understood that this is not, the first words out of that clinical implication slide, this is not a benign disease. And every clinician cannot feel comfortable just watching moderate aortic stenosis anymore, and that includes Dr. Rado, because that disease should be put on alert. And that means you've got to have qualified people doing further investigation, trying to define what would be, we think, an at-risk population that would be amenable after careful discussion and after weighing all the facts, getting a CT scan, seeing what the anatomy is like, that these patients first, would they qualify for TAVR? And if they do, an open discussion about whether or not that would be the preferred therapy, both to prevent more than 50% reduction in heart failure hospitalizations in the first two years and a significant reduction in those patients who had decompensated epithelios with an average 17-point drop in KCCQ score. I wouldn't want my mother to be waiting for a 17- point drop in kccq score or until they get severe aortic stenosis before applying a therapy that could prevent those things with a zero percent mortality and a zero percent disabling stroke rate so and again getting back to the mortality why did we show a difference because the surveillance was so good I mean these patients progressed more quickly than we thought the severe AS and they were treated so they didn't die so when you look at the control arm you don't see a difference and and but I'm still not sure that when we wait not at two years But when we wait for three years, four years, five years, now we're seeing, if you look, and you know the data better than anybody, when you look at early TAVR now, we just presented the median follow-up at New York VALS at five years. Now we're seen a change in heart endpoints. Now we've seen death and stroke at five year with a median follow up in asymptomatic severe AS is better with preemptive treatment. so this is only the first look but this is a turning point but it's also a starting point this is the first looking at a data set that's going to continue to mature and there'll be other studies will get done there'll be corroborative studies that are already in the works that that this difference is meaningful it didn't show a mortality change of two years it might by five or or further down the line we never thought we never were powered to show a true mortality difference, especially with the kind of surveillance that was applied to the control arm. If the control arm was community care of moderate AS patients, we would have shown a mortality difference. But that's not what the control alarm is or could be in a trial like this. So we were not surprised. And holding the study up to that standard is absurd, frankly. Thanks. Robbie Marcus, J.P. Morgan. and there's a much more favorable TCTMD article out there. Which I also didn't see. I saw it. It was a great one. And I'm sorry to get emotional about this, but I've been doing this since, you know, we began enrolling patients in these clinical trials in 2005 when we did our first case at Columbia and started enrolling the predicate studies to partner. And, yeah, this is the 32nd New England Journal of Medicine manuscript that I've co-authored and been involved in, and I would argue potentially is the most important. And as we continue to talk, I'll tell you why. So there were a lot of great points you touched on there. We're all financial people. I think it's clear this is going to be adopted by physicians moving forward with such good clinical data. How should we think about some of the timelines going forward? You know, is this enough for FDA approval? Is this enough for indication expansion? How should we think about reimbursement timing? And on adoption, how should we think about how quickly this can start to roll into practices? Are these patients being seen already? Some of the referral challenges or pathways that need to be opened up? Thanks a lot. Do you want to answer any of that? Sure. I think And I think, firstly, from what does this data say about what can be done immediately, it certainly, if you're a physician out there, it certainly wouldn't stop you from doing an advanced screening on a patient or certainly wouldn'T stop you for referring a patient with this disease to a heart valve clinic for further assessment. clearly an indication is important if it's going to enable us to better serve this very underserved patient population we don't typically speculate on the timing of you know indications etc or the relative you know impact of that and so you know what i suggest is as we sort of get into our december investor conference we can talk a little bit more about what our anticipation or what we're how we're thinking about that in in 2027 and perhaps the longer-term impact beyond that in December maybe I can give you a glimpse of response for a clinical work when we start to screen for progress we advertise and people start to send their patients for every for every 100 patient I was seeing 30% were severe actually there's a base a big miss that knows diagnosis in the community there's a big underestimation of the severity of AS and what is labeled as moderate aortic stenosis out there when they come to us in valve clinic where we do a deeper echo not a screening echo when we do a CAT scan we realize this is a valve is severe or critical so there's a high proportion of the patient that were excluded from progress okay which is the main reason 20 it's like almost 40 50 percent because the patient didn't have moderate AS you have either severe or mild but most of the time severe so the first thing people would say hey and and I will really start to do this and that you bring me your moderate we're going to stratify them and a third at least would be severe so there's a lot of things we can start tomorrow and then you follow them and it a follow-up should be every six months and then they're gonna express themselves as severe at six months twelve months so this is going to be the direct impact and every time I did a partner trial get a partner trial got published when partner three published that published I finally could treat all the intermediate risk when Erdi Taver was treated all the partner three were coming and it's not a problem I suspect though this trial will unleash all the severe with no symptom and also the patient that had mild symptom not ready to be treated so I think you can have an uptake in the severe because that's confirmed that severe you should not wait anymore and send me your moderate because you may have classes misclassified them for a couple of years so I think this is this side effect and I always see it because obviously I'm more Center and we or TAVR is like excluding because we screen moderate and we find a lot of severe so so there's more to just oh I'm going to get CMS approval before we can start to do those patients Travis Congrats on the data. Maybe first of all, we touched on this a little bit earlier, but just curious of the moderate population, what portion, is it roughly half maybe of these patients likely are at risk that you'd see in the real world? And then do you think the FDA label and reimbursement would probably have a similar restriction on the moderate patients to be more like you had in the trial? I know the NCD left a pathway for moderate coverage up to the max, so I don't know if there's anything to say on the NPD. Just curious on the reimbursement. And I know one other thing was heart failure hospitalizations, a big economic impact too. Just curious how that ties into the reimbursements. Reimbursement conversations. Yeah, I would start by saying that this population, the bucket of at-risk feature is at least 50%, but actually the activate showed that it's 70% to 80%. So it's not a niche for sure, um it's the majority and the majority defined between 50 to 80 percent depending how you know you capture the data actually but the that's majority uh for the rest um i will let you answer this maybe the simplest way to answer your questions is the study was designed in collaboration with the fda right so it's important so like there shouldn't be any surprises on what the indication is when you know when or if it is given again we can't really speculate exactly on how they're thinking or exactly what that might look like um and and we can maybe like similar what i was saying before um have a another conversation about how we're thinking about that in terms of what it means for 2027 and beyond and and how we'RE thinking about what the longer term impact might be as far as reimbursement goes you kind of touched on it right like we have an ncd in play it was just up updated from a reimbursement perspective it while it didn't specifically include moderate as patients nor can it because it's not an indication that exists there is room in there for the first time deliberate room in the language was provided by a CMS to talk about you know how reasonable and necessary applications of TAVR can be used by working directly with the max and that's important and that going to be super important for this population I'm sure the physicians would agree given that these patients you know the the disease is not benign and and and they're looking for something that's going to help them make make them feel better and and potentially reduce some serious cardiovascular events yeah I just wanted I'll just follow up for a second if that's okay remember 95% of these patients were symptomatic and a third of them had class 34 symptoms so this is a very symptomatic population of patients that were being treated optimally by their physicians and we're still symptomatic and severely symptomatic the relationship with the FDA is a very good one a very close one we can ever predict exactly what they're going to do but they're very full fully aware of this study they were involved in every aspect of its development they even tried to to work with multiple sponsors to see if the endpoints can be not unified but made similar so the way when they looked at the totality of the data they'd be able to be looking at endpoints that they could relate to from multiple different studies so that's the level of engagement that the FDA has had on this they view moderate AS as being a significant clinical problem and I would certainly I personally be very surprised if the extension of the indication to the moderate population wasn't done in with all due haste reimbursement I think it's another matter but I think that's something that we're going to be able to overcome, given the compelling nature of the quality of the outcomes here. And I'll alert you to another late-breaking trial that was presented yesterday by Neil Butala, which was a cost-effectiveness study of early TAVR, which Was a fascinating trial, and we never thought that this would be cost-effective. But they, with their statistical wizardry and extrapolations and imputations and all kinds of other things. Looking at now the median five-year follow-up data indicated that this was strongly in the cost-effective range of treatments compared to other therapies that are currently being reimbursed by CMS. So that's asymptomatic severe AS. So when we do the cost effectiveness studies with this, there's no question that this is going to be a cost-effective therapy as well, which I think will add to the reasonable and necessary component. But look, it's one study. We're not going to get a class one indication on a single randomized trial. If they were to reclassify, it'd probably be 2A to start, but there may be a second study coming before too long. If it corroborates these results, you can expect that there would be a class 1 indication for treating moderate ASK aortic stenosis within the next several years Matt thank you I appreciate the comments on the editorial and I'm happy to bash that with you more later but I did want to follow up in your comment Marty you said that you had 32 publications and this might be the most important those are real teaser I want to hear why why you said that what this could lead to why is it the most importance well because I think this opens the door for us really exploring something that we've all been thinking about for more than a decade which is this anachronistic dichotomous categorical description of aortic stenosis is not human biology we don't deal in buckets mild moderate severe aortic stenosis the disease is a continuum and defining it only on the basis of echo hemodynamic severity at the valve level is not an appropriate clinical classification we've identified a subgroup now that very clearly has clinically significant aortic stenosis that doesn't qualify into that neat bucket of being severe symptomatic and it's going to result in a redefinition of how we define this disease how we follow it and how we treat it whether we use terms like clinically significant aeric stenosis rather than moderate or severe, we'll come up with the right terminology. And whether we start to impute other factors to be able to define what that clinically significant population is, this is going to change the way we think of the disease, change theway we follow it, and change the way we treat it. And it allows us to get back to the continuum of human biology as opposed to the categorical way that we currently describe things, which were developed more than a half century ago. Unfortunately, Gene Brownwald is no longer with us. He was truly an iconic pioneer. We had this discussion before he died a few years ago, and he, who categorized these different buckets of aortic stenosis, clearly realized that that was artificial and anachronistic. And what we want to do is to bring aortic stenosis therapy into the modern era. And this is a turning point and a starting point. And that's why I say it's potentially transformational in terms of opening up the therapy options for this disease. One last question. Joanne? Thank you very much. Joann Lynch from Citibank. Thank you for your time this evening. If I hear you correctly, a year, two years at some stage in the future, we're not going to be talking about moderate AS and severe AS. You're just going to have AS. Well, that's a little bit simplistic. I mean, we're going to go much further. We're going to be able to define the characteristics that differentiate patients that have clinically significant disease, and the trigger point for therapy is going to shift. It's not going to be just AS. It is going be AS with a continuum, but that continuum is, yes, hemodynamic severity, yes, the effect on other cardiac structures like ventricular function, yes, but it's also going to be a variety of other clinical factors that makes patients vulnerable and defines them to be at risk requiring treatment a little bit earlier in the hemodynamic sequence. So the hemodynamics do not predict the clinical outcomes. Follow-up. When physicians leave TCT and go back to their practices, how do you think they change their practice? How do you think they change viewing the patients? And do they have sort of a pool of people that were like, you can come in now? So I'm going to start to this, but yeah, absolutely. So what's happening is good news is this paper is in New England. So all the doctors in the universe will see this paper. And they will look at this and say, oh, shit, I have to treat my moderate AF patient now. So they're going to freak out. They're going call a guy like me. Hey, Philippe, what's the hell I need to treat those patients I said you can just start by sending me the patient and we're gonna do a CT scan and repeat an echo and we start by them okay perfect which one I should look at it start with the one with symptoms started with the 1 with a fib and start with a 1 and low EF or you know what start with sending me everyone because actually it's 80% of population okay so that's exactly what's going to happen so and I can tell it's already starting my phone is busted and blowing up because should I treat patient with out of the ass and the reality is we're not going to treat everyone when what are they yes okay we probably gonna treat 80% okay and and it's not going to be tomorrow I know all through this in patient but it's going to be really on gradual but what's gonna happen is and I can tell you right now is if one patient go see a cardiologist X it's a hey I read this paper because everybody's well-informed right now which are GPT and everything I the general said that we need to treat to treat me I said no no we don't do that here she's gonna go see someone who's gonna know my office is full of patient that I want to since already to ever in progress and and and with the trial so that's what's gonna happen the patient will is gonna be the answer will be in at the end of the patient I don't feel well they tell me I'm moderate but I feel like severe I feel that shit so I'm gonna go see the doctor who's going to listen to me and help me and one thing that was clear in progress is when I treat those patients at 30 days they were thanking me they say I feel so much better and this quality of life is not only a bogus number it's real and this is where one day I had a nurse who came to me especially but she's working as a patient feels completely different is better color and it's feel better this is real this is not on the me saying this is that we do this for patients so I think that to Marty's point is going to we're not going to treat all the AS what's going to happen is going to tell I think this patient need it so if it's approved for severe it's a proof of moderate it's going to give back the power to the physician to decide who needs it based on clinical judgment in that first feature and and and will be able to help the patient that needs it so I think that's what you know gives back the powers with a clinical judgment to see who's needing it and there's a lot of patient that means it that's the reality yeah Philippe's correct and I I know we're running over, so I'll be brief. I'll try not to be as emotional. But we're going to make... Usually I'm the emotional guy. Yes, true. We're going make everybody feel very uncomfortable about moderate AS. The fact that 20% don't even get a repeat echo, the fact that 80% don'T get a BMP drawn, the fact THAT none of them ever get a CT scan to see if they're even a candidate for therapy at some point in the future, even with severe symptoms is ridiculous so we're going to change the way people think about this disease and make them very uncomfortable about just watching these patients now many of the practitioners who see them for the first time are going to be equally uncomfortable but equally uncomfortable about doing the necessary evaluations so they're going to get rapidly referred to expanding valve clinics and we're gonna do the necessary tests we're getting get a BMP we're you get a CT scan we're going to look at the echo more carefully and we can try to understand more about about the patient's symptoms, and then discuss whether or not they fall into an at-risk category that would potentially qualify them for therapy. So it's this issue of recognizing moderate AS is not a benign disease, first. Second, that many of these patients, if not all of them, should be referred higher up the chain to qualified centers that can do a comprehensive evaluation, which is not hard to do. It can be done very easily and very quickly in a single day. And that there now are other treatment options, and the therapies are going to be more advanced. But those will be discussed with patients, and it'll be prioritized. There are going be all kinds of reasons why you would or would not do a TAVR immediately. But you certainly are going to follow these patients more quickly and more carefully. You're going to recognize when they convert to severe AS, and you're going to be applying the kind of appropriate management that prevents mortality, as we demonstrated in the clinical surveillance, so I'm in this trial. Great. Well, thank you for all the questions. I'll turn it over to Dan. Thank you. So maybe as a reminder, just stay, gentlemen, just for a quick second. as a reminder our investor conference is in New York later this year and Marty is based in New York and Philippe is based New Jersey which is very close and so I highly recommend that you read the papers that we're talking about because there might even be a test before you can ask another question so what I'd like to do is just very briefly summarize I think there was so much rich discussion here oops let's let's go one way Marty mentioned it Philippe mentioned it we're at a turning point we're out of turning point in our both understanding and the management of moderate AS and the data is not only of the highest quality but as you can appreciate from what our leaders the trial leadership here are talking about it's very very important and it's important for three reasons one clearly identifying that there is an underserved patient population here that is sizable and that moderate AS doesn't fit in a box this is a heterogeneous population in nature and it is not benign the second point is is that CAVA in the this particular patient population which is moderate AS with at-risk features provides a significant benefit and the results both from a safety perspective and from a superiority to the composite primary endpoint for effectiveness shows and validates that TAVR with a sapien 3 in moderate AS with at risk features is valid the third point here is and what we were just talking about here it forces us to challenge the current guideline directed surveillance paradigm which is passive in nature no matter how you look at it the disease progression was unpredictable right over 60% of the patients in the control arm ended up having delayed AVR and not with better outcomes by waiting and so we just talked about this we have to move away and we're going to be forced to move way from passive surveillance in the clinic in the in the community to active surveillance whereby comprehensive tests is done early and we get the right information to determine the optimal treatment strategies for these patients to get them their optimal outcome so it's an exciting time we're very happy and pop with these positive results I can't thank both dr. Jenner and dr. Leon enough for their trial leadership and I'd like to pass over to Bernard for closing remarks thank you everyone I know that you know we are passing over the time here but you know you know what an insightful little conversation here what I like to do is a little bit of a big-picture comment at the end so what did we know you know before today we know that in a section is the most studied travel valves 20 years of landmark trials thousands of patient studied millions of patient globally benefited we know that we had you know seven year data so this platform is durable and all of these results you know we were very careful about you know talking about taver today but all of his results were possible with sapien and so not only you know it is an exceptional you know taver platform but it is a durable valve platform but what we learned today is few things the disease is not benign and the progression to severe as frequent impossible to predict so think about the patient think about the opportunity think also about you know what we have ahead of us you know to do you know all together CPL has shown remarkable performance unparalleled safety moderate patient population is a large one you know and it is you know it is also redefining the way we are going to think together about you know aortic stenosis so also we talked a little bit about it Dr. Leon talked about it but I think Dr. General also I like to take the two disease studies together early TAVR and progress and these studies are advancing the understanding of aortic stenosis and how clinicians should manage this patient going forward it's an exciting time a ton to do, pivotal moment for physicians, for patients, and I want to recognize all of the investigators in all of these studies to have made this possible. 15 years ago, 20 years ago I know Martin can talk about that, it was a vision again, and this vision is happening, and there's still a lot to do here. So what you can expect from us is we are going to continue to innovate. We are going continue to bring evidence. We are going to continue to educate the field, to train physicians, and to take care of all of these many patients. And I cannot close without recognizing the leaders who had the vision how many years ago? Seven, maybe eight years ago. The vision for this progress trial. Obviously, Dr. Leon, Dr., General, but also Dr. Raj Maka and Dr. Jordan Bax who are not with us tonight and the many investigators globally who have made this possible. Together with the Edwards employees, the Tavir employees who have been working very hard to bring these landmark trial results today which is going to change the way we are thinking about the space. So again, thank you everyone. Thanks for your interest. I hope you're very excited about what we were able to achieve today. Thank you, and have a great evening.