Good afternoon and welcome to the fireside chat titled, "A Clinician Perspective: Holistic Approach to Managing PKP2-Associated Arrhythmogenic Cardiomyopathy," hosted by Lexeo Therapeutics. As a reminder, this call is being recorded today, Tuesday, December 9th. I would now like to turn the call over to Louis Tamayo, Chief Financial Officer of Lexeo Therapeutics. Louis, please go ahead. Thank you. Welcome to this fireside chat session. Joining us today on the call from D.C., where they are both participating in the Cardiovascular Clinical Trials Forum, are Dr. Eric Adler of Lexeo Therapeutics and Dr. Victoria Parikh, Clinician Scientist and Director of the Stanford Center for Inherited Cardiovascular Disease at Stanford School of Medicine. Before we begin, I would like to remind you that this call may contain forward-looking statements regarding Lexeo's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. Additionally, both Dr. Adler and Dr. Parikh's disclosures are listed on the slide. With that, I would like to turn the call over to Dr. Eric Adler. Thanks, Lou. I'm really happy to be here today at this session. As you know, at Lexeo, our mission is to change how genetically mediated cardiovascular diseases are treated by research and applying pioneering science. Currently, we have a cardiovascular gene therapy candidate, LX2020, that's being evaluated in clinical trials for the treatment of Plakophilin-2 Arrhythmogenic Cardiomyopathy, otherwise known as PKP2 ACM. While a lot's known about ACM, as the treatment landscape evolves, perspectives on how ACM is viewed and managed are also evolving. There's growing evidence, both in the literature and from clinical experience, that supports approaching complex diseases like Arrhythmogenic Cardiomyopathy from really a holistic perspective, something we'll discuss more today, and to do that, I'm really excited to have Victoria Parikh with us. Vicky is the director of one of the largest inherited cardiovascular diseases centers in the country, the Stanford Center for Inherited Cardiovascular Disease. She's an associate professor at Stanford and just a wonderful clinician and scientist. We're really lucky to have her today. Her center specializes in the care of patients with genetic cardiovascular conditions, including ACM, and her clinical experience provides valuable insights into expert-level and world-class patient care. And I'm sure we're going to learn a lot today and have a great conversation. So let's dive right in, Vicky. Thanks for joining us today. Thanks so much for having me, Eric. Yeah. So to start off, give us a little bit of background on your experience in managing patients with Arrhythmogenic Cardiomyopathy. You know, as you said, our center is one of the largest in the country, in the world, and so we see thousands of patients with inherited cardiomyopathies, families with inherited cardiomyopathies. And one of those, of course, is Arrhythmogenic Cardiomyopathy. You know, one of the things that we're really focused on and traditionally have been focused on at our center is implementing precision medicine, and as you all know, that is something that is uniquely suited to genetic cardiomyopathy, so not only do we see and diagnose sort of the clinical phenotype of patients with Arrhythmogenic Cardiomyopathy, but we also are really focused on deploying genetic testing and genetic diagnosis to be able to get to the root cause of those diseases in the clinic. Great. So with all that being said, let's dive in a little bit to discuss ACM. Can you give us a little bit of background on the disease and its etiology? Absolutely. So Arrhythmogenic Cardiomyopathy, or ACM, is first and foremost, as it is named, a cardiomyopathy. But clinically, what we see in these cardiomyopathies is that progression toward heart failure is coupled with a particularly arrhythmogenic substrate, meaning that there's a structural change in the heart muscle that is also conferring very high risk of early and life-threatening arrhythmias like ventricular tachycardia. So it turns out that this particular disease is slightly more rare than other inherited cardiomyopathies, but is still present in about 125,000 individuals in the U.S. Of these individuals that have been diagnosed, about 20% on clinical presentation actually come to our attention because they've had a sudden cardiac arrest. So it is a very severe disease. And that sudden cardiac arrest is often caused by ventricular tachycardia or fibrillation. Most of these patients, when we do genetic testing, especially those who have their right ventricle involved, have a genetic diagnosis of Plakophilin-2, which explains more than 50% of those ARVC ACM subset patients. Great. Let's dig in a little bit more. How does a mutation in PKP2 gene actually contribute to the development of ACM? What do we know about the kind of pathobiology? That is such an important question. The way that PKP2 or Plakophilin-2 works is it's part of the glue that holds heart cells or cardiomyocytes together. And it turns out that just like humans, cardiomyocytes need to talk to each other in order to stay in rhythm and work together. So when you lose PKP2, which is part of that glue, also called the desmosome, you lose those connections. This leads not only to abnormalities in rhythm because those cells can't talk to each other very well, but also to the death of those cells because they are overworking and therefore leading to more arrhythmias and then when they die, to replacement of that section of the heart by scarring or fibrosis. So it's a complex situation with PKP2 ACM, but the bottom line is that mutations or variants in PKP2 and other desmosomal genes lead to significant electrical and structural abnormalities. Yeah. It's such an interesting disease, especially this unique infiltration of fibrofatty tissue. So it's just fascinating. So with all that background, talk to me a little bit about your approach to assessing and managing ACM patients? Yeah. It's tough. We don't have a lot of options for them. I think, you know, as a clinician, I tend to sort of separate simply each disease into how I diagnose it and then how I follow it and manage it going forward. With respect to actually diagnosing ACM patients, as I mentioned, many of these folks, their first clinical manifestation is a significant ventricular arrhythmia, like ventricular tachycardia. But when that happens, there are a lot of reasons why patients might get ventricular tachycardia. So what we're doing is we're making a systematic evaluation of that patient from the structural disease in their heart all the way through to electrical changes that might actually tell us a little bit more about the underlying etiology of that VT. So for patients with ACM, we generally, especially in the right-sided ACM, right ventricular ACM, use what we call the Task Force criteria, which came out a long time ago, but are still really tried and true for defining this disease. Those are complicated because this disease spans both structural and electrical abnormalities. Some salient examples of that are that we're going to take really, really detailed pictures with MRI imaging and echo of both ventricles to try to understand whether that fibrofatty replacement that you mentioned is actually disrupting the function of those ventricles, and in particular in certain spots of the ventricle. And then we also do a really thorough electrical evaluation. So that includes an ECG where we try to understand if the heart is depolarizing, so that means activating, right, normally, but also if it's returning back or repolarizing correctly as well. And then we look for arrhythmias. So the first thing that we look for is this patient having something called non-sustained ventricular tachycardia? That is a really, really good sign that, especially if we can localize it, that they are developing worsening ARVC or ACM. And then, of course, we also look for PVC count. You know, these can show up a little bit earlier than non-sustained VT, but when those PVC or premature ventricular contraction counts are quite high, that can give us a clue as to whether this is an ACM patient. So importantly, though, you can't base the diagnosis on just one of those. There's a very sort of complicated point system where you have to show that within those structural and electrical categories, multiple of them are actually disrupted in order to make the diagnosis of ACM. So that's the diagnostic criteria, which are quite complicated. But moving forward, right, you look at the management buckets in terms of what's going on with their arrhythmias or their electrical complications and what's going on with their structural disease. So when I'm monitoring these patients, I'm very frequently monitoring their rhythm. The first decision we have to make is whether they are at high enough risk of a sustained ventricular tachycardia or major ventricular life-threatening arrhythmia in order to warrant implantation of a defibrillator, right? And there's a complicated calculus that goes into that. And then, of course, I'm looking for the development of heart failure, which tends to appear a little bit later in this disease, but is certainly a huge and currently really unmodifiable progression that we see. Great. Curious, how often do you see cascade patients as well? So family members that just might, you know, might have a family member with ARVC? Yeah, absolutely. Come in your clinic. To your point, we, of course, are using genetic testing as part of that diagnostic criteria. As we mentioned, having a known causative variant in, for example, Plakophilin-2 is going to get us closer to a diagnosis. And so when we can make those genetic diagnoses, that helps us to screen family members because if they then don't carry that causative genetic variant, we can often release them from screening, which can be lifelong. So we do see those patients. We see folks with very early stages of disease where they carry a PKP2 truncating variant. Maybe they're having a run of non-sustained VT. Maybe their right ventricle is a little bit big. In that diagnostic criteria, we do heavily weigh the presence of that genetic diagnosis, that PKP2 truncating variant, for example, because that can really help to tell us how closely we need to monitor this patient in order to catch disease before it becomes a sudden cardiac arrest. Got it. Yeah. That's great. Okay. Well, let's transition a little bit to this area around non-sustained ventricular tachycardia and SVT and PVCs. There's this clear consensus to look at the components of the diagnostic criteria, that these various parameters need to be looked, you know, as we said, holistically when assessing a patient's cardiac status as well. You want to talk about how you look at these two parameters and arrhythmias in general? Yeah, absolutely. So, I mean, diagnostically, they're actually differentially weighted. So it turns out that non-sustained VT, which is basically a run of, you know, rapid extra beats that are coming from the wrong place in the heart, from the ventricle, they should be coming from the atrium in normal beats. So non-sustained VT is something that is heavily weighted in the diagnostic criteria if it seems to be coming especially from the right ventricle. And so it's a major criterion for diagnosis, which gives it more weight in that sort of summative formula that we were talking about in the task force criteria. And then PVCs, if that patient's having more than 500 PVCs or single extra beats from the bottom of the ventricle per day, then that counts actually as a minor criterion, which is sort of a half of a point. So diagnostically, they're weighted differently, certainly. When we're thinking about following patients going forward, I think of PVCs really as a diagnostic sign of disease. When I start to see non-sustained VT or NSVT, then I'm thinking more about disease progression. Certainly, we see increasing PVC numbers associated with disease progression as well, but it's a little bit of a chicken and an egg there in terms of whether that's actually going to worsen the patient's status or whether that is just a diagnostic sign. With non-sustained VT, if that becomes more frequent, longer, faster, those are things that make us worry about the patient then having a sudden cardiac arrest. In fact, when we have developed risk calculators as a community in this ACM population to try to determine who's going to benefit most from a defibrillator, it turns out that non-sustained VT has a really, really big effect on that percentage likelihood of sudden cardiac arrest or sustained VT than the number of PVCs, so in sum, you know, we have to think about both of these things, they're both important, but when I'm following patients in the clinic, I am very, very concerned when I see non-sustained VT, and I think reversing that gets us sort of closer to reversing the risk of sudden cardiac arrest. Do you think about them differently in terms of kind of the pathology of disease, like PVCs, you know, being a spark, and then you have to actually have reentry for an SVT or something like that? Yeah, that's a good point. I think that's probably the underlying reason for my gestalt about NSVT being sort of a heavier sign when I weigh disease progression. So, you know, as you're pointing out, non-sustained VT, because it's many rapid beats in a row, often it's happening around scar or fibrofatty infiltration in the ventricle that you've described. And so that can sort of tell us that there is a worsening structural disease in addition to those electrical abnormalities. PVCs by themselves can often be a, you know, very small number of cells that are not necessarily causing multiple beats around a fibrofatty scar, but instead are sort of beating out of turn more frequently. So you could, I think, put that together to say, look, non-sustained VT, because it's reentrant, has the ability to turn into a longer sustained symptomatic, potentially life-threatening VT, whereas a PVC is terminating, right? It's one beat at a time. And so theoretically, it's not going to turn into VT by itself. But there is a lot of complexity that goes into that pathophysiology that, you know, makes it an imperfect model. Got it. Okay. That's great insights. Let's switch gears a little bit and talk about management for these patients. So can you walk through how your current management approach? Yeah, absolutely, well, I mean, I think the first thing to say is that our management approaches are largely trained on the electrical arrhythmias that we see, and that's because we've had some amazing leaders in this field who are, in fact, electrophysiologists, and because, as I mentioned, this is the more common presentation of symptomatic diseases to have a sustained ventricular tachycardia or symptomatic non-sustained VT, so for those arrhythmias, the first thing that we try is a beta blocker. It turns out that they are somewhat sensitive to blocking adrenaline, which is what beta blockers do, but in general, for patients that are having those non-sustained VTs, they are going to progress at some point to having a sustained ventricular tachycardia. And so, like I said, we do those risk calculators to make sure that we are understanding the risk-benefit ratio for each patient in terms of giving them a defibrillator, which is, of course, implanted and carries some risk with it. But that's, of course, to prevent sudden cardiac arrest. So that is the second sort of mainstay of therapy is to prevent sudden cardiac arrest with ICDs. And then additionally, as that disease progresses, as their VTs become longer, as they become more symptomatic, there are other antiarrhythmics that can be used. Most recently, flecainide paired with beta blockers has been shown to be relatively safe. There was some concern about that in terms of very old trials with ischemic cardiomyopathy. And then sotalol is another one that can be used, although there's some data to suggest that that's not as effective. I think in summary, what we're trying to do with ARVC patients is tamp down their arrhythmias and cross our fingers that they're not going to really progress to heart failure. Because when they progress to heart failure, we do not have good disease-modifying agents. You know, this is a disease that's a huge area of need to be able to actually reverse disease and medically stop the risk of arrhythmia and heart failure. Sure. And are some of these patients getting ablations, like surgical procedures or interventional procedures? Yeah, thanks for bringing that up. Of course, if the medical intervention of flecainide, for example, fails to control their ventricular tachycardia, these patients absolutely can go for a VT or ventricular tachycardia ablation. There are some amazingly skilled electrophysiologists around the U.S. who can provide that service to patients both from inside of the myocardium and outside. It's called an epicardial ablation. The problem is that in many of these patients, you know, the entire myocardium is affected because the entire myocardium doesn't have enough PKP2, right? So you ablate one VT and then you wait for the next one to happen, and it can turn into a game of Whac-A-Mole, right? So even ablation is not a cure. So it's a hard disease to take care of in many patients. Even that doesn't really change the underlying progression to heart failure, right? Exactly. Exactly. Yeah. All right, well, that naturally opens up the opportunity and need for novel therapies like gene therapy, so this is obviously a big topic on many people's minds. No gene therapies are currently approved specifically for cardiovascular disease, but there are several investigational gene therapies in clinical trials, and they're getting a lot of attention from clinicians. I noticed this topic all over the agenda. Both you and I have been spending some time at CVCT discussing it, highlighting the fact that there's interest to physicians and investigators, regulators, etc., and patients, so where do you think gene therapy could fit in for cardiovascular disease? And how do we move gene therapy forward? Who could be the right candidate, etc.? Yeah, these are the most critical questions that the, you know, clinical community is asking right now. I think in terms of what is the right disease for gene therapy, the first question that we ask as clinicians is, who is undertreated, right? What is the disease that we don't have any other answer for? And then also, what is the complexity of that disease? So arrhythmogenic cardiomyopathy is a great example of a disease that, number one, we don't have great options for treatment, especially in terms of progression to heart failure, as you and I just talked about. We have really bad outcomes in this disease that include things like sudden cardiac arrest. You know, and even for patients that we identify early by family screening, we can't always prevent that, right? We have to use a defibrillator to prevent it, which itself is a really, you know, it carries risk, especially when you're putting a defibrillator in a 35-year-old who's got to have wires in their body till they're 80, right? And then I think once you've talked about area of needs that ACM has huge needs, as we're discussing, you need to think about sort of which patients with that disease are the right patient to treat. And I think because we've developed so many risk scores and because we have a knowledge of how this disease progresses once it shows up, we're able actually with ACM to find the right patient and tell that patient, you know, I think that you could benefit from a potentially disease-reversing therapy. And that's a really powerful thing. So this is, I think, the right disease for this type of precision medicine. How about within ACM? Is there a sense you're getting in your mind about which patients might be the right patients? Yeah, I think so. You know, I think that as we talked about, patients present mostly with these pretty severe arrhythmias. And I can tell you from the patients that I've talked to, the first time they've had an arrest, the first time they've had a really, really symptomatic fast ventricular VT, even if they didn't lose consciousness, or the first time they've been shocked, they're telling me, "Sign me up." Because I know that this is going to happen again, right? I know I don't want it to happen again. And I also know that there's nothing that you, my physician, can do to stop the progression of heart failure when it comes. So, you know, give me something to repair the underlying defect, which is that my body's not making enough plakophilin-2. So I think that as soon as we start to see those first signs of VT, especially symptomatic, especially requiring shocks, that those are the right patients to try to jump in and reverse disease in. Great. You know, I don't think we got to capture this at all thus far, but can you talk a little bit about what you might be looking for to measure the benefit of gene therapy then, the signs and signals? Yeah, absolutely. So I think the holy grail here is, you know, as somebody who sees a lot of cardiomyopathy, to be able to prevent or reverse even progression of that fibrofatty infiltration, which we can see as an increasing size of the right ventricle, as weakness in the right ventricle. But we know that that will probably take quite a bit of time, especially if we expect to reverse disease, which we all know that replacement of cardiomyocytes is really hard to overcome just based on sort of the biology of the way they, you know, don't necessarily divide once they're differentiated, etc. I think that really what would be extremely meaningful to my patients would be to see that their heart is less electrically active over time. And so we're thinking about those things like non-sustained VT, which we know is a huge risk factor for having more VT or sudden cardiac arrest. And certainly, you know, looking at how PVCs change can be helpful too, although, as we mentioned, that's a minor criterion and not as predictive of events in the future. So that would be my hope that we would definitely see fewer of those non-sustained and sustained arrhythmias over time, and that in the long term, we would hope to see at least less progression to heart failure, if not repair of existing weakness in the right ventricle. Great. Well, thanks so much, Vicki. I think that last point really drives home the key takeaways that we, you know, we have to look at this holistically. And I think, you know, hopefully by focusing on totality disease, we can better understand patient needs and the true impact of emerging therapies like gene therapy. So, you know, thank you so much for spending some time with us this morning at CVCT. And let me hand this back over to Luke so we can take some questions from folks. Thank you, Dr. Parikh and Eric. We'd like to open the call for Q&A. Please note that while we welcome general questions about ACM and today's discussions, we cannot address any inquiries specific to our LX2020 program at this time. We look forward to sharing clinical data related to LX2020 early next year and addressing those questions at that time. Thank you. To ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. We ask that you please limit yourself to one question, one follow-up. One moment while we compile our Q&A roster. Our first question comes from the line of Gula Lifshitz with Chardan. Your line is open. Please go ahead. Good afternoon. Thanks for that really helpful overview. I guess just to better understand that NSVT and PVC component, are there thresholds with respect to levels of NSVTs and PVC that might significantly change management that you would be looking for in terms of degrees of benefit? And just in general, with respect to the efficacy that you see with the antiarrhythmic drugs and the ablation, is there additional color that you can provide on the kind of degree of benefit that those provide versus what you'd be looking for with a gene therapy approach? Thank you. Yeah, of course. So I think the first point to make is that mainly what we want to do is reduce patient symptoms. So that's always the first thing that matters to us in terms of especially PVCs. The threshold of NSVT that we're looking for, you know, it depends on how fast it is and how long it is, and then also on sort of the number of times we see it. You know, meaningful reductions in NSVT have not been modeled very well in terms of risk of needing an ICD shock or of having a sudden cardiac arrest. Usually, it's a binary variable: is there NSVT or not? That's not to say that clinically when we see, you know, a small reduction in NSVT, we're not happy. It's just that I can't give anybody, you know, meaningful changes in outcomes with like a specific threshold change in those two factors. Got it. Thank you. And one moment for our next question. Our next question comes from the line of Paul Matteis with Stifel. Your line is open. Please go ahead. Hi, this is Matthew on for Paul. Thanks for taking our question. Our question is for Dr. Parikh. Can you help us understand the natural rate of disease progression in these PKP2 patients? Do you expect electrical measures like PVC or QRS or heart function markers like LVEF to worsen within one year, within two years? And is there any specific marker that progresses faster than others in patients? Thank you. Yeah, thanks, so a couple of things there, so in terms of what we see change first in a patient population that is genotype positive, meaning that we know that they carry a PKP2 variant, but they have not yet presented with disease. These are people that are being family screened, basically. What we know is that the first change we see is in the ECG, and then we tend to see arrhythmias come up after that, but once the diagnosis has been made, in particular, someone who has positive findings on a cardiac MRI that would lead to diagnosis, as well as NSVT and the other things that we have been mentioning, I think that the progression is generally relatively rapid for us. So I would, you know, I would say that of my patients who I've seen present with a symptomatic arrhythmia, we move from medication treatment to ablation therapy relatively quickly. So likely within, you know, one to two years of seeing their first significant, you know, VT, we're going to be sending them for an ablation, if, you know, if not sooner, depending on how fast that VT was. And then we tend to see the cardiomyopathy or the heart failure aspect of this disease start to show up later than those ablations. So generally in these patients, those that I'm sending for transplant, for example, are patients that have ended up with really, really bad heart failure, you know, after having, you know, five or six different ablations who have been on medical therapy for, you know, five to ten years. So those are the type of time horizons that we see. But in general, I think it's obviously different for every patient. There are certainly patients who present with heart failure earlier, etc. Thank you. That's so helpful. Thank you. One moment for our next question. Our next question comes from the line of Brian Skorney with Baird. Your line is open. Please go ahead. Oh, great. Thanks so much for doing this call, Dr. Parikh. So I guess we're going to see a bunch of different measures in future studies of gene therapies and PKP2, both electrical and structural. And I guess my question would be, if you could just kind of discuss the inherent variability of each of these measures that you might see within a PKP2 patient, especially when you introduce a level of care that would be associated with a clinical trial. And what I'm really getting at is what sort of changes could absolutely not be a placebo effect of a clinical study, right? In oncology, we generally don't think a tumor could show a 30% decrease on a scan. You know, there's this regulatory view that a greater than 10% improvement in left ventricular mass within a year would not be seen in the absence of intervention. Is there any way to kind of think about what you can exclude as just normal variability when we see initial data from some of these therapies? Yeah, I wish that I could give you exact percentages, and it's really hard, you know, because we don't have a tumor that's growing back, right? We have a sort of stochastic arrhythmia that's going to kind of come and go as it wants. What I can comment on, I think, is sort of the relative variability of those outcomes, so in terms of PVC count that we talked about with diagnosis, that can fluctuate rapidly, like whether you're talking about ARVC or whether you're talking about a relatively healthy patient who just, you know, gets PVCs with their menstrual cycle, for example, so it's really hard to say what the sort of error bars would be around those variations. The same, of course, can be true for non-sustained VT, but again, we're really looking at, for many of our predictors, at a binary variable there. But in general, I think we're happy with any reduction that we can see as providers who are trying to treat these patients. And then when it comes to the function of the myocardium, I think that any improvement is great. I think that that's probably going to be something when you have serial measurements where the trend over time will be less variable than the arrhythmias. I might jump in, Brian, as Eric. One of the things that you can think about is, can you reduce the variability in and of itself? So in other words, patients with ARVC will have these, you know, spikes in PVCs. So the reduction in spikes or the, you know, in and of itself is something interesting and that could be quantifiable and measurable, you know, obviously over a longer period of time. But we, you know, we often see these patients have this variability, have these spikes, and the absence of that would be, you know, something to keep an eye on for sure because the accumulation of spikes is prognostic in and of itself, and there's some recent data to support that. Great. Thanks, Eric. Thanks, Dr. Parikh. Thank you. One moment for our next question. Our next question is going to come from the line of Mitchell Kapoor with H.C. Wainwright. Your line is open. Please go ahead. Hi, this is Jane on for Mitchell. Thanks for taking our calls. So could you approximate how many patients are coming to you from that family diagnosis versus a referral from a community cardiologist upon, you know, presentation of symptoms? And how severe are those symptomatic patients generally coming in by the time they've been referred to you? Yeah, great question. So it's a mixed bag, right? So I would say that in general, the majority of new referrals to us from the community are going to be those that already have disease. They usually present with a really bad arrhythmia, so like a sustained VT that was so symptomatic that they went to the ER. And they come to us like with a LifeVest and on, you know, Amiodarone or some medication that it's going to be really hard to get them off of. But because it is a really scary presentation is my point. The patients that we see with family screening are generally going to be those patients that we have recommended be screened based on one of their family members being diagnosed with disease or be referred to us by another physician who, you know, cares for ARVC or ACM patients in particular. It is, I think, an important challenge that many people in the genetic cardiomyopathy community are trying to address in terms of how to help these families understand that they need to be screened. And we've made significant progress there. I think there are specific centers where there are folks who basically live near their families, right? So I live in California. My families have like pretty broad diaspora, right? So I'm trying to find them a place to be screened that's in Ohio or something like that. But there are other places like in Boston or like in Spain where family units tend to stick together, and then you're going to see a much higher sort of percentage of family members there. So it's really going to vary by geographic location, but those are sort of the sources of referrals, if that makes sense. But so what's your particular percentage? Is it like 80% patients with symptoms when they come to you, 20% family members? And would you consider that the proportion of your patients who are coming to you symptomatic, do you think that they could be eligible for a gene therapy, or are they too far gone by the time they're seeing you? I would say that the proportion of patients who come to me who would be eligible for a gene therapy is actually quite high. So the majority of those folks who come and they've had their first sort of major arrhythmic event, like that VT that I described, those are patients who it's like time for gene therapy, right? We should try because it's not like we're at a point of disease where they're so far progressed and their right ventricle is blown out that we're not going to be able to make a difference for them simply by replacing the gene that they've lost. And then in terms of our clinic, I have to be honest with you, I don't have the exact numbers, but I would estimate that it's something like 75% folks who have been diagnosed with disease already. And then within the PKP2 truncating variant population, it's probably, frankly, even higher just because it's very specific for ARVC as an entity. All right. Thank you so much. Thank you. One moment for our next question. Our next question is going to come from the line of Tessa Romero with J.P. Morgan. Your line is open. Please go ahead. Hi, thank you for taking our question. This is Maryam on for Tessa. We are curious on, can you just quantify how many patients with PKP2 ACM do you think would be eligible for a gene therapy approach? And how are you thinking about the patient funnel who would most likely adopt a gene therapy? Thank you. Yeah, that's a great question. Again, of the patients that come to my clinic who would be eligible or I think early enough in their disease for a gene therapy approach, I will say that it's pretty high. I think it's going to be something like, you know, 70% of them. Very few patients with PKP2 truncating variants present to me at the time when like they're ready for a heart transplant, at which case it would be too late, I think, for gene therapy. And then there is, as I mentioned, a small population that's slightly too early, which would be, you know, just genotype positive at this point and phenotype negative. And then I'm sorry, the second part of your question was? How are you just thinking about the funnel that patients would most likely adopt a gene therapy? Yeah, so I think that this is a really specific type of disease where the first time that a patient presents with symptoms is often very, very, very scary and life-threatening, and so of those patients, the ones that I would recommend for gene therapy, I think the uptake and readiness among them would be very high, like 80%-90%. Thank you. And one moment for our next question. Our next question will come from the line of Leland Gershell with Oppenheimer. Your line is open. Please go ahead. Oh, great. Thanks for taking my question and thank you very much, Dr. Parikh, for this educational session. Just a question for me, which may overlap a little bit with what's been asked before, but just want to understand, you know, obviously you're at a, you know, tertiary referral center. There's many patients out there in the community who may be kind of a longer journey to getting properly diagnosed and treated. To what extent do you think that would change with the hopeful introduction of a gene therapy for PKP2 ACM? And as you yourself begin to adopt, you know, what could be an approved product down the road, you say that you'd expect most of your patients to be eligible. But would you expect the initial uptake, you know, as all physicians kind of maybe take some time to become used to using a new product, would it be used primarily in patients who are younger? Would you look to try to kind of seek the maximum amount of benefit from patients who have not progressed as far? Just want to sort of ask kind of on the cadence of your adoption as based on what we know now and then to follow up for the management team. Thank you. Of course. I think that I can speak from our recent experience both with cardiac myosin inhibitors for hypertrophic cardiomyopathy and then, of course, various therapies for cardiac amyloid, which have come out in the last few years. So number one, our referral volumes went up massively. So I think what this meant was that those community providers heard, "Oh, hey, there's actually a therapy for this patient now. Let me get this patient to someone who knows how to do it." And then I think, you know, the next step in that process is for us and for the folks who make these drugs to get out there and educate those community physicians on how to use those drugs safely. But I can tell you that for cardiomyopathies like those, which are very common, of course, it can overwhelm the system. I think with ARVC, you're kind of in a sweet spot where you can likely handle at expert centers gene therapies for all the patients that are going to be sent to you or set up expert centers pretty easily at other academic institutions. So I think that there most likely will be an uptick in what's referred to us when we start to see precision therapies for these other cardiomyopathies. And I think that there are absolutely, you know, enough resources in our system to be able to get them the therapy that they need. Right. Thank you. And then just a question for the company you've indicated will have a data update, I believe, next month. Just wondering if you could remind us the scope of what you plan to present on? Thank you. Sure. So we'll have updates on, you know, as we said, this is a trial with 10 patients. We'll have updates on eight of them and clinical and some of the clinical endpoints as well as readouts from the pathologic studies done. Great. Thanks very much. Thank you, and one moment for our next question. Our next question will come from the line of Hana Wei with Guggenheim. Your line is open. Please go ahead. Hi. Thank you for taking my question. And my question is, for evaluating the efficacy of PKP2 gene therapy, which is more important? The patient has disease manifestation primarily in the right ventricle or more dispersed disease. Thank you. Thanks. So I think that the most important thing that we know about PKP2 truncating variants is that they cause RV disease predominantly. There are certainly patients who have disease that affects both ventricles. I think that classically, because this was first sort of reported in autopsy theories, it was thought that having both ventricles involved necessarily meant worse disease. I think that what we've seen as a community is that that's certainly not, you know, evidence that this patient is going to not be repairable, right? Like not everybody that has biventricular involvement goes to transplant, for example. So what I would say is that the majority of these patients will present only with RV disease and that there is a significant proportion of patients with biventricular dysfunction who would also be able to still benefit from gene therapy. Great. Thank you. Thank you. And as a reminder to ask a question, please press star 11 on your telephone. Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald. Your line is open. Please go ahead. Hi, Dr. Parikh. Thanks for these insights. I wanted to drill down about understanding whether there's anything different. We We should be thinking about the profile of those patients that have already had sudden cardiac arrest, especially as it may not necessarily have been correlated with their disease progression, but rather activity that led to it. That's a great point. There has been a lot of data, especially early on in studying this disease, that potentially, certainly long-term high-intensity endurance athleticism, so we're talking about marathon runners, Ironman, like really, really high intensity and endurance athleticism could increase the progression of disease. However, if a patient had a sudden cardiac arrest or, you know, a prolonged and symptomatic fast VT, that patient still requires medical and potentially also ablative therapy, so even if the patient has a history of being a really serious endurance athlete, if they carry a PKP2 truncating variant and they've had an arrest, then we still treat them the same as if they hadn't been an endurance athlete prior. Okay, and on that point, though, thinking about their future progression on some of these endpoints and measurements we talked about, would you expect them to progress perhaps at a different rate versus somebody that has not had a cardiac arrest yet, or would you expect them to follow a pretty similar path? I understand. So for just looking at sudden cardiac arrest, I think that is a tipping point for these patients. And so if they've had a sudden cardiac arrest, then that tells me that pretty quickly within, you know, a short number of years, we're going to be looking at somebody who's getting multiple ablations. I think that if they're an athlete, they're an endurance athlete, I should say, and they continue to exercise at that high level despite recommendations, then there is evidence to suggest that that will increase their disease progression. But it's not clear how something like a gene therapy would affect that trajectory. The idea would be that you replace the PKP2 and that you end up now being able to be an endurance athlete without having a risk of progression. And it's just something that needs to be proven. Thank you. Thank you. I would now like to hand the conference back over to Louis Tamayo for closing remarks. Thank you, Michelle. Thanks again, Dr. Parikh, and thank you, Eric, for facilitating such a great discussion. To those that listened and asked thoughtful questions, we hope this was informative and helps to shed light on this complex disease through the eyes of expert clinicians that care for and manage these patients. As we said, we look forward to sharing more data on our LX 2020 program with you soon, and we'll share that new data from our phase one two trial at the J.P. Morgan conference in January. So for everyone, thank you for joining us today, and we hope you have a great day. Michelle, I think you can close the call there. Thank you. This concludes today's conference call. Thank you for participating, and you may now disconnect.