Okay, the voice requirements have been supported. Now, to complete the presenting, any recording may also be posted on their website. The opinions expressed by any experts speaking on this call are those of the speakers and not of Lexeo Therapeutics. After this conference call may also be reproduced to JPMorgan Research. If you have any questions, you may disconnect at this time. This call is intended for JPMorgan clients only. Other participants are not permitted on this call, and you may disconnect now unless otherwise permitted by internal JPMorgan policy. Members of JPMorgan International Group are not permitted on this call, and you may disconnect now. I would now like to turn the call over to Tessa Romero to begin. Please go ahead when you're ready. Thank you, Operator, and thanks everyone for joining us today. My name is Tess Romero, and I'm one of the senior biomedical analysts here at JPMorgan. I'm joined by Adiraj Shahan and Caroline Walker from the team. We're continuing our 2025 CEO fireside series today with Lexeo Therapeutics, and we're really pleased to be joined by CEO Nolan Townsend. Nolan, I'm going to hand it over to you for a couple of minutes here to make a couple of brief opening comments, and then we'll begin with questions. Thanks, Tess. It's great to be here and spend some time talking about Lexeo. As background for the audience, Lexeo is a clinical stage cardiac genetic medicine company. We have two clinical stage cardiovascular therapy programs, the most advanced of which is focused on the cardiac pathology of a disease called Friedreich's ataxia. Many would know this as a neurologic disease; however, the cause of death for Friedreich's ataxia patients is cardiomyopathy. This is why we're focused on this component of the disease. We've completed enrollment of a phase one study and are rapidly moving into a registrational study, which I think we'll spend some time talking about today. Interestingly, we're having an impact on both the cardiac disease but also the broader Friedreich's ataxia pathology with some interesting results in some of the neurologic scales as well. We're excited to have a treatment that addresses both the cardiac component of the disease but also some of the other aspects of the broader preexisting tachycardia disease burden. Our next most advanced program is treating arrhythmogenic cardiomyopathy, and here we're focused on the PKP2 mutation. This is a relatively large rare disease. It's more than 50,000 patients in the U.S., making it more than twice the size of the advanced muscular dystrophy or roughly the size of the treatable population of cystic fibrosis. What I'm describing is a very meaningful commercial opportunity. We've completed enrollment of our first two cohorts of patients in the study. We're quickly moving into an expansion cohort. We're also moving towards a data readout associated with this program in the second half of the year. It's going to be the year for us to excel, and I think this has all been supported by the technology and caps that have allowed us to treat the types of diseases that I've just described. I think we'll probably spend some time talking about our caps technology and how we're applying it to cardiac disease. Thank you for the time today, and we look forward to the questions and discussion. Okay, great. Just as a reminder to our listeners, please feel free to email me or anyone on my team if you have a question for Nolan, and I can mute it in as we're chatting here. We thought we would start with a bit of a big picture question before we get into some of these details on your programs, Nolan. Safety is certainly in the spotlight in the gene therapy space after a string of negative updates for the field broadly. What gives you confidence in this regard around Lexeo's construct after immune suppression regimen in adults, now also thinking about moving into some younger patients as well as into the pivotal phase two trial in FA cardiomyopathy? Specific to that, I think it's a question of front and center in gene therapy. I think I'm seeing little debate about the efficacy that gene therapies are able to achieve, but I think there is quite a bit of debate about the safety profile and therefore the risk-benefits for patients. The first thing I'd say is safety in gene therapy is entirely linked to dose. You see the more material safety against the gene therapy at the higher doses. This is probably an obvious point, but it's one that's important to note. Typically, when you approach 1E14 vector genomes per kilogram, you would typically begin to observe safety events of the type that we've seen, whether it's complement activation or liver toxicity. First and foremost, our strategy at Lexeo is to find a way to treat the diseases of interest, but do so at the lowest dose possible. As examples I give is our preexisting tachycardia program. The highest dose we're utilizing is 1.2E12 vector genomes per kilogram, which is a full two logs or 100x lower than the 1.0E14 threshold that I mentioned previously. I think this should give some comfort at the doses. There's never been substantial safety issues observed across gene therapy at that type of dose level. The reason we're able to dose at that level and still achieve protein expression that can allow us to correct the disease is because of capsid selection decisions. I would say here all capsids are not created equally. They're very different from one another. For example, the capsid AAV9 that is commonly used, it's a capsid that's utilized in the Zolgensma and the Muscular Atrophy Program. When used with either larger patients at higher doses, it has been associated with historically complement activation in these patients. This is across studies, whether you look at advanced muscular dystrophy and other studies. When you look at another clade of vectors, the clade that the vector we're utilizing comes from, we're utilizing AAVrh.10, it actually has a history of not having complement activation associated with it. Across all the patients we've treated in our studies, we've seen no instances of complement-mediated toxicity. This is at five different dose levels, more than 20 patients, and also in the other studies that utilize the same capsid. I would say that because we do not have complement activation that has been associated with our capsid, we do not need to implement immune suppression approaches to manage that complement activation. Thus, we have less immune suppression with our programs than what you may observe with others. Our preexisting tachycardia program is utilizing only prednisone. Our PKP2 arrhythmogenic cardiomyopathy program is using simply prednisone and rapamycin. Therefore, we have had no reported drug-related SAEs other than a grade 2 SAE in our FA program, and certainly nothing related to the immune suppression. I am going to end with just the broader concept of just risk-benefit in general. I think we look at the effect we are having in efficacy and, for example, our FA program. With the safety profile we are bringing forward, we think this represents a very compelling risk-benefit for patients. We're doing the same in our arrhythmogenic cardiomyopathy program, which is in a phase two stage test inclusive of all the patients' dose, including at our higher dose. We've reported no drug-related SAEs. Across all of the patients we've dosed in two studies, all we have reported is a single grade 2 SAE. I think this is a pretty compelling safety profile. We're looking at diseases of this profile with no existing treatment, and we've been able to achieve the clinical results that I think we'll discuss today. Thinking through your FA cardiomyopathy program, Nolan, what learnings do you want investors to come away with in 2025 related to this program? I think the first is we are having a very meaningful impact on the hallmarks of preexisting tachycardia cardiomyopathy. The hallmark of this disease is cardiac hypertrophy, the thickening of the heart wall. This progresses until the patient experiences heart failure and would experience mortality roughly in the third decade of life. Our data that we presented in April demonstrated, on average, we're reducing left ventricular mass, which is a biomarker we're utilizing to evaluate heart mass or hypertrophy. We demonstrated a 25% reduction in left ventricular mass. This corresponded with reductions in other important MRI markers, which is lateral wall thickness. We use lateral wall thickness by a double-digit percentage as well. We also reduced troponin by an average of 60%. Troponin is a blood type biomarker that is so sensitive that cardiologists use it to predict heart attacks. We reduced troponin by 60%. This also corresponded to improvements in the FARS scale, which is the scale used to evaluate progression of preexisting ataxia, not only the cardiac component of the disease but the neurologic component. We showed an improvement in FARS. The therapy by Skyclarys, the omaveloxolone drug, was approved on a 2.5% improvement in FARS. We are seeing a greater than 2.5 point improvement in FARS today with our therapy. We are also showing improvement in the Kansas City Cardiomyopathy Questionnaire, which is another functional scale used to evaluate cardiomyopathy. This outlines two MRI markers, one blood-based biomarker where we are having a very clinically meaningful effect. It also outlines two different functional scales, one looking at the neurologic disease, one looking at the cardiac disease, but we are showing clinically meaningful improvements, again, improvements that have supported the full approval of other therapies in this disease. I think we're seeing a very consistent effect. If you look at it via biomarkers, we're seeing a consistent effect. If you look at it via functional scales, then we just simply need to replicate these same results in a registrational study to see the therapy approved. That's what I would come away with is I think we're looking at a very de-risked clinical profile, a very compelling safety profile associated with this. Across a range of patients, we have 17 patients dosed today across the two studies, and we're excited to move forward into the registrational study that we have planned to start by the beginning of 2026. You may have alluded a little bit to this already, Nolan, but specifically, what were the key takeaways from cohort three for you? How is this data from this cohort informing how you think about what dose to move into a pivotal study? I think you have talked about the highest dose, the 1.2E12 dose being your pivotal dose. First, I'd start with safety. We've given a safety update recently. We've seen no SAEs in this cohort three. That's an important note given how we started the conversation with respect to safety. Our highest dose has no SAEs associated with it today. The second point I'd note is what we observed across several of the endpoints is a trend towards a dose response. For frataxin expression, which is one of the co-primary endpoints in our registrational study, we showed more frataxin expressed at the highest dose than at the lower two. I think it's more comfortable being able to clear the threshold on frataxin expression in the registrational study. The next point is we saw a deeper and more rapid response in left ventricular mass at the higher doses. If you look at the study plots, we saw that the patients were reaching normalization of their heart mass faster when utilizing the higher doses. I think it's an important trend to note that we have a clean safety profile, a rapid response when we've been treated with the higher doses, and we think that that's the best dose to take forward into the registrational study. I think we're well-positioned to do that also from a CMC manufacturing point of view as well. Okay. Okay. Moving ahead now, what are the key dating items between now and the start of the registrational trial? When do you expect the final alignment to take place? Kind of why not get this going sooner? Yeah. No, it's a good question. Just to recap where we are, we've reached alignment with the FDA on the accelerated approval path and the design of the registrational study. This includes the endpoints, the primary endpoints, the secondary endpoints, functional measures we'll evaluate. Also the dose, and the last component that we are working to complete is the statistical analysis plan. We're in a place where the FDA has just asked us to submit that plan to them as a written comment, if any. This does not require a meeting to reach that final alignment. That's the stage that we're at today. It's really, in our view, a process step that would allow us to reach the final alignment on the study. We'd expect to give a regulatory update on that within 2025. The vector production for the registrational study is ongoing currently, and the study contains a natural history control arm. That natural history study has already started, and it's starting roughly four to six months ahead of the treatment study. We've designed this natural history study to be larger than what's required as external control because this could potentially allow some of the patients in the natural history study to cross over into the treatment study. This is upfront investment that we're making. It really de-risked enrollment on the back end that we are even today potentially finding some of the patients that will ultimately cross over into the treatment study, allowing for rapid enrollment of that trial. We're in the process of getting the sites up and running. I think finalizing the protocol with SVP is the last step, and then we'll be moving forward. We can commit to the guidance of closing the study by the beginning of 2026. That is the timing that we're working towards. How much of a framework can you give us on how you're thinking about the statistical plan? Correct me if I'm wrong, but is the adult cohort a little bit smaller than your original expectation? I feel like we might have been pointing to something more like in the 20s, and now you're closer to like a 12-16 patient. Yeah. Yeah. Obviously, study sizes are linked to, in large part, effect size. I think when we were forecasting the numbers of the size of the study, we were doing this against data from our lower dose cohort that we were now seeing. We're seeing deeper and more rapid effect sizes at the higher doses. This allows us to power the study a bit differently. When we do that work and look at both the effect size and other factors, we landed at a 12-16 patient registrational study. Finalizing the statistical plan will allow us to have a single number that we can guide to. We also have adolescent and pediatric cohorts as part of the study. The influence for those are simply safety. We need to show that the therapy's safe in those populations, and then we'll have an opportunity to add those populations to the label as well. In totality, 12-16 adults, and then three adolescent, three pediatric, and that's the totality of the trial that we would be advancing next year. I think what's new is just the pretty dramatic and compelling effect sizes that we're observing in one of the two co-primary endpoints, which is left ventricular mass index. We have a 10% threshold. We're observing, on average, a 25% reduction in left ventricular mass. We're clearing that threshold pretty readily here, and that's embedded in the design of the registrational study. What elements of the registrational trial, in terms of the future results here, will ultimately matter most to physicians in driving a view of the overall profile? What has been the feedback that you've gotten so far from KOLs and institutions on your data, and what are the key unanswered questions that they have? Yeah. Commonly, diseases like this, and I would broaden it to other hypertrophic cardiomyopathies and even arrhythmogenic cardiomyopathies, these diseases are typically treated by heart failure specialists. These cardiologists are accustomed to treating patients who may ultimately find themselves on a transplant list, so in some cases, some very advanced and complex cardiovascular diseases. I think, on one hand, they're used to evaluating patients via cardiac MRI and looking at hypertrophy, left ventricular mass. I think they would understand that increases in left ventricular mass would imply that a patient is progressing towards heart failure, and they would understand that that needs to be managed. I think we see this across some of the other HCM programs as well. The other thing that's notable, and when cardiologists see it, they get very excited, are the results in troponin reduction. We have patients whose troponins are being reduced by up to 80%. I mean, this is unheard of, frankly, with any other therapy beyond a gene therapy. This is not something a procedure can't do. I would argue that this is something that only a gene therapy or genetic medicine can achieve, these 80% reductions in troponin. Imagine you're a cardiologist, and you use a biomarker like this to predict heart failure, and then it decreases by 80%. That's something they look at. I think that's a real effect of a therapy on a biomarker that they use every day to evaluate the progression of cardiac disease. The other one I would point to are the functional scales. On one side, you have a lot of neurologists that treat Friedreich's ataxia patients. These would typically have been the primary provider of treatment because, obviously, the patients present first with neurologic disease. The first patient to diagnose them is typically a neurologist. Neurologists are typically focused on scales like FARS to evaluate if the patient is progressing. To see the patients improving on the FARS scale really excites neurologists. I mean, while we have been talking about this as a cardiovascular therapy, the actual fact is we are actually having a broader impact on the disease than just in heart measures. I mean, as we look at the data and digify it more, that makes sense. These patients are frataxin deficient in all organs, in skeletal muscle, in dorsal ganglia, and so on. We are using a ubiquitous promoter in our frataxin construct, which means we are expressing frataxin in all organs. We're restoring protection, therefore, in dorsal ganglia, in skeletal muscle, and so on. What that means is it appears that that reduction of those other organs is resulting in some benefit on the FARS scale, and I think we're seeing neurologists that are excited about that. On the other side, the Kansas City Cardiomyopathy Questionnaire is a well-known questionnaire that evaluates quality of life measures and function in cardiomyopathies, and we're seeing improvements on KCCQ. KCCQ was part of the amyloid studies. It's been part of other hypertrophic cardiomyopathy studies, so I think cardiologists are very familiar with it. When you see a greater than 5-point improvement in KCCQ, that creates excitement about the impact that the therapy can have on improving patients' lives and how they feel and function. I would point to those, LVMI, troponin, and KCCQ from a cardiologist perspective. I would point to FARS as the endpoint functional scale that the neurologists have treated, and FDA would be most excited about. Those results are certainly very compelling on their own. Interesting. Yeah. This study has some recent survey work that our colleague, Eric Joseph, did. It seems like SKYCLARYS was used pretty ubiquitously in ambulatory adults and regularly in non-ambulatory adults. Other pharmacological options are also used, but seemingly on more of a case-by-case basis and likely according to patient symptoms. What are you hearing in the market around interest in a therapy targeted at the cardiac manifestations of the disease primarily? I know you heard from others. I think the point is, one, there is a neurologic treatment that for some patients appears to slow the progression of the disease. Many patients would understand that the cause of death in FA is cardiomyopathy. If you want to address mortality, which most patients would, the only way to do that is through cardiovascular treatment. The way I look at it is we can deliver cardiac treatment to patients. Ultimately, this will address mortality in the disease, and these patients will live long enough to see progressively improved neurologic therapies introduced to address that component of the disease. The other point I make, which is what I was stating earlier, is this is not just the cardiac therapy we're finding. I think we're finding that it is addressing comprehensively many aspects of Friedreich's ataxia. It's probably not getting into the deep cerebellum or the dentate nucleus. There are certainly some components of the disease that are mediated by that structure. For the rest, we're actually seemingly improving in FARS, again, to the degree of or even greater than what we've seen with SKYCLARYS. I think it's a perfectly viable treatment option here for patients that may say, "Do you require SKYCLARYS in combination with this treatment?" I think that that's what we're hearing, is that they want to address mortality associated with the disease. Cardiac therapy can offer that. I think the emerging data would suggest that it's doing more than just addressing the cardiac component of the disease, which I think will make the interest in treatment even greater than before. I think it expands the population we can consider and that have some form of cardiac involvement to maybe all of the patients with Friedreich's ataxia over time. I would expect, from a commercial rollout perspective, the focus on the higher-risk cardiac groups first. I think as we expand, we would begin to treat patients that are earlier in the cardiac disease continuum, and then ultimately patients that do not yet have cardiac involvement, and hopefully prevent them from progressing into the cardiac disease. I think the safety profile that is associated with the therapy today can certainly make a strong case for a broad range of FA patients being treated with this therapy. Okay. Okay. Oh, great. We actually have an email question that just came in on my topic, and it's really, "Nolan, are you conducting any work on the potential neurological impacts of LX2006 and if it penetrates into the cerebellum or dentate nucleus? I think what we will look at is transduction of, for example, skeletal muscle. We have a body of work that we're beginning to evaluate that. We believe that is playing a large part in the improvements we're also seeing on the FARS scale. That's something forthcoming that we'll be doing some work on. We also, obviously, are evaluating FARS as part of this study and as part of the future study. We think this could be a potential full equivalent point. We'll continue to evaluate that. It will be a challenge to understand transduction in the brain. Obviously, we can, in a clinical trial, take tissue samples of the heart. We can't, obviously, take tissue samples from the brain. It'll be difficult to understand the degree of transduction we are seeing in the brain. Frankly, I think the amount of AAVrh.10 that passes through the blood-brain barrier is probably pretty limited. I would say even CNS-administered therapies would have some challenge getting in sufficient amounts into the deep cerebellum or the dentate nucleus. I think the most efficient approach to address that component of the disease is probably through an intraparenchymal route of administration. There is a company that's working on that. I think that that's probably the best way to address the symptoms or pathology that are mediated by the deep cerebellum through an intraparenchymal route of administration. What I would note is it's not clear to us that if you're treated with gene therapy systemically, it would make you ineligible for treatment of an intraparenchymal therapy. I think there may be a world where intraparenchymal protection therapy is synergistic with protrusive scar growth. I think we'll have to see, and we have some non-human primate work that's designed to give us an answer to that question. Those are a few thoughts that I have. I think this therapy appears to be addressing a significant portion of the disease burden pretty comprehensively, except for the aspects that are mediated by the dentate nucleus. Probably that's where an intraparenchymal approach would be best suited. Okay. Do you think you might be able to see some of that non-primate work this year? I do not think we can commit to this year, but I think we can commit to it soon in the next, call it, 12 months or so. I think this is what will help us support future engagement with the community. Certainly, as we think about when we treat earlier populations, we want to make sure patients have all the information they need about their eligibility for future therapies after being treated with LX2006. This is work that is ongoing and work that we hope will help to elucidate the picture of the idea of sequential dosing or dual routes of administration and what it means to use different vectors and different compartments, whether it is the brain or systemically. I see a world here where many of the treatments that are being developed are actually synergistic with one another. The patients can choose the right mix of therapies that work best for them and that sustain the disease that they see today. I think this all starts with this therapy in that it should address mortality, help patients live longer, help them feel better. Again, as progressive neurologic therapies develop, we hope that they can be added on in the future. Interesting. Okay. Stay tuned. Okay. Nolan, can you talk a little bit about your level of regulatory engagement around this program? Who have you been specifically interacting with in CBER, and when is your next planned engagement? We have been working with the former OTP. This is Nicole Verdon's organization. We've seen no changes in their response rates or how they're collaborating or any of that. I think if we close our eyes and ears to the news and everything going on, actually, we have felt no differences in how they're working with us on this program, pre and post some of the transitions at the FDA. I was very encouraged earlier this morning. There was a telegene therapy session at the FDA that was very well attended by the state commissioner, Secretary Kennedy, and so on, all making very supportive statements for rare diseases, finding ways to accelerate getting treatment to patients. Same comments on flexibility that we've been hearing out of the Peter Marks-led CBER. I was very heartened to hear that, and it was consistent across all of the basic tests and FDA leadership that was in that session. I think that that's where we sit today, that there's a commitment to getting rare disease therapies to patients quickly, continuing to utilize accelerated approval pathways. I think we've seen other companies, other peer companies of ours, report the outcomes of their alignment with the FDA that have resulted in those changes versus where they were previously guiding. For us, there's no interaction necessary, no meeting necessary to complete alignment with the FDA. As I mentioned, we need to simply submit the statistical analysis plan, and it's something that would be a written communication to finalize. We do not have a subsequent meeting planned associated with this program at the current time. Our approach would be just to finalize the SAP, and we'll report when that is finalized here with the CBER CAR-T. Great. Okay. Let's move now. I want to kind of switch gears here and move over to chatting a little bit about LX2020 and PKP2 ACM. Where do you currently stand with this program? And similar question that I asked for FA cardiomyopathy, what learnings do you really think investors will be able to come away with by the end of 2025 here? Yeah. So just taking a step back, we have an ongoing phase I-II study. It's three cohorts. Cohort I is our low-dose 2E13 vector genomes per kilogram. We've enrolled three patients. Cohort II is our high-dose. This is 6E13 vector genomes per kilogram. We've enrolled three patients there. So the total of six patients treated to date. Cohort III is an expansion cohort. It's one of the two chosen doses. This is designed to be another four patients. We expect to have a total of 10 patients treated in this program within 2025. We are working towards and are guided towards a second-half readout for this program. This will include patients in cohorts I and II. We've already reported the biopsies from cohort I, so we'll be reporting the biopsies from cohort II. There will be three biopsies. We also will have all of the patients from cohort I and II beyond six months of follow-up, which means we'll have the clinical efficacy biomarkers associated with those patients also in the readout. These are such biomarkers as premature ventricular contractions, which we think is a discerned endpoint for this disease. We'll have EKG as well, QRS intervals, T-wave inversions, right ventricular function. We are also looking at some functional scales such as New York Heart Association Class and some other quality of life scales. This is a simulation of data that will be available at the end of this year or in the second half of the year. I think this will be the most robust picture of this therapeutic approach of gene therapy and arrhythmogenic cardiomyopathy today. I think there's a few key questions that this dataset may help to answer. The first question that we often get is, "What amount of PKP2 protein do you need to restore to correct this disease, to correct arrhythmogenic cardiomyopathy?" Our first patient reached 80% of normal protein at our lowest dose, and that corresponded to almost a 70% reduction in their premature ventricular contractions. Importantly, the PVCs went from about 800 down to the 200 range. The threshold for having arrhythmogenic cardiomyopathy in the first place is 500 PVCs. If you drop below 500, one could argue one of the important aspects of being diagnosed with arrhythmogenic cardiomyopathy has now been resolved. You could argue that that represented some form of normalization. The point I get to is what we do not know today is, do you need to reach 80% of normal in order to correct the disease, or do lower percentages allow for correction? What is that threshold where you begin to see this correction of the disease? Is it at 80? Is it at a lower number? And so on. I think we will have a suite of biopsies there to report. We will have the corresponding efficacy data to evaluate. We will have this across a pretty broad range of patients. I think for the rest, the cohort III patients will likely get a safety update for those other patients at that point in time as well. Do you have any further comments on how you benchmarked your expectation for what is good for the second-half update? Yeah. I think first, on the biopsy front, we expect to see a dose response. We had one patient reach 40% of normal. The patient started with a pretty low pretreatment baseline of 18% of PKP2 levels. They reached 40% of normal. The first patient reached 80% of normal. I think we'd expect to see, on average, a dose response at the higher dose. Secondarily, I think we would expect to see resolution of some of the disease burden across the endpoints that I described. We'd expect to see a response in reduction of premature ventricular contractions. We'd expect to see a response in some of the other EKG endpoints that we're evaluating. Those are the expectations that I would say we have for this cohort: a dose response from a biopsy perspective, and then seeing a resolution or reduction in some of the other endpoints that we're evaluating as part of this study. It sounds like we're coming up a little bit short of providing any kind of quantitative sort of expectation. On PVCs, you're saying? Yeah. PVCs and the other endpoints that you're following. Yeah, I think so. The challenge with PVCs, for example, is patients are starting at very different pretreatment baselines. We have some patients that have thousands of PVCs at baseline. Some patients are in the high hundreds or low thousands. It's hard to sort of triangulate to a single number for prediction. I think we'd like to see a response of PVCs to the increase of them PVC II because this would mean that the biology that appeared to be very straightforward preclinically is also translating now in the clinical setting. I think from a guidance perspective, we'd expect to see a dose response from cohorts I to II. We'd expect to see the PVCs and other endpoints respond to that risk as well. How should we be thinking about what a registrational trial would look like here in PKP2 ACM? Do you think the goal here is to kind of collect these data and meet with the agency and sort of provide a view at that time, or is there any initial thinking that you would be able to share? Maybe it's just to see more data. Yeah. I think just on maybe process, and then I'll come back to the content point. I think we'd like the data to get to a sufficient amount or stage of maturity in order to have a comprehensive discussion with the FDA. I mentioned we expect to have 10 patients treated this year. That collection of data certainly can give us a sufficient picture of what effect lines we're seeing across the endpoints and obviously can support the right conversation with the FDA. If you go in earlier with too few patients, you may come away with one impression. If you get more data, you may come away with a different one. I think we'd like to ensure we've collected a sufficient amount of data and it's reached a certain amount of stage of maturity in order to drive the best discussion with the FDA. I would guide that that's probably a 2026 event, that discussion with the FDA, given where we are with our expansion cohort and our distant patients. Coming back to the content, I think I mentioned PVCs. I think this has a lot of attributes that could be an interesting surrogate endpoint for this disease. It's projective. It's measured via Holter monitor. It corresponds to the disease itself in that PVCs are a predictor of these sudden arrhythmic events. It is a good surrogate from that perspective as well. I do think there are other endpoints there. Some of the EKG endpoints are important: right ventricular ejection fraction, RV function could be another endpoint. PVCs is not the only endpoint. We may find ourselves in a place where PVCs plus something else that we're considering. I would expect PVCs to be part of the picture either way. As we've seen with our FA program and other programs in the space, the target engagement or expression of the therapeutic protein has been important in these other diseases. I think the only unique aspect of PKP2 that may make this a little bit more challenging is these are heterozygous diseases. So these patients are presenting with meaningful amounts of PKP2 protein at baseline. They start at different points. You'll see in the data that we presented in the first quarter. While I could see PKP2 expression being part of the picture for a registrational study, I think there's a little bit of nuance to it that could be different than what we've seen in some of the other genetic cardiomyopathy that have included protein expression in their registrational studies. More to come on that. I think that's the picture that we have today, and we'll have to have the right discussion with the FDA to get to a conclusion on it. We sometimes get the question here in the PKP2 ACM studies as to how to think about segmenting this market into those that would be more likely to adopt this therapy like LX2020, right, and the unmet needs there. How do you think about that, Nolan? I honestly think the adoption of gene therapy in PKP2 ACM will be entirely related to the safety profile of the treatment. I think if there is a safe treatment where the risk-benefit makes a lot of sense, we'll see a number of patients engaging in that treatment. I think we can't remove the ultimate safety profile of the treatment from the adoption rates, right? I think that would be if the treatments have safety events associated with them, probably adoption rate's lower. If they have little or no safety events with them, then adoption rate's higher. I would note we've reported no treatment-related SAEs in our study to date. I think that's an important aspect to note. Now, if we just think aside from that fact, there are patients that experience a double-digit number of sudden arrhythmic events per year. This typically results in their ICDs firing, and this is a very traumatic experience for patients. I would expect the patients that have more instances of their ICDs firing, and those typically would be the patients with the highest number of premature ventricular contractions. Those are probably the earliest adopters. That is the highest disease burden these patients may experience. There also are many of these patients that would go on to require heart transplants. Anyone that is progressing towards finding themselves on the transplant list would probably also be patients that would be the early adopters of therapy. I think as those patients are treated and as the treatment experience broadens for gene therapy in this disease, we would expect to see patients that have fewer sudden arrhythmic events, have lower levels of PVCs, begin to consider treatment. That is how I would expect the commercial rollout to progress. The most important thing, and this is our goal in designing this treatment, is that if we want to convince 60,000 people to consider being treated with gene therapy, the therapy must be safe, right? This is not Duchenne muscular dystrophy. This is not spinal muscular atrophy. It is a very different disease. These are adult patients with ICDs. They are living with a very serious disease and a very serious disease burden. They may go on a heart transplant, but that is not immediate. I think that this therapy needs to demonstrate a compelling safety profile that has any means to uptake in this population. Our goal in finding a way to treat patients at lower doses with less immune suppression is the aim in designing the ideal treatment for this type of disease. Yeah. I mean, I think as a follow-up to this, another question that we got was around kind of the size of the safety database that you think would be needed to support an approval for either one of these candidates. Can you walk us through how you think about that? Yeah. I think it's one, it's a question that's probably on the other side of a discussion with the FDA, to be honest. But what I can say is we have now utilized AAVrh.10 across 17 patients in our pre-adjunctive practice program. I mentioned six patients here. We did intend to enroll the expansion cohort as well. So we're talking upward of 30-plus patients who've been treated with this vector for cardiac disease. I think across the two programs, there will be a number of patients for which we have experience with the vector. Interestingly, this transgene has been at very high levels in nonhuman primates. It has not shown any transgene-specific toxicity effects. So it appears that you can dose this transgene at very high levels and not see problems. I think what we're probably thinking about here is, is there any toxicity related to the capsid? Provided we're able to demonstrate that it's safe on the capsid basis, I'm not sure the transgene itself is that overly problematic. I'd also note we're using a cardiac-specific promoter, so the likelihood of off-target is very, very low. That's how I see it. I think the safety database we have from our FDA program will benefit this treatment. I think, again, with the patients we're enrolling across our phase one and then the registrational study thereafter, I would expect to have a more than sufficient safety database for the use of AAVrh.10 in this population, but also in pre-adjunctive practice as well. I'd love to close the call with a couple of quick take covering a couple of different topics here. What do you think is the next step for the LX1001 program in APOE4 homozygous for Alzheimer's disease? What is the degree of engagement around this program in regards to a potential partner? Yeah. Just the background on this, we completed a phase one two study demonstrating APOE2 expression in all of the patients treated. We also showed in the patients with moderate AD a reduction in several different TAU and also TAU biomarkers. Obviously, TAU is viewed to be a surrogate of progression of Alzheimer's disease. To see that kind of signal in that population was an encouraging sign. I think that obviously the challenge for Alzheimer's is this is a capital-intensive disease area. Even in using surrogates for potential approvals, we're still looking at meaningfully larger clinical studies than what we would be evaluating for our cardiac programs. What this leads to is you're working with a deep-octane partner who can help to explore all the different clinical avenues that the therapy could have ahead of it. We're in those discussions now. I think what attracts people to this approach is we're obviously focused on APOE4 homozygotes. The existing approaches, the amyloid antibodies, the risk-benefit does not make much sense for the APOE4s because they have substantially higher risks of ARIA, which is a brain-swelling disease that can lead to death. They also have substantially lower efficacy than the other E382s that can be treated with the amyloid antibodies. The point is that the unmet need in APOE4s remains very significant. The idea, I think, a lot of the companies that either are working in Alzheimer's or have interest in Alzheimer's is precision medicine would make a lot of sense for this population. Here we have a precision medicine that was able to see some movement in the TAU biomarker and do so without any risk for ARIA. For a company that wants to comprehensively address the Alzheimer's population, today the APOE4s are not addressed by the existing therapies. This one has the potential to do that. We are seeing engagement in this. Obviously, partnerships can take some time. We are working through that process. We would like to find the right home for it so that it is progressive because we think it is a treatment option that deserves to be explored further. That is enough that I think we will be able to provide within 2025. What is your cash runway, and how do you think about your operating expenses over the next several years? Yeah. So we last week completed an equity financing of $80 million. We additioned our existing cash of about $110 million. Extended our runway into 2028. We would expect to have the data from our pre-adjunctive practice registrational study reading out in 2027. We have a couple of quarters of runway beyond that data readout that we're capitalized against. We think some very material value-inflection points that are possible within the existing cash runway. We're managing expense against that goal, a low $20 million a quarter in burn we're expecting. That's the goal we have is to get the FA program through its registrational study, see the data readout, and then also prepare it for the BLA filing thereafter. To round out the call, can you touch a little bit on your long-term vision for the company, Nolan? Where do you really hope to see Lexeo in the next three to five years? Yeah. When we started on this journey at Lexeo, the idea of gene therapy in cardiac disease was relatively nascent. We decided to first focus on pre-adjunctive practice because what we observed was that small amounts of protecting protein were having a very material impact on the disease. We said, "This is a good place to start because at relatively low doses, you can have a big impact on this disease." Our ambitions were and are broader than that. We think for the moment that the AAV vector is the most efficient way to deliver a genetic payload to the cardiomyocyte because the elliptic nanoparticles for the moment, ASOs and so on, it's not calculated in the heart. We see a range of cardiac diseases that would benefit from gene therapy. Provided we can design treatments that are safe, we think we can have a very material impact on cardiovascular disease, allowing this increased progression of treatment into rare diseases in cardiac. I think we've seen a very successful case in the amyloid area of a treatment or a set of treatments that are meaningful commercial potential, obviously impacting patient lives very meaningfully. Amyloid is not the only cardiac disease out there that has promise commercially. I think we're currently developing at least two that have multi-billion dollar potential. We have some of the preclinical trials that have the same potential associated with them as well. I think the strategy here is to continue to advance genetic medicines for cardiac diseases, use AAV potentially over time, other delivery systems to address these cardiac diseases. I think we'll begin to see the rare precision cardiac field begin to develop beyond what we're seeing today, which is effectively only the amyloid area. I think that that's where the company is headed. I think that we have the right modality, the right toolkit, and frankly, the right team and experience set here, both with our past experience, but also the experience we're gaining even with the therapies we're developing now. How do you get a genetic medicine for cardiac disease right through the clinic, through an approval, into commercialization? The other point I'd note is many of these rare and genetic cardiac diseases are treated only by heart failure specialists. There's 3,000 heart failure specialists in the US. To the extent we're delivering a successive set of treatments into this precision population, we will have the capability to work very closely with them both on the clinical side but also on the commercial side to ensure that the broadest number of patients with complex genetic cardiac diseases can find treatment. That would be the goal over time to really own that physician segment and to really own that population of complex genetic cardiac diseases that currently, many of which are undiagnosed, underdiagnosed, or there are no treatments. Okay. Great. Nolan, I want to thank you so much for taking an hour out of your day to chat with me. This is a time for the company. Thank you. I also want to thank all the investors for taking the time to join us as well. Please reach out to me or Nolan if you have any questions. We'd be happy to follow up with you. Thanks. Thank you so much. Appreciate it. Thank you for taking the time. Take care, everyone. Thanks, everyone. This concludes today's webinar. You may now disconnect from the call.