Lexeo Therapeutics, Inc. (LXEO) Earnings Call Transcript & Summary

[Audio Gap] available to clients of JPMorgan where a company is presenting. Any recording will also be posted on their website. Views and opinions expressed by any external speakers on this call are those of the speakers and not of JPMorgan. Part of this conference call may also be reproduced in JPMorgan Research. If you have any objections, you may disconnect at this time. This call is intended for JPMorgan clients only. Participants that are not permitted on this call should disconnect now. Unless otherwise permitted by internal JPMorgan policy, members of JPMorgan Investment and Corporate Banking are not permitted on this call and should disconnect now. I would now like to turn the call over to Tess 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 biotech analysts here at JPMorgan. I'm joined by [indiscernible] and Caroline Pocher 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. So as background for the audience, Lexeo is a clinical-stage cardiac genetic medicines company. We have 2 clinical-stage cardiovascular gene 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 70% of Friedreich's ataxia patients is cardiomyopathy. So this is why we're focused on this component of the disease. We've completed enrollment of a Phase I/II 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. So 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 Friedreich's ataxia 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 60,000 patients in the U.S., making it more than twice the size of Duchenne's 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 2 cohorts of patients in the study. We're quickly moving into an expansion cohort, and we're also moving towards a data readout associated with this program in the second half of the year. So it's been a busy year for us at Lexeo, and I think this has all been supported by technology in capsid that has allowed us to treat the types of diseases that I've just described. And I think we'll probably spend some time talking about our capsid technology and how we're applying it to cardiac disease. So thank you for the time today. We look forward to the questions and the discussion.

Okay. Great. Well, just as a reminder to our listeners, please feel free to e-mail me or anyone on my team if you have a question for Nolan, and I can use it in as we're chatting here. But 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 constructs, vector, immune suppression regimen in adults, but now also thinking about moving into some younger patients as well as into the pivotal Phase II trial in FA cardiomyopathy?

Thank you for that. And obviously, it's a question that's front and center today in gene therapy. I think I'm seeing a 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-benefit for patients. The first thing I'd say is safety in gene therapy is entirely linked to dose. So you see the more material safety events in 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. So 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. And as examples I give is our Friedreich's ataxia program, the highest dose we're utilizing is 1E12 vector genomes per kilogram, which is a full 2 logs or 100x lower than the 1E14 threshold that I mentioned previously. So this is -- I think, should give some comfort at these doses, there's never been substantial safety issues observed across any gene therapy at a dose -- 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. And 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 been utilized in the Zolgensma spinal muscular atrophy program. But when used with even larger patients at higher doses, it has been associated with historically complement activation in patients. This is across studies, whether you look at Duchenne muscular dystrophy and other studies. And so when you look at another clay of vectors, the clay that the vector we're utilizing comes from, we're utilizing AAVrh10, it actually has a history of not having complement activation associated with -- across all the patients we've treated in our studies, we've seen no instances of complement-mediated toxicity. And this is at 5 different dose levels, more than 20 patients and also in the other studies that have utilized the same capsid. So I would say that because we don't have complement activation that's been associated with our capsid, we don't need to implement immune suppression approaches to manage that complement activation. And thus, we have less immune suppression with our programs than what you may observe with others. Our Friedreich's ataxia program is utilizing only prednisone. Our plakophilin-2 arrhythmogenic cardiomyopathy program is using simply prednisone or rapamycin. So therefore, we've 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 would end with just the broader concept of just risk-benefit in general. I think if we look at the effect we're having in efficacy and, for example, our FA program and with the safety profile we're bringing forward, we think this represents a very compelling risk-benefit for patients. We're seeing the same in our arrhythmogenic cardiomyopathy program. We've given a safety update that's inclusive of all the patients dosed, including at our higher dose, and we've reported no drug-related SAEs. So across all of the patients we've dosed in 2 studies, all we have reported as a single grade 2 SAE. And 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?

Yes. So I think the first is we are having a very meaningful impact on the hallmarks of Friedreich's ataxia cardiomyopathy. So the hallmark of this disease is cardiac hypertrophy or thickening of the heart wall, and this progresses until the patients typically experience heart failure and would experience mortality roughly in the third decade of life. We -- our data that we presented in April demonstrated, on average, we're reducing left ventricular mass, which is the 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 such as lateral wall thickness. We reduced lateral wall thickness by a double-digit percentage as well. We also reduced troponin by an average 60%. And troponin is a blood-based biomarker that cardiologists -- it's so sensitive that cardiologists use it to predict heart attacks. Here, we've reduced troponin by 60%. This also corresponded to improvements in the mFARS scale, which is the scale used to evaluate progression of Friedreich's ataxia, not only the cardiac component of the disease, but the neurologic component, we showed an improvement in mFARS. The therapy, the SKYCLARYS, the Reata drug was approved on a 2.5-point improvement in mFARS. We're seeing a greater than 2.5-point improvement in mFARS today with our therapy. And we're also showing improvement in the Kansas City Cardiomyopathy Questionnaire, which is another functional scale used to evaluate cardiomyopathy. So I've just outlined 2 MRI markers, 1 blood-based biomarker where we're having a very clinically meaningful effect, also outlined 2 different functional scales, one looking at the neurologic disease, one looking at the cardiac disease where we're showing clinically meaningful improvements, again, improvements that have supported the full approval of other therapies in this disease. So 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. And we just simply need to replicate these same results in a registrational study to see this therapy approved. That's what I would come away with is I think we're looking at a very derisked clinical profile, a very compelling safety profile associated with this across a range of patients. We have 17 patients dosed today across the 2 studies. We're excited to move forward into the registrational study that we have planned to start by the beginning of 2026.

And you may have -- you alluded a little bit to this already, Nolan, but specifically, what were the key takeaways from cohort 3 for you? And how is this data from this cohort informing how you think about what dose to move into a pivotal study? I think you've talked about the highest dose, the 1.2E to the 12 dose being your pivotal dose.

Yes. Yes. So first, I'd start with safety. We've given a safety update recently. We've seen no SAEs in this cohort 3. That's an important note given how we started the conversation with respect to safety. So our highest dose had 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. So for frataxin expression, which is one of the co-primary endpoints in our registrational study, we showed more frataxin express at the highest dose than at the lower 2. So I think that gives more comfort of 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. So if you look at the spaghetti clots, we saw that the patients were reaching normalization of their heart mass faster when utilizing the higher doses. So I think it's an important trend to note that we have a clean safety profile, a rapid response when being treated with the higher doses. And we think that that's the best dose to take forward into the registrational study. And I think we're well positioned to do that also from a CMC and manufacturing point of view as well.

Okay. Okay. And so moving ahead now, like what are the key gating items between now and the start of the registrational trial? And when do you expect the final alignment to take place? And kind of like why not get this going sooner?

Yes. No, it's a good question. So 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, the functional measures we'll evaluate and also -- and 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 with -- for written comments, if any. This does not require a meeting to reach that final alignment. That's the stage that we're at today. So 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 4 to 6 months ahead of the treatment study. We're -- we've designed this natural history study to be larger than what's required as an external control because this could potentially allow some of the patients in the natural history study to cross over into the treatment study. So while this is upfront investment that we're making, it really derisks 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. So we're in the process of getting the sites up and running. I think finalizing the protocol with [ FAP ] is the last step, and then we'll be moving forward. And I can -- we can commit to the guidance of starting the study by the beginning of 2026 is the timing that we're working towards.

And how much of a framework can you give us on how you're thinking about the statistical plan? And correct me if I'm wrong, but is the adult cohort a little bit smaller than your original expectations? I feel like you might have been pointing to something more like in the 20s, and now you're closer to, I think, 12 to 16 patients.

Yes. Yes. So obviously, study sizes are linked to -- in large part, to effect size. So I think when we were forecasting the numbers of the size of the study, we were doing this against data from our lower-dose cohorts. I think we're now seeing -- we're seeing deeper and more rapid effect sizes at the higher doses. So this allows us to power the study a bit differently. But when we do that work and look at both the effect size and other factors, we landed about a 12- to 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 endpoints for those are simply safety. So we need to show that the therapy is safe in those populations and then would have an opportunity to add those populations to the label as well. So in totality, 12 to 16 adults, and then 3 adolescent, 3 pediatric, and that's the totality of the trial that we'd be advancing next year. But I think what's new is just pretty dramatic and compelling effect sizes that we're observing in 1 of the 2 co-primary endpoints, which is left ventricular mass index, where we have a 10% threshold, we're observing, on average, a 25% reduction in left ventricular mass. So 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?

Yes. So 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. So I think on one hand, they are used to evaluating patients via cardiac MRI, 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. And I think we see this across some of the other HCM programs as well. I think the other thing that's notable when cardiologists see it, they get very excited are the results in troponin, troponin reduction. We have patients whose troponins are being reduced by up to 80%. I mean this is unheard of with -- frankly, with any other therapy beyond a gene therapy. This is not something -- a placebo can't do that. I would argue that this is something that only a gene therapy or genetic medicine can achieve this 80% reduction in troponin. Now imagine you're a cardiologist and you use a biomarker like that to predict heart failure, and then it decreases by 80%. I mean that's something they look at and say that's a real effect of the therapy on a biomarker that they use every day to evaluate the progression of cardiac disease. The other one I would point to is -- are the functional scales. And 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. So the first patient to diagnose them is typically a neurologist. The neurologists are typically focused on scales like mFARS to evaluate if the patient is progressing. So to see the patients improving on the mFARS scale really excites neurologists. And while we have been talking about this as a cardiovascular therapy, the actual fact is we're actually having a broader impact on the disease than just in heart measures. And actually, as we look at the data and think about it more, that makes sense. I mean these patients are frataxin-deficient in all organs, in skeletal muscle, in dorsal ganglia and so on. We're using a ubiquitous promoter in our FA construct, which means we're expressing frataxin in all organs. We're restoring frataxin, therefore, in dorsal ganglia, in skeletal muscle and so on. So what that means is it appears that that transduction of those other organs is resulting in some benefit on the mFARS 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 is part of the amyloid studies. It's been part of other hypertrophic cardiomyopathy studies. So I think cardiologists are very familiar with it. And when you see a greater than 5-point improvement in KCCQ, that creates excitement about the impact that this therapy can have on improving patients' lives and how they feel and function. So I would point to those LVMI, troponin and KCCQ from a cardiologist perspective. And I would point to mFARS as the endpoint or functional scale that the neurologists that treat FA would be most excited about, and those results are certainly very compelling on their own.

Interesting. Yes. So just pointing to some recent survey work that our colleague, Eric Joseph did, it seems like SKYCLARYS is used pretty ubiquitously in ambulatory adults and regularly in non-ambulatory adults. Other pharmacological options that are also used, but seemingly on more of a case-by-case basis and likely according to patients' symptoms? So what are you hearing in the market around interest in a therapy targeted at the cardiac manifestations of the disease primarily because I know you...

Yes. Well, I think the point is, one, there is a neurologic treatment that for some patients appears to slow the progression of the disease. So many patients would understand that the cause of death in FA is cardiomyopathy. So if they want to address mortality, which all patients would, the only way to do that is through cardiovascular treatment. And 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. But the other point I'd make, which is what I was stating earlier, is this is not just a 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 and the dentate nucleus, and there are certainly some components of the disease that are mediated by that structure. But for the rest, I mean we're actually -- we seem to be improving mFARS, again, to the degree of or even greater than what we've seen with SKYCLARYS. And so I think it's a perfectly viable treatment option here for patients that may say, do you require SKYCLARYS in combination with this treatment? So I think that that's what we're hearing is that they want to address mortality associated with the disease. This cardiac therapy can offer that. But 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 from those 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. But 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. And I think with the safety profile that is associated with the therapy today, we can certainly make a strong case for a broad range of the FA patients to be treated with this therapy.

Okay. Okay. And -- okay. Great. We actually have an e-mail question that just came in on this topic, and it's really, Nolan, are you conducting any work on the potential neurological impacts of 2006 and if it penetrates into the cerebellum or in dentate nucleus?

Well, I think the -- 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 mFARS scale. So that's something forthcoming that we'll be doing some work on. We also obviously are evaluating mFARS as part of this study and as part of the future study. We think this could be a potential full approval endpoint. So 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. So it will be difficult to understand the degree of transduction we are seeing in the brain. And frankly, I think the amount of AAVrh10 that passes through the blood-brain barrier is probably pretty limited. I would think even CNS administered therapies would have some challenge getting in sufficient amount into the deep cerebellum with the dentate nucleus. I think the most efficient approach to address that component of the disease is probably through an intraparenchymal route of administration. And there is a company that's working on that. So I think that that's probably the best way to address the symptoms or pathologies that are mediated by the deep cerebellum is through an intraparenchymal route of administration. And 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. So I think there may be a world where an intraparenchymal frataxin therapy is synergistic with our approach. I think we'll have to see, and we have some nonhuman primate work that's designed to give us an answer to that question. So those are a few thoughts that I have. I think this therapy is addressing -- appears to be addressing a significant portion of the disease burden pretty comprehensively, except for the aspects that are mediated by the dentate nucleus. And probably that's where an intraparenchymal approach would be best suited.

Okay. Do you think we might be able to see some of that nonprimate work this year?

I don't think we could commit to this year, but I think we can -- could 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. And certainly, as we think about can 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. So this is work that's 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's the brain or systemically. I see a world here where many of the treatments that are being developed are actually synergistic with one another, and patients can choose the right mix of therapies that work best for them in the stage of disease that they sit at today. But I think this all starts with this therapy in that it should address mortality, help patients live longer, help them feel better. And again, as progressive neurologic therapies develop, we hope that they can be added on in the future.

Interesting. Okay. We'll stay tuned. Okay. So 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?

Yes. So we have been working with the former OTP. This is Nicole Verdun'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 would -- 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 cell and gene therapy session at the FDA that was very well attended, the FDA Commissioner, Secretary Kennedy and so on, all making very supportive statements for treatment of rare diseases, finding ways to accelerate getting treatments to patients, same comments on flexibility that we've been hearing out of the Peter Marks-led CBER. So I was very heartened to hear this, and it was consistent across all of the HHS and FDA leadership that was in that session. So 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 no changes versus where they were previously guiding. For us, there's no interaction necessary, no meeting necessary to complete the 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 communications to finalize. So we do not have a subsequent meeting planned associated with this program at the current time. Our approach would be just to simply finalize the [ FAP ], and we'll report when that is finalized here within 2025.

Okay. 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?

Yes. So just taking a step back, we have an ongoing Phase I/II study. It's 3 cohorts. Cohort 1 is our low dose 2E13 vector genomes per kilogram. We've enrolled 3 patients. Cohort 2 is our high dose. This is 6E13 vector genomes per kilogram. We've enrolled 3 patients there. So have a total of 6 patients treated today. We -- our cohort 3 is an expansion cohort at one of the 2 chosen doses. This is designed to be another 4 patients. So we expect to have a total of 10 patients treated in this program within 2025. We are working towards and have guided towards the second half a second half readout for this program. This will include the patients from cohorts 1 and 2. We've already reported the biopsies from cohort 1. So we will be reporting the biopsies from cohort 2. So there will be 3 biopsies. We also will have all of the patients in cohort 1 and 2 beyond 6 months of follow-up, which means we'll have the clinical efficacy biomarkers associated with those patients also in the readout. And these are such biomarkers as premature ventricular contractions, which we think is a good surrogate endpoint for this disease. We'll have EKG as well, QRS interval, T-wave inversions, right ventricular function. And then we're also looking at some functional scales such as New York Heart Association class and some other quality-of-life scales. This is accumulation of data that will be available at the end of this year or in the second half of the year. And I think it will be the most robust picture of this therapeutic approach of gene therapy in arrhythmogenic cardiomyopathy to date. And 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 protein, PKP2 protein, do you need to restore to correct this disease, to correct arrhythmogenic cardiomyopathy? And 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. And importantly, the PVCs went from about 800 down to in the 200 range. The threshold for having arrhythmogenic cardiomyopathy in the first place is 500 PVC. So as you drop below 500, one could argue one of the important aspects of being diagnosed with arrhythmogenic cardiomyopathy have now been resolved. So you could argue that that represented some form of normalization. So the point I get to is what we don't know today is, do you need to reach 80% of normal in order to correct the disease? Or do lower percentages allow for correction? Or -- and what's 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? So I think we'll have a suite of biopsies there to report. We'll have the corresponding efficacy data to evaluate. We'll have this across a pretty broad range of patients. And then I think for the rest, the cohort 3 patients -- we'll likely give a safety update for those other patients at that point in time as well.

And any further comment from you on how you benchmark your expectation for what is good for the second half update?

Yes. I think first, on the biopsy front, we expect to see a dose response. So we had one patient reached 40% of normal. This patient started with a pretty low pretreatment baseline of 18% of PKP2 levels. They reached 40% abnormal. We -- the first patient reached 80% abnormal. So I think we'd expect to see, on average, a dose response at the higher dose. And 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 the reduction of premature ventricular contractions. We'd expect to see a response in some of the other EKG endpoints that we're evaluating. So those are the expectations that I would say we have for this cohort a dose response in -- from a biopsy perspective and then seeing a resolution or reduction in some of the other endpoints that we're evaluating as part of the study.

But it sounds like [indiscernible] coming up a little bit short of providing any kind of like a quantitative sort of expectation...

On PVC, you're saying?

Yes. PVCs or any of the other endpoints that you're following.

Yes, I think so. The challenge with PVC, for example, is the 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. So it's hard to sort of triangulate to a single number percent reduction. I think we'd like to see a response of PVCs to, say, increases in PKP2 because this would mean that the biology that appeared to be very straightforward preclinically is also translating now in the clinical setting. So I think from a guidance perspective, we'd expect to see a dose response from cohorts 1 to 2, and we'd expect to see the PVCs and other endpoints respond to that dose as well.

And how should we be thinking about your -- like what a registrational trial would look like here in PKP2-ACM? Do you think is the goal here 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 or maybe it's just too early to see more data?

Yes. So 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. So that collection of data certainly can give us a sufficient picture of what effect size we're seeing across endpoints and obviously can support the right conversation with the FDA. If you go in too early or with too few patients, you may come away with one impression, whereas if you get more data, you may come away with a different one. So I think we 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 in our existing patients. Coming back to the content, I think -- I mentioned PVCs. I think this has a lot of attributes that could make it an interesting surrogate endpoint for this disease. It's objective. It's measured via Holter monitor. It corresponds to the disease itself, and that PVCs are a predictor of these sudden arrhythmic events. So it is a good surrogate from that perspective as well. Now I do think there are other endpoints there. Some of the EKG endpoints are important, right ventricular ejection fraction or RV function could be another endpoint. So PVC is not the only endpoint. We may find ourselves in a place where it's PVCs plus something else that we're considering. But 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 to PKP2 that may make this a little bit more challenging is these are heterozygous disease. So these patients are presenting with meaningful amounts of PKP2 protein at baseline. They start at very different points, as you can see in the data that we presented in the first quarter. So 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 cardiomyopathies that have included protein expression in the registrational study. So 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.

And we sometimes get the question here in the PKP2-ACM space as to how to think about segmenting this market into those that would be more likely to adopt the therapy like LX2020, sorry, and the unmet needs there. So how do you think about that, Nolan?

Well, I think the -- I actually 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. So 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 is lower. If they have little or no safety events with them, then adoption rate is higher. I would note we've reported no treatment-related SAEs in our study to date. So I think that that's an important aspect to note. Now if we just think aside from that fact, there are patients that experience a number of sudden -- 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. So 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's the highest disease burden these patients may experience. There also are many of these patients that would go on to require heart transplant. So anyone that's progressing towards finding themselves on the transplant list would probably also be patients that would be early adopters of therapy. But I think as those patients are treated and as the treatment experience broadens for gene therapy in this disease, we'd expect to see patients that have fewer sudden arrhythmic events, have lower levels of PVCs begin to consider treatment. And that's how I would expect the commercial rollout to progress. But the most important thing, and we -- 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's muscular dystrophy. This is not spinal muscular atrophy. It's a very different disease. These are adult patients with ICDs. They're living with a very serious disease and a very serious disease burden. They may go on a heart transplant, but that's not immediate. And so I think that this therapy needs to demonstrate a compelling safety profile to have any meaningful uptake in this population. And 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.

Yes. And 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?

Yes. 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 AAVrh10 across 17 patients in our Friedreich's ataxia program. I mentioned 6 patients here. We intend to enroll the expansion cohort as well. So I mean we're talking upward -- 30-plus patients that have been treated with this vector for cardiac disease. So I think across the 2 programs, there will be a significant number of patients that -- for which we have experience with the vector. Interestingly, this transgene has -- even at very high levels in nonhuman primates has not shown any transgene-specific toxicity effects. So it appears that you can dose this transgene at very high levels and not see [indiscernible]. So I think what we're probably thinking about here is, is there any toxicity related to the capsid? And provided we're able to demonstrate that it's safe on a capsid basis, I'm not sure the transgene itself is that overly problematic. And I'd also note we're using a cardiac-specific promoter. So the likelihood of off-target is very, very low. So that's how I see it. I think the safety database we have from our FA program will benefit this treatment. I think, again, with the patients we're rolling across our Phase I and then the registrational study thereafter, I would expect to have a more than sufficient safety database for the use of AAVrh10 in this population, but also in Friedreich's ataxia as well.

Well, I'd love to close the call with a couple of quick hits covering a couple of different topics here. What do you think is the next step for the LX1001 program in APOE4 homozygous Alzheimer's disease? And what is the degree of engagement around this program in regards to a potential partner?

Yes. So just some background on this. We completed a Phase I/II 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 phospho-tau biomarkers. So obviously, tau is used to be a surrogate of progression of Alzheimer's disease. So 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. And 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. So what this leads to is working with a deep-pocketed partner who can help to explore all the different clinical avenues that the therapy could have ahead of it. And 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 these APOE4s because they have substantially higher risks of ARIA, which is a brain-slowing disease that can lead to death, but they also have substantially lower efficacy than the other E3 and E2s that could be treated with the amyloid antibody. So the point is that the unmet need in APOE4s remain very significant. And I think a lot of the companies that either are working in Alzheimer's or have interest in Alzheimer's is a precision medicine would make a lot of sense for this population. And here, we have a precision medicine that was able to see some movement in the tau biomarker, but do so without any risk of ARIA. So for a company that wants to comprehensively address the Alzheimer's population, today, the E4s are not addressed by the existing therapies. This one has potential to do that. So we are seeing engagement in this. Obviously, partnerships can take some time. So we're working through that process. We'd like to find the right home for it and so that it progresses because we think it is a treatment option that deserves to be explored further. So that's an update, I think, we'll 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?

Yes. So we last week completed an equity financing of $80 million in addition to our existing cash of about $110 million, extended our runway into 2028. We would expect to have the data from our Friedreich's ataxia registrational study reading out in '27. So we have a couple of quarters of runway beyond that data readout that we're capitalized against. So we think some very material value inflection points that are possible within the existing cash runway. And so we're managing expense against that goal. Low $20 million a quarter in burn, we're expecting. And that's the goal we have is to get the FA program through its registrational study to a data readout and then also prepare it for a BLA filing thereafter.

And to round out the call, can you touch a little bit on your long-term vision for the company, Nolan, and where you really hope to see Lexeo in the next 3 to 5 years plus?

Yes. When we started on this journey at Lexeo, the idea of gene therapy in cardiac disease was relatively nascent. And we decided to first focus on Friedreich's ataxia because what we observed was that small amounts of -- in preclinically, small amounts of frataxin protein were having a very material impact on the disease. So we said this is a good place to start because at relatively low doses, we can have a big impact on this disease. But 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 for the lipid nanoparticles, for the moment, ASOs and so on cannot get uptake in the heart. So we see a range of cardiac diseases that would benefit from gene therapy. And provided we can design treatments that are safe, we think they can have a very material impact on cardiovascular disease, allowing this increased progression of treatments 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 patients' lives very meaningfully. Amyloid is not the only cardiac disease out there that has promise commercially. I think we're currently developing 2 -- at least 2 that have multibillion-dollar potential. And we have some on the preclinical front that have the same potential associated with them as well. So I think the strategy here is to continue to advance genetic medicines for cardiac diseases, use AAV, and potentially over time, other delivery systems to address these cardiac diseases. And I think we'll begin to see the rare and precision cardiac field begin to develop beyond what we're seeing today, which is effectively only amyloid -- on the amyloid area. And so I think that that's where the company is headed. And 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 progress through the clinic, through an approval into commercialization. And 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 U.S. So to the extent we're delivering a successive set of treatments into this physician 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 treatments. And so that will be the goal over time to really own that physician segment and really own that population of complex genetic cardiac diseases that currently, many of which are undiagnosed, underdiagnosed or there with no treatments.

Okay. Great. Well, Nolan, I want to thank you so much for taking an hour out of your day to chat with me and a busy time for the company. And thank you. And 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. So thanks.

All right. Thank you so much. Appreciate it. Thank you for taking the time.

Take care, everyone.

Thank you, everyone. This concludes today's webinar. You may now disconnect from the call.

Thank you.