All right, let's get started. Good afternoon. I am Geulah Livshits, a biotech analyst at Chardan, and it's now my pleasure to introduce Nolan Townsend, CEO of Lexeo Therapeutics. Thanks for joining us today. Thanks for having me. Maybe to begin with, can you give us a brief overview of Lexeo and highlight catalysts for the remainder of the year? So Lexeo is a clinical-stage gene therapy company focused in genetic cardiac disease and a gene variant associated with Alzheimer's disease. We have two programs in the clinic on the cardiac side. The most advanced is treating the cardiac pathology of Friedreich's ataxia. We've read out data associated with this program this summer, which I'm sure we'll spend some time talking about. Our next most advanced cardiac program is treating arrhythmogenic cardiomyopathy, and here we're focused on the most common mutation, which is a mutation in Plakophilin 2, or PKP2. This program, we're also in the clinic. We're expecting data in the coming months. And third, on the CNS side, is our APOE4 homozygous Alzheimer's disease gene therapy program. Here we're delivering the APOE2 gene to the CNS of E4 homozygotes. This program will have a readout in the coming weeks, and you know, we'll talk more about this one as well, I think. Mm-hmm. So three programs in the clinic, all three with data in the near-term timeframe, and all three, I think, are exciting, you know, for each for their own reasons. Mm-hmm. Great. So maybe let's start with the Friedreich's ataxia program on which you reported data. Can you talk a little bit about the indication and what the unmet need looks like there before we dive in the data in more detail? Yeah. Yeah, so many would think of Friedreich's ataxia as a neurologic disease, and it very much is. It starts with gait abnormality for patients early in their life, but this typically progresses to a form of cardiomyopathy, and 70% of patients, the cause of death is this cardiac disease. So you can only improve mortality in FA by addressing the cardiac component of the disease, and this is where, you know, our therapy is focused. There is a commercially approved therapy, Skyclarys, that treats the neurologic component of the disease. I think we would envision this cardiac therapy being used concomitantly with that. The hallmark of FA cardiomyopathy is cardiac hypertrophy, so this is thickening of the heart wall. You can measure this in two ways, or via two biomarkers. One is left ventricular mass index, and the other one is wall thickness. We showed reductions in both left ventricular mass and in wall thickness via our data that was presented in July. Another way to look at the disease is via a biomarker called troponin, which is a measure of cardiac cell death. We saw about a 50% reduction in troponin across the patients that we presented. From three different biomarkers, we showed a clinical effect, and also via cardiac biopsies, we showed increases in frataxin versus all of the patients' pre-treatment baselines across two different assays. On all the biomarkers we evaluated, we saw the therapeutic effect that we were seeking. Mm-hmm. So for the LVMI, you talked about, in your data release, the high proportion of patients with elevated LVMI that at baseline had an over 10% improvement. Yeah. But the trial did include a broader range of patients. Yeah. Right. So some patients obviously didn't have that, and it makes sense on the one hand to be able to try to treat a wide population of patients who are healthy enough to benefit from the therapy. But just from a trial design and data interpretation standpoint, how do we show a clear divergence from the natural history in that setting? Yeah. So the disease, and what's being described is that, you know, eight of the 11 patients in our update had elevated left ventricular mass, and three of the 11 did not. And our strategy with the design of this study was to enroll patients that had across the wide swath of FA cardiomyopathy. And the way this disease presents is that it presents first with elevated wall thickness, and this precedes elevations in LVMI. So you could have a set of patients that are earlier in the disease continuum with elevated wall thickness, but without elevations in LVMI. So we enrolled some patients of that profile. We also enrolled patients that were more advanced in the disease, that had an elevated LVMI. We showed a 14% reduction in wall thickness. So these are the earlier patients for which we have shown a reduction in that biomarker, but we also showed an 11.4% reduction in left ventricular mass. So what this means to us is that we can credibly treat the broad swath of patients with FA cardiomyopathy. But what this then leads to is, what's the right endpoint for the pivotal study? And our view is that left ventricular mass is the most validated endpoint in its correlation to mortality in Friedreich's ataxia, and this is, you know, evidenced by natural history- Mm-hmm ... and there are some papers that support this. So we think this one is probably the most relevant for endpoint for the purposes of a pivotal study, given that correlation to mortality, and that's the direction- Mm-hmm ... that we're headed. But we will have data, and do have data, treating patients that are earlier in the disease and potentially preventing them from progressing into more advanced stages of the disease. Mm-hmm. So as we get to the other side of a pivotal study- Mm-hmm ... start to talk about label and commercial potential- Right ... we have this data that will suggest we can credibly treat, you know, most- Mm-hmm ... if not all of the patients that present with any form of FA cardiomyopathy, whether you look at it via wall thickness or via LVMI. Mm-hmm. And in terms of the magnitude of effect, that's considered meaningful for LVMI? Yeah, so there, there's a paper, it's on our website, that- Mm-hmm ... links a 10% increase in left ventricular mass to a 20% increase in mortality. So that 10% is the bar we've thought of. 10%'s also the bar that's being used in another genetic cardiomyopathy as the effect size in LVMI, so it's clearly an effect size that the FDA has viewed to be clinically meaningful. Obviously, that's a different disease, but I think the- Mm-hmm ... the two, you know, both our natural history and also that precedent sort of, you know, meet at the same point, at this 10% being the- Mm-hmm ... you know, appropriate threshold for, you know, for LVMI. Mm-hmm. And what about some of the other metrics that you talked about, the LV wall thickness, the troponin protein expression? We touched on some of this in the panel, but kind of what does a win look like for some of these other ones for this indication? Yeah, I think, you know, a greater than 30% improvement in troponin is clinically meaningful. We achieved a- Mm-hmm ... you know, 50% improvement in troponin. I, I think wall thickness is a little bit less validated. Mm-hmm ... endpoint, admittedly, and for us, it would probably be a secondary endpoint. Mm-hmm. But here we showed a 14% improvement in wall thickness, and this is across patients that are even earlier in the disease as well. Mm-hmm. If you talk to cardiologists, a lot of them would evaluate hypertrophy via wall thickness. So I think this is something that maybe is a little bit less relevant for the investment community. Mm-hmm ... maybe a little bit less relevant for the FDA, but could be very relevant for cardiologists- Mm, interesting ... who are actually treating this disease on a day-to-day basis. And so that's why we included that endpoint. That's why 14% is probably meaningful for that, the population- Mm-hmm ... of cardiologists that treat FA patients. Mm-hmm. Got it. And on the protein expression front? ... Yeah, so, we've also looked at Frataxin expression via cardiac biopsies. We're looking at two different assays. One's a mass spec assay that looks at the total amount of protein. The other one is an immunohistochemistry assay that looks at the percent of cells transduced. I think what we're seeing is, the IHC assay and the coverage of the percent of cells transduced corresponds more closely to the therapeutic benefit that we're seeing in patients. Mm-hmm. So while we're evaluating both, we're presenting both, and certainly talking about both, we think the IHC assay is the most relevant one from a forward-looking perspective into the pivotal study. Mm-hmm. Got it. And the study has a third cohort as well. Can you talk a little bit about what you hope to learn from that one? Yeah. So our third cohort, we're seeing an effect size in LVMI at 11.4%. This clears the 10% bar that- Mm-hmm ... we'd set. We're seeing an effect size in troponin of 50%. This clears the 30% bar. We're seeing an effect size in wall thickness, as I mentioned, probably less validated, but certainly 14% we think is meaningful. I think the place where we're sort of on the border of what we'd like to achieve is on frataxin expression. And so for example, in our LC-MS assay, we're sitting just below 5% of normal. Mm-hmm. We'd like to clear that bar of 5%, and on the IHC side, we'd like to ensure that every patient is sitting above, you know, 40%. Mm-hmm ... in terms of the% of cells transduced. So that dose escalation was focused purely on achieving frataxin expression that, you know, comfortably clears these thresholds that we think are clinically meaningful in this, you know, in this disease. How much information do you need from that cohort? Is this something where you'll just look at the biopsy and then make a decision on the go-forward dose, or? That's- Mm-hmm ... our approach- Mm-hmm ... is to look at the biopsies, and so this would be something that- Mm-hmm ... certainly would be within 2025. Mm-hmm. Got it. So it's not a long-term, durability type, readout that you need- We- ... for this cohort to- We do not expect that, no. Got it. And then you've started to engage with regulators, I understand, on potential surrogate endpoints and other study endpoints. What kind of color can you provide on that front? I guess you already did a little bit. Maybe expand. Yeah, so you know, what I provided earlier, I think, is the guidance we could give at this point. Mm-hmm. You know, we're focused on the endpoints that I described. Mm-hmm ... and LVMI frataxin expression, wall thickness, you know, troponin- Mm-hmm ... I think those are the ones that are in the picture. We've guided to a regulatory update on our conversations with the FDA this year. So that update- Mm-hmm ... we will provide, and I think we'll give more color, that- Mm-hmm ... the market's seeking. Yep. Great, and then just in terms of the read-across, again, that we talked about on the panel a little bit, but, you know, again, we often see read-across from Rocket Pharmaceuticals program. Anything to highlight with respect to key differences that we should keep in mind? Yeah, I think they're different diseases. Mm-hmm. I think that that's an important element. I think, you know, the Danon disease, as far as I know, these are the large, you know, most hypertrophied hearts- Right ... the largest hearts on human record. So, but FA patients will have less hypertrophy, but they will also die with less hypertrophied hearts. Mm-hmm. The fact that the hypertrophy is less does not correspond to, you know, less at need- Mm-hmm ... or less effect. And so if you see lower reductions in LVMI than what you would expect in Danon, that doesn't mean that it's not having an impact on the disease or on mortality of the disease. So I would just, you know, point out that every, you know, genetic cardiac disease, every genetic cardiac disease mediated by hypertrophy is not identical. Right. They will look different. While we may look at the same endpoint, you will expect to see the patients presenting in a different way. Mm-hmm. You will expect to see baseline criteria that looks different, and you will expect to see an effect that looks different, and yet that doesn't mean that the therapies are themselves not having a benefit. So I would just say there are differences. The commonalities are probably that some of the same endpoints are relevant. Right. but the effect sizes you would expect to see across the endpoints are definitely going to be different- Mm-hmm ... across all of these genetic cardiomyopathies. Mm-hmm. Got it. Maybe let's shift gears and talk about PKP2. Can you talk a little bit more about the rationale for that program and what elements of the preclinical package give you confidence on the clinical side? Yeah, so this is a really interesting opportunity, I think, just in general based on unmet need, but also the size of the disease. So this is arrhythmogenic cardiomyopathy. The disease is mediated by insufficient amount of plakophilin 2. This impacts the desmosomal function, so the cell-cell junction. Mm-hmm. The cells kind of move apart. They're almost like islands you could think of them as, and this is what causes- Mm ... the arrhythmias. Restoring the protein restores desmosomal function, and then has been shown in murine models to, you know, completely reverse the mortality associated with the disease and completely eliminate what's called premature ventricular contraction. So these are extra heartbeats, which are kind of the precursor to these large, sudden arrhythmic events. So in the murine models, we've been able to reduce PVCs almost to zero- Mm-hmm ... and also improve mortality across every dose cohort where we studied the, you know- Mm-hmm ... where we studied this, this therapy. So I think the preclinical studies, and this isn't only. We have one murine model that's using a CRISPR-Cas9 edited mouse. There's two other companies working on the same disease- Mm-hmm ... different murine models. They showed, you know, similar benefits. So I think, you know, biologically, the thesis is very sound. Mm-hmm. We also, at least in our studies, did not see tox even at, you know, eight times wild type. So it appears that the- Mm-hmm ... you know, efficacy to toxicity window is quite wide. So there's a lot of things that we've seen in the preclinical studies that would suggest that this is a very good target.... It's also a 60,000-patient, you know, rare disease in the US, so it's, you know, let's say, more than twice the size of Duchenne's muscular dystrophy. So everyone's very excited about, you know, what Sarepta's achieved and the commercial potential of that therapy. Here we have something that's potentially twice the size. So I think this is a very substantial opportunity, you know, based on the preclinical studies, based on the epidemiology of the disease, and based on the unmet need in which there is no existing commercially approved therapeutic for- Yeah. PKP2 ACM. And so I think this is just- Mm-hmm. You know, a pretty interesting area to focus on. And so, can you tell us about the trial design and frame expectations for the upcoming readout? Yeah. So, we are in two dose cohorts. The first is two E thirteen vector genomes per kilogram. The second is six E thirteen vector genomes per kilogram, three patients per dose. We are taking cardiac biopsies for each of the patients in the study. So, via forthcoming readouts, we'll be looking at protein expression via those cardiac biopsies. We're also collecting biomarkers that are consistent with, let's say, efficacy in the disease. So, these are biomarkers like premature ventricular contractions, you know, measured via Holter monitor and other imaging- Mm-hmm. Echo-related biomarkers. In terms of the readout, this will be up to three months. This will be both cardiac biopsies, but also the biomarkers consistent with efficacy. I would say the focus at the early days is on safety. I think this will be an important theme in this disease. We are delivering an E13 per kilogram dose, but these are adult patients. Mm-hmm. So you look at the total amount of virus. We want to ensure that, you know, we're achieving a safety profile that's compelling. And I'd also argue that if you want to convince 60,000 people to be considered with the gene therapy, which will be the most that anyone's ever- Mm-hmm ... attempted to do, you need to show that the gene therapy is safe. Right. So that is an important theme in this early readout, showing safety. We'll be looking at biodistribution via the cardiac biopsies- Mm-hmm ... and then these biomarkers consistent with efficacy. But what I'd say for those is, you know, these will be at three months, so it may be early to expect a significant improvement in PVCs or anything of that profile- Mm-hmm ... at this early time point. Mm-hmm. So I think safety and biodistribution will be the focus of. Got it ... of the upcoming readout. And the expectation is that PVCs and some of the other, additional disease metrics might evolve over time? That's the expectation. Mm-hmm. Got it. And anything else on PKP2 that you wanted to highlight before we shift entirely to Alzheimer's? No, I think just, you know, when I'm typically asked about, you know, what is the market missing in the story- Mm-hmm ... I mean, I think this is one of the key aspects of it. Mm-hmm. I realize that because it's the second program, but sitting behind FA- Mm-hmm ... FA is probably the focus, but this is a very important opportunity, both within gene therapy, but also within, you know, cardiovascular disease more generally. Mm-hmm. And so I think it should get greater focus over time. Mm-hmm. Anything to comment on regarding differentiation from the other gene therapies, or is it a, "We'll see the data when we see the data? I think, you know, each company is using a different serotype, vector. Mm-hmm. So that may- Mm-hmm ... you know, yield some differences in the expression profile and safety profile, and I think the, you know, the preclinical studies give, could give some read into some of that, but ultimately, the clinical data is what will- Mm-hmm ... determine some of these differences. Got it. All right, let's shift to Alzheimer's. So your Alzheimer's program targets APOE4 genetic forms of the disease. Over the past year, as we were talking about earlier, it seems like there are additional papers kind of highlighting the role of the APOE4 allele or isoform in the pathogenesis. So can you maybe talk about your program and help us understand what we should expect from the readout that you're- Yeah ... gonna be doing? So just as background, there's the APOE gene is a major determinant of risk or protection against developing Alzheimer's disease. Most of the population are APOE3s. APOE4s have the highest risk of developing the disease, so this is 15-20 times higher than. Mm-hmm ... than the normal or average. However, APOE2 is at the lowest risk of developing the disease. But interestingly, E2, E4 heterozygotes- Mm-hmm ... the existence of E2 removes the E4 risk, and you go back to normal. So this is the thinking behind the gene therapy program. We're using APOE2 as a therapeutic, which we believe can stop or slow many of the pathogenic processes that are believed to be associated with Alzheimer's disease. So this is the phase I study, which we've completed enrollment for. We have a data readout at the CTAD conference, that's in a couple of weeks. This data readout will be focused on both APOE2 expression relative to E4, but also some of the biomarkers that are commonly associated with Alzheimer's disease, amyloid, tau, phospho-tau, and, you know, and others. I think the ability to show that adding this E2 gene fundamentally impacts some of these biomarkers will, in a way, validate the genetic thesis of APOE with its link to Alzheimer's disease. And obviously, there's a number of therapies focused on some of these downstream- Mm-hmm ... pathogenic mechanisms, whether they're amyloid therapies that are approved, or there's, you know, a lot of companies, a lot of programs working now on tau approaches. So impacting any of these biomarkers with an upstream genetic medicine is an interesting approach because it could mean that you're impacting a broader component of the disease than what an individual pathogenic therapy could, you know, could. Mm-hmm ... could impact on its own. Mm-hmm. And so can you elaborate a little bit more on the Alzheimer's disease landscape and how you think that it might fit into that space? Yeah. So, in general today, the amyloid antibodies are one size fits all treatments. All patients, pretty much all patients with Alzheimer's disease are eligible to be treated with these therapies. But if you look at the subsets of data, you know, the different APOE variants respond differently to therapy. APOE4s did not see- Mm-hmm ... a statistically significant improvement in efficacy, and yet they had a 30%-40% risk of ARIA, which is the brain swelling disease that can lead to death. Right, right. So this is a serious side effect of these amyloid antibodies. So what that means is if you're an APOE4, you, in exchange for a 30%-40% risk of ARIA, you do not necessarily get a benefit from the therapy, which means that this, the risk benefit may not exist for APOE4s in treating with those. So in effect, they may not have a viable treatment option for the, for the disease. But what this means to us is that precision medicine is likely to play a role in the evolving Alzheimer's treatment landscape. We have one of the most advanced precision medicines focused specifically on APOE4s, designed for APOE4s, and this is the therapy- Mm-hmm ... that we're advancing, and so we think that this may be, could be a therapeutic solution, you know, for that population, even in the existence of the amyloid antibodies like Lecanemab and Donanemab that are, you know- Mm-hmm ... that are out there today. Mm-hmm. And what could the registrational path potentially look like in this space? Yeah. You know, I think the perception is that for a large disease like this- Right ... you have to run a large cognitive decline study and- Mm-hmm ... so on. But I, I think what's interesting in Alzheimer's disease is that we do have, you know, biomarkers that are correlated to the disease, and we have biomarkers correlated to the disease that the FDA has already accepted for the acceler- Mm-hmm ... accelerated approval of existing therapies. So lecanemab was accelerated approved on amyloid PET scans. So there is no reason why a gene therapy could not attempt the same approach. You know, we could look at amyloid PET scans or now tau PET scans that are commonly part of certainly the tau clinical trials that are ongoing. We've collected amyloid and tau PET scans as part of our study. So what I'm describing is a potential regulatory path based on a biomarker that the FDA has already accepted for another therapy. Right ... that may be relevant in the case of our, you know, our gene therapy. So what I would envision is that such a biomarker would be the focus of a discussion, you know, with regulators in the future, and that that would be the path by which you would see an Alzheimer's gene therapy ultimately- Mm-hmm, right ... you know, approved via an accelerated approval. Mm-hmm. And so from a strategic standpoint, obviously, you have a lot going on in the cardiomyopathy pipeline. How are you thinking about advancing this, you know, with partners? When might be the right time to do that? Yeah. We've expressed an openness to partnership, in particular for this side of our pipeline. I think the opportunity in APOE gene therapy is probably most best realized with the- Mm-hmm ... you know, deep-pocketed partner alongside us for that. In terms of timeframe, I wouldn't be able to guide to that, but I think the data update, Mm-hmm ... that's forthcoming will be- Yeah ... a good milestone, and I think some other things are likely to play out ahead of that, but I think we are open to such partnerships. Mm-hmm ... as time progresses. Where are you with manufacturing for your pipeline? Yeah. So, we have a CDMO that we're working with on a suspension process. Mm-hmm. So all of our existing and forthcoming therapies are manufactured via that process. So I think, you know, historically, it's something the gene therapy field has struggled with. We've oriented on Sf9. Mm-hmm ... cell line, which is high yielding. It has a relatively low empty capsid, you know, ratio. Yeah. We're seeing pretty compelling yields out of this. You know, yields, which we believe can deliver the commercial demand for therapies like Plakophilin-2. Mm-hmm. As I mentioned, this is an e13 per kilogram dose, times adult patients- Mm ... times 60,000 patients, so it's a pretty substantial vector demand. We believe our Sf9, you know, platform can supply the commercial demand for that. And then, you know, not to mention Alzheimer's, which obviously lower doses because it's CNS- Right ... but obviously with that, that patient population, we think our Sf9 platform again, Mm-hmm ... can both meet the yields and demand, but also do so at a cost of goods that will yield a price point that is reasonable for- Mm-hmm ... an Alzheimer's disease, you know, population. Mm-hmm. I think we're, you know, on a good path from a CMC perspective. Mm-hmm. Great. And you kind of preempted my last question, but with your answer earlier, but I'm gonna ask, what do you think investors might be missing about the Lexeo story? And it, PKP2 and beyond. Yeah, so I mentioned, you know, for PKP2, it's clear to me that as these therapies begin to read out clinical data, there will be a turn of attention to them. Mm-hmm. So it's the days- Mm ... where there is probably very little PKP2 in the valuation of our company, potentially others. And so I think that that's something the market is missing today, and that data is not too distant for- Mm-hmm ... probably for us and others. I'd also note our APOE4 homozygous Alzheimer's- Mm-hmm ... disease, therapy. This is a, you know, call it maybe $10 billion peak sales- Mm-hmm ... commercial opportunity, for which there's a gene therapy reading out data in the coming weeks. Mm-hmm. I don't think there's sufficient, you know, focus on this. Mm-hmm. I think there's a couple of things here that are forthcoming, at least for us, that are interesting, and- Mm-hmm ... and certainly should be value drivers for the company's shares. And we hope to engage with you know, yourself, others, other analysts, other investors, to discuss these opportunities as they both- Mm-hmm ... as they, as they develop. Mm-hmm. Fantastic. Very much looking forward to the data readouts, and let's all thank Nolan again for the great discussion. Thank you so much. Appreciate it.