Good morning and welcome to the Citizens JMP Healthcare Conference that's kicking up, kicking off, right now. It's my pleasure to host Lexeo Therapeutics, Nolan Townsend, CEO, and Sandi See Tai, Chief Medical Officer or Chief Development Officer. Thank you so much for joining us today. Okay. Thank you for having us. It's a pleasure to be here. So to start, Lexeo is a company that's fundamentally focused on the introduction of precision medicine into disease areas that have seen limited or no penetration of precision medicine to date. Our core focus is the cardiovascular disease area, where we've seen fewer than 10 precision medicines approved, and several of these are treating the same disease. Now, this is very different from oncology, where you see 50%-60% of the treatments are precision medicines. But there's a reason for this difference, and the primary reason has been the regulatory landscape. The FDA has typically required cardiovascular outcome studies with hard endpoints like mortality to support the approval of cardiovascular therapies. This has confounded the development of rare disease treatments in the cardiovascular disease area. However, recently, the FDA has become more flexible with cardiovascular endpoints with an evolution from the approval of mavacamten using function, symptom, and biomarker-based endpoints. Then more recently, a gene therapy for Danon disease has reached alignment with the FDA on pivotal study endpoints that are biomarker-based. This evolution leads to a regulatory landscape that can support the introduction of rare disease medicines in the cardiovascular disease area. But fundamentally, we see an important role of the AAV vector in the cardiac disease area. At the moment, there's no better way to deliver a genetic payload to the heart than the AAV vector. ASOs, lipid nanoparticles, cannot access the cardiomyocyte. We see a unique opportunity for gene therapy in the cardiovascular disease area supported by this regulatory landscape that I described. In terms of Lexeo, as a company, and the highlights, are on the cardiovascular side, our most advanced program is treating the cardiac pathology of Friedreich's ataxia. Here we're in an ongoing phase I-II study, which we'll talk about today. Our next most advanced program, which is also in the clinic, is treating arrhythmogenic cardiomyopathy. Both programs will have data readouts within 2024. On the Alzheimer's side, we have a completed phase I, where we'll be reading out data at the CTAD conference later this year. In terms of our pipeline, as you can see on the slide, I think what's most important are the clinical data readouts within 2024, which there are three. Our FA Cardiomyopathy program will have a readout in the middle of 2024, and our PKP2 program will have a readout by the end of 2024. We'll also have a readout, as I mentioned, with the APOE4 Alzheimer's program at the CTAD conference, so three clinical data readouts this year, starting with the Friedreich's ataxia readout at mid-year. Our fundamental thesis on gene therapy in cardiovascular disease is that we can treat a range of different cardiomyopathies with the AAV vector. And as you can see shown on this slide, each of our programs addresses a different component of the cardiomyocyte. FA is a mitochondrial disease, TNNI3 is a troponin mutation, you know, and so on. So our ability to deliver therapeutically relevant doses of gene therapy to treat these conditions will give us a read-through to other diseases which we can treat with AAV gene therapy. So really, I would say that the four indications you see on the slide are really the tip of the iceberg for what we believe we can achieve in in cardiovascular gene therapy. What supports this is the capsids that we're utilizing. We've done a lot of work to understand the cardiac tropism profile of various capsids, and we found that AAVrh10 has the most compelling cardiac tropism profile of the known vectors. And here you can see this data across both minipigs and across non-human primates. You can see about a 1.5-2x greater biodistribution profile with AAVrh10 versus a commonly used vector such as AAV9. So what this allows us to do is to transduce the heart at doses that are relatively low for systemic gene therapy but still achieve protein expression that allows us to correct the disease in question. This has been demonstrated in the bottom of the slide in a disease model for arrhythmogenic cardiomyopathy, demonstrating that the functional benefit when treated with rh10 is greater than that of another commonly used vector. So switching gears here to the Friedreich's ataxia program. Just some background on the disease itself. FA is a mitochondrial disease. Deficiency of the frataxin protein is the cause of the disease. This results in mitochondrial dysfunction, deficiency in energy production. This is what yields the cardiomyopathy that's typically associated with the disease. And importantly, while this is known as a neurologic disease, up to 70% of the patients, their cause of death is a cardiovascular disease. So this is a very important component of the disease to treat. While you can address quality of life when treating the neurologic disease, you can really only impact mortality in Friedreich's ataxia by treating the cardiac component of the disease, which is the part of the disease we're focused on at Lexeo. In terms of the preclinical model sitting behind our program, there are a range of models. But I think importantly, this question of how much protein do you need to correct the disease is front and center. There is an animal model, the YG8 murine model, which is a murine model with 800 GAA repeats. These mice, with 5% of frataxin in the heart, 5% versus normal, have close to normal cardiac function and cardiac output. So this is one line of evidence suggesting you do not need a lot of frataxin to correct the disease. That potentially 5% is could be enough. Our preclinical studies were roughly consistent with this, showing this dramatic improvement in survival and cardiac output at a dose of 5.6 × 10^11, yielding a protein expression profile in that same range as well. So we have preclinical evidence supporting the concept that 5% or greater could be sufficient to correct the cardiac component of Friedreich's ataxia. This has been, this is being studied in an ongoing phase I-II study. It's a classic dose escalation study, 3 patients per dose. We are treating patients that have the symptoms of FA cardiomyopathy and that they have left ventricular hypertrophy and other cardiovascular symptoms. I mean, as part of this study, we're looking at imaging endpoints such as structure, function, hypertrophy. We're also looking at cardiopulmonary exercise testing as an endpoint, and other important endpoints that are common to any study of a cardiomyopathy. I would mention as well, there are two ongoing clinical trials, one that's company-sponsored and one that's being led at Cornell. We are evaluating the same drug product in each of these studies. In totality, across both clinical trials, we've dosed 11 patients across a range of time points. We've completed enrollment of the Cohort II and are considering escalating to Cohort III. And that will be part of our update at mid-year is a decision on dose escalation or whether the Cohort II dose is reaching an effect size that we think we can take forward into the next study. In terms of the data we've shown to date, this slide is a summary of that. For Cohort I, we've demonstrated both hypertrophy reductions in terms of a reduction in left ventricular mass index, an improvement in troponin, a 40% reduction in troponin, and then an improvement in CPET across patients that we've read out in Cohort I. Also associated with this, we've shown a biodistribution via cardiac biopsies, via LCMS and IHC. In Cohort II, we have read out data from 2 patients from a cardiac biomarker perspective with the cardiac tissue samples. Here we saw about a 79% increase in frataxin expression versus the untreated tissue sample. Our readout at mid-year will be focused primarily on some of the cardiac endpoints such as hypertrophy, troponin, CPET, and we will have an additional biopsy that will be part of this mid-year readout. In terms of the regulatory precedents sitting behind this program, I'd say there's a number of them. We've been able to demonstrate improvement in left ventricular mass index. This level of improvement has been viewed to be clinically meaningful by the FDA. We've shown an improvement in troponin, CPET, and protein expression. All of these have precedents with other gene therapy programs in prior settings. I'll switch gears here to talk about now the arrhythmogenic cardiomyopathy program for which we're now at clinical stage. So, PKP2 is a desmosomal disease, deficiency of plakophilin-2, which is this protein is the cause of the disease. This results in desmosomal disintegrity and ultimately results in arrhythmias, which are the common symptoms associated with this disease. We have several lines of evidence suggesting that with the doses we're applying, utilizing AAVrh10, we can achieve correction of the disease. You see this improvement in survival on the bottom left. On the top right, we see a reduction in premature ventricular contractions, which is an important endpoint for this disease. We also see broad biodistribution of the vector in various chambers of the heart, including the right ventricle, which is the location in which the symptoms ultimately emerge from. The important, you know, when we start a program is to think about the end here and also think about the types of endpoints that we would consider in a clinical trial or what ultimately could be part of a pivotal study. Across our preclinical studies, we have seen improvement in premature ventricular contractions, survival, QRS interval, you know, cardiac function and dilation. So across a range of different endpoints that we believe will be relevant for a future pivotal study, we've seen improvement of these in our murine models. So this would suggest an ability to take a patient who has arrhythmogenic cardiomyopathy and ultimately convert them to an individual who does not have the disease via the doses that we're applying here in the clinic. And this is being studied in an ongoing phase I-II study. There are two dose Cohorts, a 2E13 per kg dose and a 6E13 per kg dose. We're looking at it. It's a safety study, obviously, as a phase I, but we're also looking at important changes in endpoints such as premature ventricular contractions, which we think will give a read-through to an ability to correct the disease more fundamentally. We're also going to be looking at our readout this year at biopsy tissue samples, so the amount of plakophilin-2 protein that we're able to achieve at these doses. I'll end with the APOE4 Alzheimer's program and just a snapshot of the update here. So importantly, for APOE4 homozygous Alzheimer's disease, as you can see on the left, APOE4s have about 15 times higher likelihood of developing Alzheimer's disease. This is more likely than normal APOE3s, which most of us are. However, APOE2s have the lowest risk of developing the disease. But most interestingly, if you're an E2, E4 heterozygote, the existence of E2 removes the E4 risk, and you go roughly back to normal. So this is the thinking behind the program, where 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. And there remains substantial unmet need within the treatment landscape despite the introduction of the amyloid antibodies. As you can see on the right, the APOE4s do not have statistically significant improvement in efficacy, and yet they have up to 30% higher risk of ARIA, which is a serious side effect, the brain swelling disease. So the risk-benefit for an APOE4 being treated with an amyloid antibody is different than that of other genotypes in this disease, meaning there remains unmet need within the APOE4 patient population. This is being studied in an ongoing phase I-II study. We've completed enrollment of the trial, so that's patients across all four dose Cohorts. We're looking at patients that have symptoms of Alzheimer's disease, but importantly, they have biomarkers that are consistent with the disease, so abnormal amyloid beta, tau, phospho-tau, and so on. And we're looking at several things as part of this study. One is the level of expression of APOE2 we're able to achieve relative to APOE4. But also, we're looking at endpoints such as amyloid, tau, phospho-tau. The thesis behind this program is that we're going upstream, treating the genetics of the disease, which should have a downstream impact on multiple different pathogenic mechanisms simultaneously. So we'll be looking at the ability of adding APOE2, the protein, to fundamentally impact some of these biomarkers such as amyloid beta, tau, and phospho-tau. And this data, as shown on this slide, was data that we read out at the CTAD conference last year from our lowest dose Cohort. These were all of the patients that had reached 12 months at that point in time. And as you can see across the three patients, we showed a reduction in amyloid beta, tau, and phospho-tau across this Cohort. Obviously, all of the caveats with this, it's a small N and so on. It's only three patients. But I think the early results were encouraging, and we're looking forward to the readout later this year. Just to end with the catalysts that we have ahead of us, first, we have the FA cardiomyopathy data readout this year at mid-2024, the arrhythmogenic cardiomyopathy readout in the second half of 2024, and the Alzheimer's APOE4 program readout across all four dose Cohorts by the end of the year. We'll be launching IND-enabling studies for desmoplakin-mediated cardiomyopathy, which is another genetic cardiovascular disease, a highly morbid, high mortality risk, no existing therapies. So another indication which we think gene therapy can play a fundamental role in treating. In terms of our financial picture, the company has a runway into 2027 with about $195 million of cash on our balance sheet today. I'll end there and maybe take some questions. Thank you for listening and attending today. We appreciate it. Thank you. Are there any questions? If you could impact the gene for frataxin, what's the time between what you showed there or what you expect to see between when you impact it and when you could see actual physical improvements in the patient? Sandi, do you want to take that? Yeah, sure. I mean, normally with cardiac remodeling, there's generally some stages where you may see changes in the blood-based biomarkers such as troponin, and then the structural changes occur later. So but with in terms of the frataxin expression, we expect to see that actually quite early on. And we're, as you saw, some of the early biopsy data, which is the data looking at the change from baseline to three months, and we're seeing change in the protein expression. So I think the expression comes first, and then you see more of the changes in the biomarkers and then structural remodeling. Is that a year or like what when you get to someone actually or somebody can physically feel a difference in or see a difference in their body? Well, what I would say, the data which we reported last year showed two patients at six months, and both had seen about roughly a 10% improved 10 grams per square meter improvement in their left ventricular mass index, which is clinically meaningful. A 5 grams per square meter improvement in hypertension studies was a pivotal study endpoint that the FDA supported. So 10 grams, one would assume is clinically meaningful. And that was seen at six months. So I think we see the expression at three months, and then at six months would be probably the earliest time point where you would expect to see improvement in the cardiac remodeling or hypertrophy element of the disease. And the data that we've reported thus far supports that idea. That will show up in, obviously, the heart improvement, but actual physical, you know, the walk being different. Do you have to show those types of endpoints in your study? Do you want to show it? I mean, it's yet to be determined. That's what we're evaluating. It hasn't been done before in this population, but we would expect to see some changes by within a year, so months to a year that we're evaluating. Yeah, I think we're evaluating cardiopulmonary exercise testing, peak VO2, which is a measure of exercise tolerance, which is a more, you know, holistic view of how someone feels, I would say, in respect to exercise tolerance. But I don't think we necessarily need that to get to where we'd like to go from an accelerated approval perspective. So there are other regulatory precedents out there suggesting that imaging endpoints combined with protein expression are sufficient for, to support, you know, to support an approval here. Sarepta is one example. They achieved accelerated approval via protein expression alone. The Danon disease program is looking at protein expression and cardiac hypertrophy as two coprimary endpoints. So it may be that we do not need to show improvement in CPET initially to support an accelerated approval. It may be something that we can look at over a longer time frame. So I think more to come on that as we do begin to have these regulatory conversations, and we'll at some point update on sort of what are the key endpoints we'll be looking at as part of a pivotal study in the future. Could you maybe address the durability that you expect in the cardiomyocytes, you know, for the gene you know, frataxin gene expression that you deliver? And then could you maybe outline also what are kind of the treatment goals in the initial endpoints that you're trying to aim at, is deciding to going one more dose higher, or are you there yet? Like, what is that number that will be important in the summer to decide? I think, maybe the first one on durability, like, I think. Yeah, so cardiomyocytes have a relatively low degree of turnover. So we anticipate, you know, in relative terms, having, long durability of effect relative to what we'd see in terms of targeting, hepatocytes, for example, where there's greater turnover. The other question says. It was just about the. Dose escalation. Dose escalation. Yeah. Yeah. I mean, maybe. Oh, please, go ahead. So, you know, what we have is information from our preclinical models that suggest that actually relatively small increases in frataxin expression can translate to potentially clinically meaningful outcomes from a structural and functional perspective. We see from the animal models improved survival as well. So I think what we believe is that you don't have to get to wild-type levels or anywhere near normal that, in fact, relatively small increases, as shown in the YG8 mouse model that Nolan reviewed, where really getting to 5% of normal, that these animals reflected normal near-normal cardiac function. I don't know if you want to add that. In terms of the bar for dose escalating or not, I think, you know, the bar will be high. You know, I'd say we'd like to see a pretty dramatically meaningful improvement in the cardiac component of the disease in order to not dose escalate to Cohort 3. But I think we're also not reflexively dose escalating. We're going to be making that decision based on an accumulation of the data from the patients that have been treated. And as mentioned, 11 patients have been treated to date. So I think we'll have a robust data set to support that decision. I think the bar will be high. If we don't dose escalate, we will have seen something that is, you know, pretty compelling in respect to improvement in, for example, hypertrophy and other endpoints. So I think more to come on that as we, you know, read out the data here at mid-year. Okay. Well, thank you very much. We appreciate being here today. And thank you for the great questions. Appreciate it. Thank you. Thank you.