Hello, everyone. Good afternoon, and welcome to the Jefferies Global Healthcare Conference. My name is Ella Rosenblatt, and I'm with the Jefferies Investment Banking team. It is my pleasure to introduce Nolan Townsend and Eric from Lexeo Therapeutics. All right, thank you for having us. It's great to be here and spend some time talking about the Lexeo story. So, you know, to start, Lexeo is a gene therapy company focused on genetic cardiovascular diseases. Our most advanced programs are focused in the cardiac pathology of Friedreich's ataxia and a disease called arrhythmogenic cardiomyopathy. If I take a step back, our focus in cardiac disease is really based on treating the underlying genetics that sit behind these cardiac diseases. And we believe the AAV vector is the most efficient way to deliver genetic payloads to the cardiomyocyte or to the heart. And with the use of the AAV vector, especially at the doses which we're applying it, we've been able to see very dramatic improvements in some of the cardiac symptoms and function of these diseases, but do so at doses that are safe for commercial treatment. For Friedreich's ataxia, we see patients that about 70% of the time the cause of death is cardiac disease. This is where we're focused, is that component of the disease. We've been able to show clinical data that has improved the hallmark of cardiac Friedreich's ataxia, which is hypertrophy or thickening of the heart wall. We've also reached alignment with the FDA on an accelerated approval path, and we'll be launching that registrational study by the beginning of 2026. We expect to have data reading out from that registrational study in 2027. In arrhythmogenic cardiomyopathy, we're in our ongoing phase one two study. We've completed enrollment of our first two cohorts, and we're moving into our third cohort of patients within this year. We'll also have a readout of the two cohorts of patients in the second half of 2025. Taking a step back, you know, historically, the FDA required hard endpoints like mortality or hospitalization in order to support the approval of a cardiovascular treatment. This has been evolving over the past few years, including even recently, where the FDA has been open to biomarker-based endpoints to support the approval of cardiovascular treatments. Biomarkers such as left ventricular mass index and others are now being used to support the advancement towards accelerated approvals of cardiovascular treatments. What this has allowed for is the application of therapeutics in rare cardiac or precision cardiac indications. That is where Lexeo is focused today. One of the other benefits of treating cardiac disease is you have a number of different vantage points to evaluate disease progression or regression of the disease. You can take biopsies from the heart, so you can look at tissue samples, have non-invasive imaging techniques like MRI, and so on. These are all ways which we can evaluate the therapeutic effect that our gene therapies are having in these diseases. This also opens the door to a range of endpoints that we can consider for accelerated approvals of these treatments. Focused on our pipeline, our most advanced program, as I mentioned, is treating the cardiac pathology of Friedreich's ataxia. There are about 5,000 patients that are diagnosed with Friedreich's ataxia today, of which 70% will develop cardiomyopathy within their lifetime. Typically, these patients will experience mortality by their third decade of life. Obviously, there's very high met need here. The ability to apply a cardiovascular treatment against this disease should result in a mortality benefit for these patients. Over the short term, we expect to see improvements in cardiovascular function and other functional scales that we've evaluated as part of our phase one study. For PKP2 arrhythmogenic cardiomyopathy, this is a 60,000 patient rare disease in the U.S. It is more than twice the size of Duchenne's muscular dystrophy. It is roughly the size of the treatable population of cystic fibrosis. This is a very substantial commercial opportunity, arguably one of the largest in gene therapy today. We are in an ongoing phase one two study associated with this indication. Two cohorts of patients enrolled, and we are working towards a very material data readout in the second half of this year. We have two other preclinical cardiac programs focused on other genetic cardiomyopathies that are in the pipeline today. We have an APOE for Alzheimer's pipeline, which we're working towards finding the right home from a partnership perspective going forward. Importantly, Lexeo retains global rights to all of the programs in our pipeline. Importantly, what sits behind our strategy for treating cardiovascular disease with gene therapy is the selection of the capsid that we're utilizing. We're utilizing the AAVRH10 capsid for a couple of reasons, the first of which is its cardiac tropism profile. We've seen a 1.5x-2x greater biodistribution in the heart when utilizing AAVRH10 than the other commonly used vectors. What this has allowed us to do is to transduce the heart in doses that can and therapeutically relevant doses, but do so safely given the doses are lower than what you would typically see in systemic gene therapy. I think another attribute of AVRH10 that's unique is it does not result in any complement activity or complement activation. There's no history of complement activation when use of this capsid or others in the same clade, such as AVRH74. When we think about how we do the pre-dose immune suppression regimens associated with our therapies, we need substantially less immune suppression because we don't need to manage complement, and we're also using incrementally lower doses than many other programs, which is resulting in a superior safety profile. Across the two programs we have in the clinic today, we have a total of 23 patients dosed. We've seen nothing more than a grade two SAE across those programs. I say a very materially compelling safety profile for these cardiac treatments. This is across five doses, 23 patients in two different diseases which we've evaluated this. Now switching gears here to FA, this is our lead program, and I think it's a disease that many would know as one that's struggled from a perspective of finding the right treatment. Historically, part of this challenge has been there are really two components of Friedreich's ataxia. Many would know it as a neurologic disease. It's developed in childhood. These are patients that are called at five, eight years old or so. This progresses until a form of cardiomyopathy associated with this disease emerges. It's this cardiac disease that's a cause of death for 70% of FA patients. While you can improve quality of life by addressing the neurologic component of the disease, you can really only impact mortality in Friedreich's ataxia by addressing the cardiac component of the disease. This is where we're focused today. As I mentioned, there are about 5,000 patients in the U.S. that are impacted by Friedreich's ataxia, of which 70% will ultimately die from cardiac disease or from heart failure. I just, you know, I think here it's a very tragic patient story. Ron Bartek is the founder and president of the Friedreich's Ataxia Research Alliance. It's a very well-organized patient group in support of Friedreich's ataxia. Interestingly, his son passed away from FA cardiomyopathy at the age of 24. We have a very active, very passionate patient community that sits behind this disease that's focused on treatments. I think we see a lot of passion of this community to bring a treatment forward to address the cardiac component of the disease, because many of them know that this will be the cause of death for patients, such as Ron Bartek's son, Keith, who died from cardiomyopathy at age 24. The disease biology is, I'd say, relatively straightforward. Frataxin plays a role of binding iron to sulfur, and this results when this binding occurs, this is what enables mitochondrial function. The deficiency of the frataxin gene results in an insufficient amount of the functional frataxin protein. This results in these iron-sulfur clusters forming, and this ultimately results in mitochondrial dysfunction, deficiency in energy production. This deficiency in energy production ultimately is the cause of FA cardiomyopathy. I'd also note that the two organs which are most impacted by the disease are the brain and the heart. These are the two organs that require the most energy or have the most mitochondria. These are the two that the disease is most impacted by. Our approach is simple. We're delivering a functional copy of the frataxin gene to the heart. This expresses the functional protein. By restoring frataxin in the heart, this results in mitochondrial function restoration and ultimately results in the improvement of cardiac function. The hallmark of Friedreich's ataxia cardiomyopathy is hypertrophy or thickening of the heart walls. As the disease progresses, the heart walls thicken. This heart wall thickening ultimately leads to heart failure. What we saw in the preclinical studies was actually a regression in this hypertrophy when the mice were treated with frataxin gene therapy. The hearts returned to normal in many of these myriad studies. We'll talk a little bit about the clinical data where we're seeing something similar in our ongoing clinical trial. Just quickly on the way the disease presents from an imaging perspective, I talked about hypertrophy. The way that we measure hypertrophy is an endpoint called left ventricular mass index. This is the measure of the heart's weight versus the body weight. Higher LVMI is a bad thing. It would mean that your disease is progressing. You're moving closer to heart failure. You can see a picture here of a heart with a thickened left ventricular wall. You can see how the heart would look very different from a normal heart from that perspective. A reduction in left ventricular mass index is impacting the hallmark of FA cardiac cardiomyopathy, which is cardiac hypertrophy. A key endpoint in our study is a reduction in left ventricular mass. This is one of the endpoints that we're focused on in our registrational study as well. What we have shown here is the design of our phase one two study, which is called Sunrise FA. This was a 52-week study for which we evaluated three different dose cohorts. These were adult patients where we looked at endpoints such as left ventricular mass. We looked at functional scales like Kansas City Cardiomyopathy Questionnaire and MFARS. We also looked at other imaging measures such as lateral wall thickness. We looked at troponin, which is a blood-based biomarker typically used to predict heart attacks. Here, we're looking at the ability of our therapy to reduce troponin after its application. For the pivotal study that I'll talk a little bit about in the future, we've designed a pivotal study in alignment with the FDA. Our target reduction in left ventricular mass in this pivotal study is 10%. We are achieving a 25% reduction in left ventricular mass in our phase one study. We are clearing the threshold of that endpoint pretty comfortably. The second primary endpoint in our registrational study is frataxin expression, where we need to show more frataxin post-dose than we observed pre-dose. We achieved that threshold in 100% of the patients in our phase one study. We look at this as a pretty de-risked path to an accelerated approval. We are exceeding the LVMI threshold materially, and we are exceeding the frataxin expression threshold pretty materially as well. I'd also note we have two secondary endpoints of lateral wall thickness and troponin. We're seeing clinically meaningful reductions in lateral wall thickness and troponin in our phase I study as well. As we look at this design, it's fully aligned with the FDA from an accelerated approval path perspective. This is a study that we would intend to launch by the beginning of 2026. The data that's shown here is our frataxin expression data across the three dose cohorts in our phase I study. Here you can see we achieve frataxin expression increases across all doses. You can also see the average increases by cohort. We see some signs of a dose response. We had an average increase of frataxin of 115% at the highest dose, 69% at the mid dose, and 29% at the lowest dose. You can see these trends of a dose response across the three dose cohorts. Importantly, I think this could be one of the most important slides in the presentation, the impact we're seeing on some of the key biomarkers associated with the disease. The first I would point to is left ventricular mass index. We're seeing a 25% reduction in LVMI for the patients that have reached 12 months. You can also see some signs of a dose response in left ventricular mass index. You could see, for example, one of the patients who started with a 110 baseline left ventricular mass had a reduction of 61% at the cohort two dose. A patient in the cohort one dose had a similar starting point at a 25% reduction. We're seeing a far more dramatic, deeper, and faster reduction into LVMI improvements at the higher dose than we're seeing at the lower dose. Nevertheless, the average reduction is 25%. Again, this is versus a 10% effect size required to achieve an approval of this therapy. You can see the material reductions in lateral wall thickness. You can see that these are greater effect sizes at the higher doses. I think another very exciting endpoint is troponin. You can see the reductions there are more significant at the higher doses. This is an endpoint, a biomarker used to predict heart attacks where we're seeing a regression almost down for some of these patients, almost down to zero of their troponin pathology. These are three very important endpoints. These are the key endpoints in our registrational study. We're seeing very material improvements across all of them and a 25% reduction in the LVMI endpoint across the patients in the study. These are the spaghetti plots for the same patients. You could see the trends over time. I think the important aspect to note is that the gray is the cohort one patients. You could see reductions there. You could see the cohorts two and three or the blue and the green where we see more significant reductions and more rapidly at the higher doses. The other thing I'd note is you see six patients here. These are all the patients that start with abnormal LVMI at baseline. You can see that five of the six have returned to the normal range. We have normalized their cardiac hypertrophy if you evaluate it via LVMI. We've normalized their cardiac hypertrophy so they could view themselves as having normal-sized hearts going forward. I think normalization is also an important theme beyond just the numerical effect sizes that I mentioned on the prior slide. Just the study of the design of the pivotal study is shown here. It will be a 12-month study. LVMI endpoint at 10% effect size. We'll also have adolescent and pediatric cohorts. The endpoints for the adolescent and pediatric cohorts are simply safety. We have finalized all aspects of the alignment except for the statistical analysis plan, which we have submitted to the FDA and expect to have alignment on that within this year. That's something that we're working towards. Obviously, we'll have this finalized and we'll have a regulatory update around it within 2025. Now switching gears to arrhythmogenic cardiomyopathy. The PKP2 mutation is what we're focused on. This is about 70% of the arrhythmogenic cardiomyopathy population. As I mentioned earlier, this is a 60,000-patient rare disease in the U.S. It's a very substantial commercial opportunity that we're pursuing with this program. This PKP2 ACM is also a rare genetic cardiac disease. It's mediated by different mechanisms in FA. It's an electrical conduction disorder. You have the desmosome, which disaggregates when Plakophilins is no longer present. That disaggregation of the desmosome results in life-threatening arrhythmias. One of the important endpoints that we evaluate the progression of the disease is through premature ventricular contractions. These are extra heartbeats, which is an important surrogate endpoint in evaluating disease burden and obviously regression of the disease as well. Many of these patients would experience sudden death from arrhythmic events. They typically would have ICDs implanted. We do see instances in Europe and other places of patients without ICDs that do experience true sudden death from PKP2 arrhythmogenic cardiomyopathy. It goes without saying, the unmet need here is very significant. The ability to deliver a gene therapy to treat this disease can be an important change in the treatment paradigm for this disease. Our gene therapy approach here is also relatively straightforward. We're delivering a functional copy of the PKP2 gene to the heart, to the cardiomyocytes. It expresses the PKP2 protein. Restoration of this protein results in restoration of desmosomal function. This has been seen in preclinical studies to resolve the burden of the disease, resulting in reduction in these sudden arrhythmic events, premature ventricular contractions, and improving overall cardiac function with the treatment in the preclinical setting. We have a very robust preclinical package associated with this. Everything ranging from increases in PKP2 protein, reduction in premature ventricular contractions, increased survival on the bottom left. You could see the mRNA expression across different chambers of the heart in non-human primates. We saw compelling biodistribution both in the mice and in the non-human primates. This corresponded to improved survival. You can see in the mid dose, all of the mice survived. This also corresponded to reductions in premature ventricular contractions. A very compelling preclinical package where the biology appeared to be very straightforward, increases in PKP2 in the right amounts resulted in resolution of the symptoms of the disease. That is what you can see on this slide. The question is, what do we observe? What would we observe clinically? Before I get there, I would say that this shows the, let's say, risk calculator or the endpoints that a cardiologist would use to determine if you have arrhythmogenic cardiomyopathy in the first place. The first one is arrhythmic burden, life-threatening arrhythmic events. I talked about those, T-wave inversions, and then cardiac structure and function. These are the elements of how a patient ultimately will present with PKP2 arrhythmogenic cardiomyopathy. Across our preclinical studies, we impacted all elements of the disease. We will be looking at many of these same endpoints in the clinical trial. We have some early clinical data, which I'll discuss today. Our second-half readout will have elements of many of these different endpoints in it to show a broad picture of how we're impacting the disease with gene therapy. The ongoing phase I/II study for PKP2 arrhythmogenic cardiomyopathy is shown on this slide. We fully enrolled cohorts one and two. We are launching an expansion cohort three at one of the two doses where we'll expand to another increment of patients. To date, we have six patients treated, and we have incremental patients in cohort three, which we'd intend to enroll within this year. This is also a 52-week study. We're looking at various endpoints both on a functional basis, but also important biomarkers, some of which I described on an earlier slide. What's shown here is the data from our first cohort of patients. A few points I'd like to make here. There were three patients in our first cohort. One of the patients elected not to undergo a post-treatment biopsy. We have biopsy data from two of the three patients. You could see patient one, we saw a 71% increase in their PKP2 levels. Patient two, we saw a 115% increase. Importantly, for patient one, they reached 80% of normal PKP2 protein levels. At our lowest dose, we had one patient who achieved 80% of normal protein. The other patient started at a substantially lower baseline. They got to about 40% of normal. You can also see the corresponding increases in mRNA showing that this is protein increases that are derived from the therapeutic product that was delivered. I think that these are important biodistribution data demonstrating we are seeing target engagement. Importantly, at our lowest dose, we can get to 80% of normal PKP2 levels, which we think is an important data point. Also important is the corresponding benefit in some of the important symptoms of the disease. I talked earlier about premature ventricular contractions. These are one of the hallmarks of PKP2 arrhythmogenic cardiomyopathy. The patient who reached 80% of normal protein was also the first one to reach six months of follow-up. That is a time point where we a priori decided to look at some of the clinical efficacy measures. We did evaluate that patient at that time point. We saw about a 70% reduction in premature ventricular contractions. Importantly, this patient went from 861 PVCs per day down to 284 PVCs. The threshold for being diagnosed with arrhythmogenic cardiomyopathy is 500 PVCs. We were able to take someone who has a PVC burden that is above what you would view to have this disease to one that is now below that. You could view them as being normal from a PVC perspective at the six-month time point. I think that is an important data point to demonstrate that we are beginning to see some of the preclinical data, some of the preclinical work that I described earlier translate into the clinical setting. We also saw normalization of the QRS duration in this patient. Two different independent endpoints were showing improvement. That increase of protein up to 80% resulted in improvement of two important clinical biomarkers that are likely to be the focus of future studies. I'll stop here, the last slide, our milestones for the rest of the year. We are working towards a regulatory update that I described earlier for our FA program. This will likely be focused on the statistical analysis plan for our FA cardiac study. As I mentioned, we've aligned on all other aspects. The stats plan is the final aspect of this. We'd expect to give an update within 2025 on that finalization of that statistical analysis plan and the final number of patients in the registrational study. We'd expect to initiate the registrational study in early 2026. In the arrhythmogenic cardiomyopathy program, we're working towards an important data readout across our first two cohorts of patients. There'll be a broad range of endpoints we'll be evaluating as part of that. Lastly, we're working towards partnerships for our APOE for Alzheimer's program. We'd expect to give an update on the next steps for that program and the approach for partnership within 2025 as well. We completed an equity financing last week, which in totality with our existing balance sheet prior to the financing gives us about $181 million of capital. This gives us a runway into 2028. The Friedreich's ataxia program, we're expecting to have the registrational study data readout in 2027. We have a runway of about several quarters beyond our FA data from a runway point of view. We're in pretty good shape from a capital and runway perspective to execute against our goals for both studies. Maybe I'll stop here, see if there's any questions or any questions from the audience. Okay. Thank you so much. Thanks for having me. Obviously, always exciting to talk about the Lexeo story. We're excited about the impact we're having on these diseases like Friedreich's ataxia and arrhythmogenic cardiomyopathy and excited that cardiac gene therapy can begin to show its promise in these very important diseases. Thank you for having us here today.