Good morning, and welcome to Lexeo Therapeutics webcast presentation of Interim Phase 1/ 2 Clinical Data of LX2006 for the treatment of Friedreich's ataxia cardiomyopathy. At this time, all participants are in a listen-only mode. Following management's prepared remarks, we will hold a question-and-answer session. To ask a question at that time, please press star one and one on your telephone. As a reminder, this call is being recorded today, Monday, July 15, 2024. I would now like to turn the conference call over to Rand Monaghan, Vice President of Finance. Rand, please go ahead. Earlier today, we released interim data from both the Lexeo SUNRISE- FA phase 1, 2 clinical trial and Weill Cornell Medicine's Phase 1a trial of AAVrh10 human frataxin, known as LX2006, Lexeo, for the treatment of Friedreich's ataxia cardiomyopathy. The press release outlining the combined interim clinical data is available on our website at lexeotx.com, and an 8-K was filed with the SEC this morning. Joining us on today's call will be Nolan Townsend, Chief Executive Officer, Dr. Eric Adler, Chief Medical Officer and Head of Research, and Dr. Sandi See Tai, Chief Development Officer. Also joining us on the line and available for Q&A is Dr. Franca Angeli, Vice President of Clinical Development in Cardiology. Before we begin, I would like to remind you that this call will contain forward-looking statements regarding Lexeo's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. With that, I would like to turn the call over to our CEO, Nolan Townsend. Nolan? Thank you, Rand, and good morning, everyone. Thank you for joining our call today to review interim results from the ongoing clinical trials evaluating LX2006 for the treatment of Friedreich's ataxia or FA cardiomyopathy. Today, we will share more about this devastating and fatal disease, including findings from the literature and natural history data, which demonstrate that cardiac measures of hypertrophy and FA are elevated, associated with poor outcomes, and do not spontaneously improve without therapeutic intervention. We will also share interim results, in particular cardiac biomarker data, showing clinically meaningful reductions in left ventricular mass index, or LVMI, where 75% of evaluable patients with elevated LVMI at baseline saw greater than 10% improvement at 12 months, as well as clinically meaningful reductions in lateral wall thickness and troponin observed across a majority of participants. To quickly remind everyone, LX2006 is the most advanced program in our cardiac pipeline, with an ongoing phase 1/2 trial underway. We have two additional clinical stage programs, LX2020, our gene therapy candidate for the treatment of PKP2 arrhythmogenic cardiomyopathy, and LX1001, our gene therapy candidate for the treatment of APOE4-associated Alzheimer's disease, both in phase 1/2 studies. Importantly, we retain global rights to all programs in our pipeline. Before we jump into the results, I would like to spend a few minutes highlighting our vision of transforming the treatment landscape for genetic cardiomyopathies. As reflected on the prior slide, we have a deep pipeline of gene therapy candidates with compelling preclinical data in devastating diseases with high unmet need, and our candidates have the potential to directly target underlying genetic mechanisms of these diseases. With current technology, we believe that AAV vectors are the most efficient way to deliver genetic material to the heart, and that AAVrh10, the vector we are using, due to its ability to enable transduction of the heart at lower doses, offers one of the most compelling cardiac tropism profiles of vectors currently being utilized in the clinic. But taking a step back and looking at the broader environment, we wanted to highlight a few potential tailwinds supporting our excitement about the opportunity within genetic cardiovascular medicine. The first is increased genetic screening, which we believe will help expand awareness of genetic drivers of disease and facilitate diagnosis across genetic cardiomyopathies due to familial screening. The second is increased level of regulatory flexibility that we've seen over the last few years. First, observed with the approval of mavacamten, based on a combination of endpoints, including functional measures, symptoms, and biomarkers, in which we continue to observe with recent FDA accelerated approvals and guidance on pivotal study designs. Finally, we've seen promising developments within cardiac precision medicine, and we believe there is a significant potential for this field to develop in the same way that precision medicine has advanced and become the standard of care for oncology treatments over the past decade or so. With that, I'm pleased to share some of the scientific advancement coming out of Lexeo Therapeutics today. I'll now hand the presentation over to Dr. Eric Adler to walk through some background on Friedreich's ataxia and how LX2006 is designed to address cardiomyopathy, the leading cause of death in this disease. Thank you, Nolan. Before we begin, I'd like to thank the FA community, especially the Friedreich's Ataxia Research Alliance, for their partnership and ongoing collaboration. It's critically important to us to make sure the voice of those living with FA and those caring for and supporting individuals with FA is incorporated into each step of our development process. We sincerely appreciate their partnership to date, and we look forward to ongoing collaboration as we continue to advance our research. ... Starting with an overview. Friedreich's ataxia is a devastating, rare, and progressive disorder caused by loss-of-function mutations in the frataxin gene. The vast majority of patients with FA have expanded guanine adenine adenine, or GAA, trinucleotide repeats in intron one of both alleles of the frataxin gene. This condition impacts approximately 5,000 people in the United States. While the disease is well known as an inherited form of ataxia, a neurologic condition, it's important to note that around 60%-80% of impacted individuals ultimately die from cardiomyopathy associated with the disease. Cardiomyopathy in FA is typically characterized by thickening of the left ventricular wall, which evolves to concentric hypertrophy in later stages of disease and ultimately progresses to heart failure and death. Treatment options for FA cardiomyopathy are extremely limited. Medical therapy has not been shown to be effective, and cardiac transplantation is rarely an option, given the comorbidities associated with the disease. Currently, omaveloxolone is the only FDA-approved disease-specific treatment for Friedreich's ataxia, and while this small molecule has demonstrated efficacy on neurological measures, it was not evaluated for the treatment of cardiac dysfunction. Without a treatment specifically designed to address FA cardiomyopathy or to impact the root cause of disease, significant unmet need remains for those with cardiac complications, which again, sadly, are the cause of death for most people with FA. Individuals with FA have GAA repeats in the frataxin gene, as I mentioned, which subsequently leads to a decrease in expression of the frataxin protein. This lack of protein leads to the failure of iron sulfur clusters formation primarily in mitochondria. Iron-sulfur clusters are critical cofactors for numerous mitochondrial reactions, so this decrease in iron-sulfur results in impaired mitochondrial function in the heart, and it is thought to lead to cardiomyocyte dysfunction, hypertrophy, and cell death. Here, we provide an overview of the LX2006 construct. In terms of mechanism, our hypothesis is rather straightforward, in that restoring frataxin may enable the formation of iron-sulfur clusters with the potential to improve mitochondrial function and therefore cardiomyocyte function as well. With LX2006, a full-length frataxin gene is delivered systemically to the heart, where expression is regulated by a CAG promoter, a strong, clinically validated, ubiquitously expressed promoter. Importantly, this is all packaged within an AAVrh10 vector, which we believe is an improved capsid for transduction in the heart. We've done substantial preclinical studies as part of our foundational work and have shown that AAVrh10 is approximately 1.5-2 times more effective at transducing cardiomyocytes in large animal studies performed in both pigs and non-human primates. Based on this research, we believe the cardiac tropism of AAVrh10 may allow us to achieve targeted transduction with a lower dose of vector, hopefully limiting safety concerns while producing clinical benefit. An early finding in the SUNRISE-FA trial that we reported in March of this year is that the participants that have undergone cardiac biopsies have extremely low amounts of frataxin in the heart at baseline prior to receiving LX2006, specifically 2% or less of normal. This requires us to ask the important question: How much frataxin in the heart is needed to improve cardiac function in individuals with FA cardiomyopathy? There's not sufficient research yet to produce a definitive answer, but our hypothesis is that modest amounts of frataxin can produce clinical benefit, given the catalytic and enzymatic-like role of the protein. This hypothesis is partially based on the recently developed YG8-800 murine model, in which mice with approximately 5% of normal frataxin have near normal cardiac output and stroke volume. As such, we believe a modest amount of frataxin restoration may be sufficient to restore cardiac function or translate to clinical benefit in FA. Looking at other diseases and potential analogs, we again see some evidence to support this hypothesis. In hemophilia, factor levels of just 5% of normal can still significantly reduce bleeding and improve coagulation, and in muscular dystrophies, expression at 10%-40% of normal dystrophin results in a significantly milder phenotype of disease. To summarize, we believe preclinical models and analogs from other diseases suggest that small increases in frataxin levels may be sufficient to produce clinical benefit. As mentioned earlier, FA cardiomyopathy is often characterized by concentric hypertrophy, indicated by both increased left ventricular wall thickness and increased left ventricular mass index, or LVMI. Importantly, the link between LVMI and clinical outcomes in other cardiomyopathies has been well established, as noted on the right of the slide here. In heart failure with preserved ejection fraction, elevated LVMI has been correlated with cardiovascular death and heart failure hospitalization, and in Fabry disease, elevated LVMI has been related to a composite of cardiovascular endpoints, including hospitalization and all-cause mortality. Additionally, in research in obstructive hypertrophic cardiomyopathy, a reduction in LVMI has been associated with increased exercise tolerance and quality of life. We would also note that increasing wall thickness in the cardiac biomarker, high-sensitivity troponin I, appear to precede increases in LVMI as individuals advance towards a more hypertrophic phenotype. These changes in wall thickness are an early signal of changing geometry in the heart and something we are evaluating in the context of the ongoing clinical trials of LX2006. Of note, changes in wall thickness have also been associated with poor outcomes in hypertrophic cardiomyopathy and FA, which I'll speak to now. Looking at outcomes in FA specifically, it is well established that cardiac complications are the leading cause of death. As you can see on the left side of the slide here, hypertrophy is evident via the thickening of the heart walls in this cardiac MRI. Published literature tells us that increases in LVMI are associated with increased risk of death in individuals with FA, and that every 10% increase in LVMI was associated with a 19% higher risk of death. Importantly, increased wall thickness has also been observed to be associated with mortality. As such, we believe improvements or reduction in LVMI and left ventricular wall thickness may lead to clinically meaningful improvements in cardiac outcomes in those with FA cardiomyopathy. Now, on the left, we are presenting a new natural history subset analysis we performed using unpublished data from the Children's Hospital of Philadelphia from individuals with FA. This dataset includes echocardiography findings, and here we are showing results specifically for adults 18 to 15 years of age with FA cardiomyopathy, as defined by abnormal measures of hypertrophy. Looking at LVMI, the dotted line represents the mean, and the shaded area represents a 95% confidence band. You can see LVMI is elevated in this population at the high end of normal and increasing to abnormal with participant age. Importantly, we do not observe spontaneous improvements in LVMI, and it appears the measure is stable to slightly increasing with age. Now, looking at left ventricular wall thickness, in this case, posterior wall thickness, we know this measure is an early indicator of hypertrophy. Adults with FA cardiomyopathy are consistently abnormal on this measure, as you can see in this graph. And again, you see the pattern of stable to slightly increased abnormal wall thickness with age. Importantly, the degree of change over time for both these measures is likely underestimated in this dataset due to survival bias. Specifically, that individuals in this dataset with severe cardiomyopathy are sadly more likely to die earlier in life, so the cohort over time likely consists of individuals with less severe cardiac disease. Now on the right, we are highlighting data from 3 randomized controlled clinical trials that measure LVMI or LV mass in the placebo or control arms. In the absence of any therapeutic intervention, you can see that these measures do not meaningfully change over the course of 7-18 months, consistent with what we see in the natural history data for FA cardiomyopathy. We believe this supports the conclusion that a decrease in LVMI within a cardiac gene therapy trial is likely due to therapeutic impact of the investigational drug. Switching now to blood-based biomarkers. Troponin I is a well-validated biomarker commonly used to detect and monitor myocardial injury. A recent study in FA has shown that a relationship between troponin I levels and measures of wall thickness. Importantly, increased troponin I levels were predictive of increased wall thickness and independently associated with worse outcomes in FA, further validating this non-invasive measurement. I will now pass the presentation to Dr. Sandi See-Tai, Lexeo's Chief Development Officer, to discuss LX2006 and the interim results to date. Thanks, Eric. I'd like to remind our audience about the recent license agreement between Lexeo Therapeutics and Cornell University, in which Lexeo licensed IP, including current and future data from the ongoing Weill Cornell Investigator-Initiated Trial of LX2006 in individuals with FA cardiomyopathy. Following this license agreement, we are able to share results today from both the Lexeo SUNRISE-FA phase I/II trial, as well as the Weill Cornell Medicine trial, given both trials use the same drug product and share very similar study designs and objectives. In April, we shared that 11 participants had been dosed, with 8 participants having at least 6 months of follow-up. We are happy to share that as of today, 13 participants have been dosed. However, 2 were recently dosed, so we will be sharing baseline characteristics today on 11 participants for which data are available. Before we share any data, I think it's critical to note that these two trials are very similar, and they are in fact using the same drug product at the same dose levels in cohorts 1 and 2. Both studies share the same study design and objective, which is to evaluate the safety and efficacy of LX2006 in adults with FA cardiomyopathy over a 52-week open-label study period, followed by an additional 4 years of long-term follow-up. Both trials are enrolling adults with a confirmed diagnosis of FA and evidence of cardiomyopathy without significant neutralizing antibodies to AAVrh10. Both trials are also collecting similar measurements of cardiac structure via cardiac MRI and echocardiography, as well as measures of cardiac functional capacity via upper limb cardiopulmonary exercise testing, or CPET, and blood-based biomarkers, including high-sensitivity troponin I. The primary difference, which we noted at the time of announcing the license agreement, is that cardiac biopsies are only performed in the SUNRISE-FA trial, and therefore, frataxin protein expression at baseline and post-treatment can only be evaluated in participants from this study. This slide reiterates some of the key measurements in the studies, both at baseline and following treatment with LX2006. On the left, you can see that both trials utilize identical ascending doses in cohorts 1 and 2, although only the SUNRISE-FA trial has a third dose cohort at 1.2 × 10^{12} vector genomes per kg. Both studies also use prednisone for transient immunosuppression for approximately three months following administration of LX2006. As noted previously, in the SUNRISE-FA trial only, frataxin protein expression is assessed via cardiac biopsy at baseline, and then post-treatment expression levels are assessed after three months. Cardiac imaging, biomarkers, and cardiopulmonary exercise test measurements are also assessed at regular intervals in both studies. Here you can see the baseline characteristics of the first 11 participants treated across both the SUNRISE-FA and Weill Cornell Medicine trials. We are sharing baseline characteristics from 6 participants in cohort 1, which has completed dosing, and from five participants in cohort 2. As one might expect, these are younger patients, generally in their 20s to early 30s, who all have a genetically confirmed diagnosis of FA, with the shortest GAA repeat length above 615. Using cardiac MRI, average LVMI levels were at the high end of the normal range in both cohorts, and average lateral wall thickness was also abnormal at baseline. Additionally, high-sensitivity troponin I levels at baseline were elevated, indicating ongoing myocardial injury in both cohorts. Finally, you can see that peak VO2 results assessed by upper limb cardiopulmonary exercise testing are extremely low, which may be partially due to the neurologic impairment caused by FA and noted earlier in the presentation. Duration of follow-up is, on average, close to one year in cohort 1 and of course, shorter in cohort 2 to date. Here we have provided more detailed baseline characteristics by participant. To orient you to the slide, for LVMI and the lateral wall thickness, the darker pink shading reflects abnormal values, defined as two standard deviations above the mean from healthy volunteers. The lighter pink shading reflects elevated values at the high end of the normal range, or at least one standard deviation above the mean from healthy volunteers. As you can see, the majority have elevated or abnormal values across all three parameters highlighted. You can see that eight of 11 participants have high, normal, or abnormal LVMI, while almost all participants have high, normal, or abnormal measurements for lateral wall thickness and high-sensitivity troponin I. We believe this is consistent with the broader population, where published literature shows around 80% of individuals with FA present with left ventricular structural abnormalities. These baseline cardiac values are important to note because, as previously shared, increased wall thickness is an early sign of hypertrophy, and we believe this measure may become abnormal before LVMI. Importantly, all measures are associated with adverse cardiovascular events, which is why we are focusing here today. As the primary objective of these studies is to evaluate the safety and tolerability of LX2006, we will start by sharing these data. LX2006 has been well tolerated, with no treatment-related serious adverse events to date. We've not observed signs of complement activation or other immunogenicity, nor any cardiac or hepatic safety signals. All adverse events to date have been transient and resolved, and no participants have discontinued from either study. Following the evaluation of the safety and tolerability profile in participants treated in cohorts 1 and 2, the Data and Safety Monitoring Board for the SUNRISE-FA trial, comprised of independent external experts, recently endorsed escalation to the third dose cohort. Now, with regard to cardiac biopsy data, we have previously shared that pretreatment baseline levels of frataxin were very low. We estimate around 2% of normal, and post-treatment levels increased in all 3 evaluable participants in the SUNRISE-FA trial by liquid chromatography, mass spectrometry, or LC-MS. While we previously presented the quantified immunohistochemistry or IHC analysis from a participant in cohort 1, today we are also sharing results from a participant in cohort 2, which reaffirms the increase in post-treatment frataxin expression. As a reminder, LC-MS measures intensity of protein, whereas IHC measures distribution. In this new data point from cohort 2, a significant increase in frataxin area stained post-treatment was observed relative to baseline. Unfortunately, a sufficient sample from the cardiac biopsy was not available for IHC evaluation of participant 9 in cohort 2, but we're certainly pleased to see a consistent trend of increased frataxin in post-treatment samples across all evaluable samples to date. Now let's review the cardiac MRI and biomarker findings. What we are showing on this slide is the percentage of patients who achieve a certain threshold of LVMI reduction by time point. Looking at LVMI in the 8 participants treated to date with at least 6 months of follow-up, you can see that 50% of participants achieved LVMI reduction greater than 10% at 12 months. For the 2 with 18 months of follow-up, both achieved LVMI reduction greater than 15%. When looking at only the participants with elevated LVMI at baseline, 75% of these participants achieved LVMI reduction greater than 10% at 12 months. As we continue to collect and assess data, we are encouraged to see clinically meaningful thresholds of improvement, as well as this trend of increasing improvement over time in participants with elevated LVMI at baseline, as this is where we may expect to see the greatest potential therapeutic impact. When looking at LVMI results another way, as a continuous measure, we continue to see the favorable pattern of improvement post-treatment... For participants with elevated LVMI at baseline, the average reduction in LVMI was 6% after 6 months, increasing to 11% by 12 months and to 18% by 18 months. Results are quite similar when looking at median change from baseline as well in this group. As baseline levels are elevated in this group, this is where we would expect to observe more clinically meaningful reductions. Finally, on the right side of the slide, we're sharing average LVMI changes in the group with normal LVMI at baseline, where we see minimal change at the 12-month time point, which is expected, as we would not assume to see a significant change in LVMI for those already within the normal range. Now looking at both left ventricular lateral wall thickness and troponin across all participants in the study, we continue to see a favorable pattern of improvement following treatment. The average reduction in wall thickness was 7% after 6 months, increasing to 14% by 12 months and 13% by 18 months. Importantly, we observed a greater than 10% improvement from baseline in 4 of 6 participants at 12 months. As a reminder, elevated wall thickness is an early indicator of left ventricular hypertrophy, and we believe this is another important biomarker for evaluating therapeutic effect. Finally, troponin I levels were reduced by 28% on average after 6 months, and by over 50% at both 12 and 18 months. In this measure, we observed a greater than 25% improvement from baseline in 4 of 5 participants at 12 months. We're encouraged by these data, as we know troponin is an important measure of myocardial injury. We find these data highly encouraging, as these reductions in lateral wall thickness and troponin I further highlight the potential therapeutic impact of LX2006, and combined with the LVMI results, the data provide greater confidence of a sustained and consistent overall treatment effect. Finally, looking briefly at cardiopulmonary exercise testing, or CPET, you can imagine this can be challenging in individuals with FA that experience ataxia and progressive neurological function. In our studies, we are using upper limb CPET to enable participation from those who may be in a wheelchair or walking with assistance. There are a variety of measures captured during exercise testing, including peak oxygen consumption or peak VO2, which has historically been used to test functional capacity in cardiac clinical trials. As we reviewed earlier in the presentation, baseline peak VO2 levels were extremely low in our trials to date, likely reflecting a combination of neurological impairment and reduced cardiac functional capacity. In fact, 3 of 8 participants were not able to achieve the maximal exercise effort required for a reliable interpretation of peak VO2. Of the 5 able to exercise sufficiently, an average improvement of 1% was observed at 6 months and 4% at 12 months. As part of our ongoing clinical studies, we will continue to evaluate peak VO2, and we are also investigating other potential CPET measures that could have prognostic significance, even in the presence of submaximal exercise effort that may be common in FA. Finally, I'd like to close this section by sharing that many of the measurements reviewed today do have some precedence with regulatory authorities in terms of their use as registrational endpoints. In particular, protein or transgene expression has been used in multiple gene transfer trials to date. The changes in LVMI have been accepted as an endpoint for regulatory approval in cardiac genetic medicine. Additionally, both lateral wall thickness and troponin have been noted to be clinically meaningful and potentially supportive. So to summarize, we feel confident across the range of outcomes that can be evaluated for a future registrational trial. Now, I'd like to turn it back to Nolan to close the presentation today. Thank you, Sandi. Like you, I am very encouraged by the interim data shared today and the promise of LX2006 to treat the devastating fatal nature of FA cardiomyopathy. As we've shown today, we are quite pleased to see improvements in key clinical parameters observed after 6, 12, and 18 months, with a consistent pattern of increasing improvement over time. Together with the initial findings from cardiac biopsies, these results suggest that modest increases in frataxin protein expression may produce meaningful clinical benefits across key biomarkers of cardiac health linked to outcomes. Though these results were observed at lower dose cohorts, we are pleased to share today that in the SUNRISE-FA trial, we have endorsement to proceed to cohort 3, and this cohort has begun enrollment, and one participant has been dosed to date. In terms of next steps, we expect to share further details of these interim results, including one additional cardiac biopsy from cohort 2, at a scientific conference in the fall of this year. Thank you for your time this morning, and we will now take questions. Thank you. I will be opening the phone lines for your questions. As a reminder, press the star, then one, one to get in the queue and wait for your name to be announced. To remove yourself from the queue, press star one, one again. Stand by for our first question, please. It comes from the line of Tess Romero with J.P. Morgan. Please proceed. Good morning, Nolan and team. Thank you for the webcast this morning and for taking our questions. So first one from us is: What were the key variables, really, the pushes and the pulls that are driving the decision here to dose escalate to cohort 3 versus, say, dose expand at this point in cohort 2? And, you know, any further detail on the comment around evaluating at least three participants in cohort 3, is that... Is the view there that that will be enough to decide where to dose expand? And then we have one follow-up. Thanks, Tess, for the question. I think, you know, our view is based on a favorable safety profile, the protein expression, you know, that we've been seeing. We believe a higher dose cohort could achieve higher protein levels. And we also, you know, believe that the preclinical data would support dose escalation because we saw a continued, you know, clinical benefit or preclinical benefit in those murine models at higher doses. So I think that was a key part of the decision to dose escalate. In terms of three patients being sufficient to, you know, evaluate that, the dose cohort, you know, as you know, originally, the SUNRISE FA study was set up around three patients, you know, per dose cohort. So we did believe at that time, and we continue to believe that three patients per dose cohort could be sufficient to determine, you know, the going forward dose. I don't know if Sandi or Eric, you'd like to add anything to that. I don't think so. I think as Nolan was saying, the preclinical data supports continued improvement as we go up on the dose, and we have a wide safety margin. So it makes sense for us to at least explore this. We're not committed to the dose in the pivotal trial, but we'll be able to now establish what the best dose is moving forward. Yeah. We'll be able to look at the three doses side by side and, and determine what's the best one to take forward from here. Okay. Okay, that's very helpful. And then kind of a related question from us here is just, you know, you've shown us an array of cardiac biomarkers this morning, and the data there is grouped, and we're thinking about, you know, these are these are small n's here with different baseline characteristics, but are you seeing dose dependency in any of these cardiac biomarkers, or is it just too small of an n? Like, what are you seeing there? Yeah. Maybe I'll pass it to Sandi to answer that question. Yeah, sure. So, you know, what we're seeing in terms of a dose response is, we'd like to look towards the frataxin expression and where we've seen and what was shown early on from the, LC-MS data on protein expression, where we are seeing that potential dose-dependent, response in terms of seeing, with a 3x increase in the dose, we're seeing about a 5 times increase in frataxin protein expression, and that's consistent with what we've seen in our preclinical models. So we're really looking forward to what we would see with our next, dose level increase. From the biomarker perspective, we think it's premature to comment on that. We, only have a couple patients that are beyond the 6-month time point at this stage. We're hopeful to see as the dataset matures, that we could then comment on the dose-dependency effect in terms of the clinical biomarkers. Yeah, I mean, Tess, as you saw in the data, we see this increasing response over time in LVMI. So, you know, to the extent we have, you know, patients that are not even at six months yet, you know, we would expect to see increasing improvement in LVMI over time. So in order to compare the two dose cohorts like to like, we need to see the cohort 2 data at that longer, you know, longer time points in order to make a, you know, formal declaration about, about dose response. And so that's the, the I think, the picture that, that we're looking at today. Okay. Thanks so much for taking our questions. Thanks, Tess. Thank you. One moment for our next question, and it's from the line of Paul Matteis with Stifel. Please proceed. Hey, good morning, and congrats on the data. I have a couple questions, if you don't mind. First, I was wondering, you know, you guys talk about a flexible regulatory environment, validation of LVMI. What's your level of confidence that LVMI can be a potential registrational endpoint, given that it's not elevated across patients or that the baseline levels are variable? What would you propose to the FDA? Would you propose enriching a study for it? Like, how do you think about that? And then I guess the second question here, just on the data itself, was it always the plan to only disclose data cuts for a certain duration of follow-up? And, you know, what do you guys see for, like, onset of action and benefit over time? Like, within... At a within-patient level, does the benefit continue to improve out to a certain duration? Like, what, what's the thought process there? And then maybe just lastly, for cohort 3, are these gonna be patients that have elevated LVMI at baseline? And do you think that this is gonna set it up where you actually can elucidate a dose response if there is one? Thank you. Thanks, Paul, for the questions. We'll kind of tick through these. Maybe I'll pass it to Eric first to speak about the flexible regulatory environment, and with LVMI. Yeah, I think great question, Paul. I think in regards to LVMI, it's very well established that LVMI is associated with increased mortality and cardiovascular events across hypertrophic cardiomyopathy, hypertension, valve disease. It has regulatory precedent behind it. Obviously, we've seen recently, and we know specifically in FA, increased LVMI are associated with bad outcomes. So 10% increase in LVMI is associated with a 20% increased risk of death. So we have a high degree of confidence that that should be an excellent potential outcome moving forward, that we should look at in our trials. You asked about enrichment in the future study. I mean, we're not at a point where we can comment on regulatory discussions, but I think that's a possible, you know, pathway forward here. It's enriching for LVMI, but, you know, we've also shared this data on, you know, lateral wall thickness, which precedes LVMI. So there may be a possibility that lateral wall thickness is part of the picture here, because this would obviously allow, you know, patients that are earlier in the disease to be treated for it to show a treatment effect, and maybe they never, you know, enter into the stage where they exhibit elevated LVMI in the first place. And so that would, I think, also be a compelling picture. So that is something that we're looking at. Your next question was on duration of follow-up. And maybe, you know, one comment I can make there, we a priori, we're not sharing the 3-month time point with respect to cardiac biomarkers because those results may be influenced by the existence of prophylactic, you know, immune suppression. So we did have, in advance, this approach of sharing 6 months and beyond. And so we have patients at 6, 12, and 18 months, and that was the intention, was to share those, you know, to share those time points. And by the way, that's across, you know, that's across both studies. Your- Thanks. Nolan, do you mind if I just quickly chime in? Just one thing you said, have you had regulatory discussions yet, or are you waiting for the cohort 3 data? I think we'll comment on the regulatory picture in a future update. So we're not able to comment on that at this time. Thanks so much. And then the last question was related to cohort 3, and whether we can observe the improvements in LVMI in cohort 3. And so I think, you know, as we mentioned for cohort 2, as we are continuing to see improvement over time in these cohorts, I think we need to look at the data side by side to determine the dose that we, you know, take forward into the next study. We're seeing pretty meaningful improvements in LVMI already at these lower doses. However, we are exploring cohort 3 to understand if there is any incremental improvement in LVMI that we could expect out of that cohort. You know, as you know, we have quite a bit of room on the protein side to increase, where we have a very compelling safety profile with no drug-related serious adverse events. So I think that does support a conclusion to explore, you know, the cohort 3 dose and understand if we are, you know, able to achieve any incremental benefit in LVMI, lateral wall thickness, troponin, you know, and so on. So, we will be exploring that dose. We've dosed the patient there, and, you know, we think those results will also be something that we'll be taking a look at as we progress the program. All right. Thanks again. Thanks, Paul. Thank you. One moment for our next question. And it comes from the line of Luca Issi with RBC. Please proceed. Oh, great. Thanks for taking our questions. This is Lisa. I'm for Luca. Congrats on the data today, team. Just wondering if you can maybe put the LVMI results in context for us. You know, we have seen from two adult patients in Reata's program that they had LVMI decreased by more than 10% at 12 months. Obviously, different diseases, but just wondering if you think this is a fair comparison to the LX2006 results we've seen today. And also, can you remind us, are patients able to be on concomitant SKYCLARYS in the study? Just any color on this would be helpful. And last question, given the results today, does the goal remain to reach frataxin levels at 5% of normal, or has the thinking around this changed? Thanks so much for taking our questions. Okay. We'll work through these. Maybe I'll pass it to Eric first to talk about the LVMI effect size and the relevance of that. Sure. As you mentioned correctly, these are obviously different diseases when you compare Danon disease to FA and the severity of LVMI changes, but nonetheless, the degree of changes are actually quite consistent. So you see in our data that we showed today that we go above this 10% threshold of changes at 12 months, and even further out, you get to 18 months, that change is even more dramatic, showing that remodeling may take time, but continues as we follow these patients longer. So I think it's very encouraging data today in regards to LVMI. Maybe I'll add there. I think it's, you know, obviously a bit of a challenge to compare across programs and which are different diseases. You know, what we know about FA is a 10% improvement in LVMI is, you know, could yield about a 20% improvement in mortality. So that's the, you know, that's the effect in Friedreich's ataxia. So we do think, irrespective of what's occurred with other programs, that in this program, for this disease, greater than 10% improvement in LVMI is clinically meaningful and should be linked to an improvement in mortality. Your next question was about SKYCLARYS and concomitant use. Maybe I'll pass it to Sandi to answer that. Yeah, sure. So, within our trials, we do permit the use of SKYCLARYS. Patients are required to be on, you know, stable dose for at least 12 weeks as part of their standard of care, so that's definitely permitted. The one thing that I would add about SKYCLARYS at this point is that, it hasn't shown any evidence of being able to address the cardiac manifestations of the disease, so we do believe there's still a high unmet need that remains for these patients that we feel, based on the data that we've shared today, that LX2006 really has the potential to address the cardiac manifestations and the significant unmet need for these patients. Yep. And then your last question was about 5% of normal, you know, frataxin. Maybe I'll pass it to Eric to say a few words about that and just our overall thinking. Yeah, I mean, I think as we mentioned on the call, that there's a lot of preclinical data to suggest that 5% of normal is sufficient to have normal cardiac output in the presence of frataxin deficiency. And that really relates to the function of the frataxin protein. It's an enzymatic function. So as such, you don't need a lot of protein to improve physiologic function. Analogous diseases like hemophilia have already established that very small amounts, like 5% or more, can lead to significant improvements in function. One thing I'll add there, I think, you know, many of the lines of evidence for the 5% of normal come from preclinical studies, whether it's the, you know, YG8-800, you know, murine model, whether it's, you know, our studies and other papers, all of which are, you know, frankly focused on animal studies. I think the real answer to this question of whether 5% is enough comes from - could come from the data in this clinical trial. I think the data that you're looking at today could suggest that at levels of 5%, roughly, or maybe even below that, we're able to achieve, you know, clinically meaningful reductions in LVMI, lateral wall thickness, improvements in troponin, and so on. So the answer to how much protein you may need to correct the disease may be one that comes from the data that, you know, that we're presenting today. So I think we are. We have dose escalated to cohort 3. That's likely to produce a level of protein that is, you know, that is beyond 5%. I think we'll understand if we're seeing a greater clinical effect at greater than 5% levels, at that dose cohort. But, you know, frankly, I think the data that we presented today is pretty compelling on its, you know, on its own, and this is probably at or below, you know, 5% of normal frataxin in the heart. So, you know, I think more to come on protein levels, as we move forward here. Great. Thanks so much for taking our questions. Thank you. One moment for our next question. It's from the line of Mani Foroohar with Leerink Partners. Please proceed. Hey, good morning, guys. Thanks for taking our question. A quick clarifying one. Can you walk us through what plausible timelines would be for regulatory interactions here? And if it's not this data set, plus what you're going to show us in fall, like, what quantum of data would you need across cohorts to take to the agency and establish what a pivotal path might look like? I'm trying to get a sense of what the scale of that total data set needs to look like in your mind. So maybe I'll address that. So I think we'll give an update on the regulatory interactions at a future time point. So I would probably defer on the question of timelines with respect to that. In terms of the, you know, the data set, you know, I think the data that we're looking at does give a pretty clear picture of what endpoints we're able to impact with this therapy. LVMI, lateral wall thickness, and troponin. You know, many of those have regulatory precedents associated with them. We think the data set's pretty robust. So at a minimum, this data set can allow a productive discussion about the right endpoints, you know, for the study. And then I think the question of, you know, effect size and final dose is one that, you know, we'll have to determine, you know, at a future stage. So I think that's the picture that we're looking at today, and I think we can look forward to a regulatory update, you know, in the future, and I wouldn't be able to guide on timing for that at this point. All right. Thank you. Thank you. One moment for our next question, please. It's from the line of Brian Skorney with Baird. Please proceed. Hey, good morning, everyone. Thanks for taking my question, and congrats on the data. I think you said that you expect an additional cardiac biopsy from a cohort 2 patient in the fall. Just wondering if by that time, we could see any expression for the patient dose at 1.2 × 10^12. And also wondering if you have a preclinical upper cap on dosing you can go to, or if you see good response in cohort 3, is another escalation step plausible beyond that? And then just on the criteria for enrollment, I know the description calls for evidence of cardiomyopathies. So just looking at some of the patients with normal baseline LVMI, wondering what metrics they had to qualify for the study, and in future patients, you know, would you enroll patients that require a baseline abnormal LVMI, given sort of the importance of that metric? Okay, maybe I'll take the first one and pass the next two to Eric and Sandi. So for the cohort 2 biopsy update, I would not set the expectation that there would be a cohort 3 biopsy alongside that. I think we'll give an update at that time as to when we would expect to share cohort 3, you know, biopsy data. In terms of the question on evidence of cardiomyopathy, maybe I'll pass it to Sandi to answer that one in terms of the inclusion criteria that would have had the patients in the study despite having normal LVMI. Yeah. So you know, the inclusion criteria is such that, we do require at least two markers of cardiac abnormalities, whether it's based on wall thickness, LVMI, or changes on the EKG, such as T-wave inversion. And so we require at least two of those changes, and similarly for the, t hat's in the SUNRISE-FA, and similarly for the Weill Cornell study, where they also require at least two changes, on which at least one is an abnormality on the CPET or in terms of LVMI. That being said, there's quite a bit of overlap in the patients if we look at the inclusion criteria across the studies. So based on that, patients can certainly have at least two abnormalities, which may not have been specific to LVMI, and therefore they are included in the study. So that's why you do see some patients with what appears to be a normal LVMI baseline, but those patients certainly have abnormal cardiac structure, as evidenced by the wall thickness and also accompanying troponins and other measures. you know, Brian, I think, you know, as you would know, in a, you know, in a phase 1, we like to understand the endpoints that are relevant for a pivotal study. I think it was always our understanding that patients that did not yet have abnormal LVMI may have other structural abnormalities. We now understand that almost all of them have increases in lateral wall thickness, that, you know, precedes increases in left ventricular mass index. We now know that this gene therapy can impact lateral wall thickness in addition to LVMI. This may allow us to broaden the, you know, the population in, in the future, knowing that we do have a treatment effect on an endpoint that precedes increases in LVMI. So we may be able to prevent patients from progressing into, you know, these more advanced stages of the disease with this therapy. So I think that's a helpful, you know, learning that's come out of this data, and it's the reason why we've included patients that are across the spectrum of FA cardiomyopathy. You asked one more question, do we have the ability to go up beyond 1 E12 per kilogram? Maybe I'll pass it to Eric. I mean, in theory, I think we could. I think the preclinical data strongly supports that we shouldn't need to, that we should have sufficient, more than sufficient amount of protein and an effect size that continues to grow as we go up, but the data will dictate that. And in theory, if we had to, we could explore it. Thanks. I don't anticipate that, no. Great. Thanks. Thank you. One moment for our next question, please. It comes from the line of Mitchell Kapoor with H.C. Wainwright. Please proceed. Hi, everyone. This is Dan on for Mitchell. Congratulations on the data. Some more color as to which cohort patients were in which study, specifically, which of the data is from Lexeo's sponsored versus Cornell's? And have you seen any anecdotally quantifiable differences between comparable cohort, cohorts between the trials? And, are there any thoughts on combining the trials, and what would that look like from a regulatory standpoint? Thank you. We've not shared that as part of this update. I guess our point of view would be that it may not be a relevant metric to sort of focus on because the studies are enrolling very similar patients from a profile perspective. We're treating them at the same doses with the same drug product. So we don't see material differences between the two studies, except for the lack of cardiac biopsies in the Cornell study. We can give some thought to that, but I don't think we, you know, have a view here that there's a material difference to highlight between the two studies, and therefore, you know, why separate the data by the two? And the next question, I'm sorry, if you can repeat it, maybe, Eric. Yeah, I think you were asking about should we come—would we consider combining the data? And I would say we are effectively combining the data. We're looking at it as a data set in its entirety, and we're not trying to piecemeal it out because, as Nolan said, same drug, essentially same protocol, essentially same inclusion criteria. So we don't really see the need to divide it. Yeah. And I think, you know, in terms of combining the two studies, there is this difference of one study having biopsies in it and the other study not having them. So I think it'd be difficult at this stage to combine the two studies. You know, I would note that, you know, the Cornell study is close to completing enrollment. Lexeo study, you know, is exploring cohort 3, could complete enrollment in the not-too-distant future as well. So we may be on the other side of both studies in a, you know, pretty rapid time frame. So the value of combining the studies for the purposes of, you know, a handful of patients that we've yet to enroll, you know, I guess, you know, we wouldn't see the benefit in that, I'd put it that way. So, that's sort of the picture that we have here. We think the combined data set, in our view, is compelling. It does show a pretty clear picture of the ability to improve LVMI, troponin, and left ventricular wall thickness. You know, as Eric shared earlier, you do not see spontaneous reductions in LVMI across any study, you know, looking at HCM. We're seeing pretty material reductions in LVMI here and other endpoints. So again, we think that this data set is sufficient for the purposes that we had, which was to understand our effect size on various endpoints and then to utilize this data to support regulatory discussions to take forward into a pivotal study. We don't need to combine the studies to, you know, to get to that answer. So I think that's the picture that, you know, that we have here today. Yeah. Thanks so much. That makes sense. Thank you. Thank you. And I see no further questions in queue. I will pass it back to Nolan Townsend for final comments. Okay. Thank you for joining today. We appreciate the interest and, you know, we're excited about the data that we shared and, you know, look forward to furthering the discussion around this program. And importantly, you know, this is a very serious disease, a very challenging disease for FA patients. We're excited and encouraged by the data that we shared and the potential of a therapy for patients in that community today. So thank you for your time. Thank you all for participating, and you may now disconnect.