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

Good morning, and welcome to Lexeo Therapeutics webcast presentation of interim Phase I/II clinical data of LX2006 for the treatment of Friedreich Ataxia Cardiomyopathy. [Operator Instructions]. Following management's prepared remarks, we will hold a question-and-answer session. [Operator Instructions]. 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 I/II clinical trial in Weill Cornell Medicine's Phase Ia trial of AAVrh10 human Frataxin known as LX2006 at [ Lexeo ], the treatment of Friedreich 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 and 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 in 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 or 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 the majority of participants. To quickly remind everyone, LX2006 is the most advanced program in our cardiac pipeline with an ongoing Phase I/II trial underway. We have 2 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 I/II 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-1 ] 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% to 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 the concentric hypertrophy in later stages 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 the small molecules 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 which 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 co-factors for numerous mitochondrial reaction. 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 and 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 express 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 1.5x to 2x more effective at transducing cardiomyocytes in large animal studies performed in both pigs and nonhuman 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 abnormal. 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 FA 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 and restoration may be sufficient to restore cardiac function or translate the clinical benefit in FA. Looking at other diseases and potential analogs, we again see some evidence to support the hypothesis. In hemophilia, factor levels at just 5% of normal can still significantly reduce bleeding and improved coagulation. And in muscular dystrophies, expression at 10% to 40% of normal dystrophin results in a significantly mild to phenotype of disease. So to summarize, we believe preclinical models and analogs from other diseases suggest that small increase in the Frataxin levels may be sufficient to produce clinical benefit. As mentioned earlier, FA cardiomyopathy is often characterized 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 and obstructive hypertrophic cardiomyopathy, a reduction in LVMI has been associated with increased exercise tolerance and quality of life. We will also note that increasing the wall thickness in the cardiac biomarker high-sensitive troponin I appear to precede increases in LVMI as individuals advance towards a more hypertrophic phenotype. These changes in the 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 data set 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 the status set due to survival bias, specifically that individuals in this data set 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 to 18 months, consistent with what we see in a natural history data for FA cardiomyopathy. We believe this supports the conclusion that a decrease in LVMI with 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 noninvasive 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 license 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 have 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 to date on 11 participants for which data are available. Before we share any data, I think it's critical to note that these 2 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. 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 1.2x10^12 vector genomes per kilogram. Both studies also use prednisone for transient immunosuppression for approximately 3 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 3 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 5 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 1 year in Cohort 1, and of course, shorter in Cohort 2 to date. Here, we have provided a more detailed baseline characteristics by participant. To orient you to the slide for LVMI and lateral wall thickness, the darker paint shading reflects abnormal values defined as 2 standard deviations above the mean from healthy volunteers. And 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 3 parameters highlighted. You can see that 8 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. 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 have 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 and 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 LCMS. While we previously presented the quantified Immunohistochemistry, or IHC analysis from a participant in Cohort 1. Today, we are also sharing results from our participant in Cohort 2, and which reaffirms the increase in post-treatment Frataxin expression. As a reminder, LCMS measures intensity of protein, whereas IHC measures distribution. In this new data point from Cohort 2, a significant increase in frataxin area stand 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 increase frataxin and 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. So looking at LVMI and 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 it's 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 into 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 studies. 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, this data provides 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 efforts 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 precedents with regulatory authorities in terms of their use of 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 future registrational trial. Now I'd like to turn it back to Nolan to close the presentation today.

Thank you, Sandi. Like you, I'm very encouraged by the interim data share 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 and protein expression may produce meaningful clinical benefits across key biomarkers of cardiac health linked outcomes. 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 1 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.

[Operator Instructions] Our first question comes from the line of Tessa Romero with JPMorgan.

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 any further detail on the comment around evaluating at least 3 participants in cohort 2 -- 3 is that is a view there that, that will be enough to decide where could those expand? And then we have one follow-up.

Thanks, [ Tess ], for the question. I think our view is based on a favorable safety profile, the protein expression that we've been seeing. We believe a higher dose cohort could achieve higher protein levels. And we also believe that the preclinical data would support dose escalation because we saw a continued clinical benefit -- or preclinical benefit in those [ muri ] models of higher doses. So, I think that was a key part of the decision to dose escalate. In terms of 3 patients being sufficient to evaluate the dose cohort, as you know, originally, the SUNRISE-FA study was set up around 3 patients per dose cohort. So we did believe at that time, and we continue to believe that 3 patients per dose cohort could be sufficient to determine the going-forward dose. I don't know if Sandi or Eric, if 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.

Yes. We'll be able to look at the 3 doses side-by-side and determine what's the best one to take forward for here.

Okay. Okay. That's very helpful. And then kind of a related question from us here is just -- you've shown us an array of cardiac biomarkers this morning. And the data there is grouped and we're thinking about these are small ends 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 end? Like what are you seeing there?

Yes. Maybe I'll pass it to Sandi to answer that question.

Yes, sure. So what we're seeing in terms of a dose response is we'd like to look towards the frataxin expression. And where we have seen and what we've shown early on from the LCMS 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 5x increase in Frataxin protein expression. And that's consistent with what we've seen in our preclinical model. 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 of patients that are beyond the 6-month time point at this stage. So we're hopeful to see if the data set matures that we could then comment on the dose dependency effect in terms of the clinical biomarkers.

And [ Tess ], as you saw in the data, we see this increasing response over time in LVMI. So to the extent we have patients that are not even at 6 months yet, we would expect to see increasing improvement in LVMI over time. So in order to compare the 2 dose cohorts like-to-like, we need to see the cohort 2 data at that longer time points in order to make formal declaration about dose response. And so that's the, I think, the picture that we're looking at today.

One moment for our next question and is from the line of Paul Matteis with Stifel.

Congrats on the data. I've couple of questions, if you don't mind. First, I was wondering, you guys talked about a flexible regulatory environment, validation of LVM. What's your level of confidence that LVM can be a potential registrational end point 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 what do you guys see for like onset of action and benefit over time? Like within a patient level, this the benefit continue to improve out to a certain duration? Like what's the thought process there? And then maybe just lastly, for Cohort 3, are these going to be patients that have elevated LVM at baseline? And do you think that this is going to set it up where you actually can elucidate a dose response if there is one?

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 with LVMI.

Yes, I think -- great question, Paul. I think in regards to LVMI it's very well established. LVMI is associated with increased mortality in cardiovascular and across hypertrophic Cardiomyopathy hypertension valve disease. It has a regulatory precedent behind it. Obviously, we've seen recently. And we know specifically in FA increase in LVMI are associated with that outcome. 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 outcome -- potential outcome moving forward that we should look out in our trials.

You asked about enrichment in the future study. I mean we're not at a point where we can comment on the regulatory discussions, but I think that's a possible pathway forward here is enriching for LVMI but we've also shared this data on lateral wall thickness, which perceives LVMI. So there may be a possibility that lateral wall thickness is part of the picture here because this would obviously allow patients that are earlier in the disease to be treated for us to show a treatment effect and maybe they never 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 one comment I can make there -- we -- a priority, 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 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 time points. And by the way, that's across both studies.

Nolan, do you might 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 and a future update. So we're not able to comment on that at this time. 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 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 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. As you know, we have quite a bit of room on the protein side to increase. We have a very compelling safety profile with no drug-related serious adverse events. So I think that does support a conclusion to explore the cohort 3 dose and understand if we are able to achieve any incremental benefit in LVMI lateral wall thickness troponin and so on. So we will be exploring that dose. We've dosed the patient there, and we think those results will also be something that we'll be taking a look at as we progress the program.

One moment for our next question. And it comes from the line of Luca Issi with RBC.

Great. This is Lisa on for Luca. Congrats on the data today team. Just wondering if you can maybe put the LVMI results in context for us, we have seen from 2 adult patients in [ Rocket'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 you'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% is normal? Or is the thinking around this changed?