Good morning and welcome to the Lexeo Therapeutics webcast presentation of interim phase I-II clinical data of LX2006 for the treatment of Friedreich's ataxia cardiomyopathy. As a reminder, this call is being recorded. Today, Monday, April 7th. I will now turn the conference call over to Kyle Rasbach, Chief Financial Officer of Lexeo Therapeutics. Kyle, please go ahead.
Earlier today, we released interim data from both the Lexeo Sunrise FA phase I-II clinical trial and Weill Cornell Medicine's phase IA investigator-initiated trial of LX2006 for the treatment of Friedreich's ataxia cardiomyopathy. The press release outlining the combined interim 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 of Lexeo Therapeutics. Also joining us is Ronald Bartek, Co-Founder and President of the Friedreich's Ataxia Research Alliance, or FARA.
Before we begin, I'd 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 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'd like to turn the call over to our CEO, Nolan, for opening remarks.
Thanks, Kyle, and thank you all for joining us today. Lexeo Therapeutics is a genetic medicines company dedicated to pioneering novel treatments for genetically defined cardiovascular diseases. We have two cardiac programs currently in the clinic: LX2006 for the treatment of Friedreich's ataxia cardiomyopathy, which we will discuss today, and LX2020 for the treatment of plakophilin-2 arrhythmogenic cardiomyopathy. We are focused on areas with clear genetic causes and significant unmet needs, with the mission to fundamentally change how cardiovascular diseases are treated. We are fortunate to be joined today by Ron Bartek, President and Co-Founder of the Friedreich's Ataxia Research Alliance. FA cardiomyopathy is a devastating and fatal condition with no approved disease-modifying treatment today. I'd like to turn it over to Ron to briefly share his perspective on the condition for our audience.
Hello, I'm Ron Bartek. My wife, Raychel, and I are the Co-Founders of the Friedreich's Ataxia Research Alliance, or FARA, and I've always served as FARA's President. We established FARA in 1998, the year following the FA diagnosis of our son, Keith, at age 11, one year after the FA genetic mutation was first identified. Like two-thirds of children with FA, Keith had hypertrophic cardiomyopathy, which was present at his diagnosis and worsened relentlessly. Despite our community's tireless efforts, cardiomyopathy remains the leading cause of early death in FA patients, and we have no approved therapy for it. Applying standard cardiac management is not at all sufficient in treating this condition. Like so many FA patients, our son succumbed to congestive heart failure, dying in our home at age 24, 15 years ago.
Since the beginning of this year, we've lost six other young people with FA that we knew personally due to complications or progression of their cardiomyopathy. As you can see, there is a clear and urgent need to treat the cardiac disease caused by FA. Because our community continues to work tirelessly trying to save current and future FA patients, we are deeply appreciative of all who join us in the concerted effort to develop effective treatment for FA's most condemning symptom. Our scientific and patient communities are convinced that treatments that address the root cause of FA by increasing frataxin protein levels are our best opportunity for delivering disease-modifying, life-altering, life-saving therapy. Finally, knowing that we can achieve maximum benefit for FA patients by treating them as early as possible, our best hope is to include pediatric patients in clinical research as early as possible.
We are also deeply appreciative of all efforts to include children early in clinical trials. Thank you very much.
Thank you, Ron, for joining us and for highlighting the urgency to find new treatments for FA cardiomyopathy. We sincerely appreciate our partnership with FARA, and it remains critically important to us that feedback from the FA community is incorporated into every step of our development process. Today, we are pleased to share updated interim results for LX2006 across dose cohorts. We've completed enrollment of the Sunrise FA trial, and across both this study and the Weill Cornell Investigator Initiated Trial, 16 participants have been dosed to date. Eric and Sandi will walk through our interim results in more detail in a moment, but to summarize, we have seen increased protein expression in all participants in the Sunrise FA study, with an average increase of 115% from baseline in the highest dose cohort.
Across both studies, we have observed meaningful improvement in cardiac biomarkers such as left ventricular mass index, or LVMI, lateral wall thickness, troponin, functional measures, and patient-reported outcomes. These data give us great confidence that LX2006 has the potential to halt or even reverse the progression of cardiomyopathy that is the leading cause of death for patients with Friedreich's ataxia. We're also pleased to share that we have aligned with the FDA on key elements of our planned registration study for LX2006, and we look forward to sharing the details of that study today. As you will see in today's presentation, LX2006 is demonstrating an ability to impact underlying pathobiology of this disease while improving key clinical features of cardiomyopathy, and we have a clear path to an accelerated approval for this therapy. I'll now hand the presentation over to Dr. Eric Adler to walk through some of the background of Friedreich's ataxia and LX2006.
Thank you, Nolan. Starting with a brief disease overview, Friedreich's ataxia is a devastating, rare, and progressive multisystem disorder. This condition impacts approximately 5,000 people in the United States and 15,000 people globally. Almost all people with FA will develop some cardiac dysfunction during their lifetime, and approximately 40% have left ventricular hypertrophy as defined by abnormal left ventricular mass index. Cardiac complications are the leading cause of death, and 60%-80% of people with FA die as a result. Earlier onset of cardiac symptoms is associated with a more severe phenotype and a faster progression to end-stage disease. Sadly, there are no currently approved treatments for FA cardiomyopathy. Individuals with FA have very little frataxin protein expression, which leads to impaired mitochondrial function in the heart, causing cardiomyocyte dysfunction, hypertrophy, and cell death.
LX2006 is designed to treat the root cause of disease by restoring frataxin with the potential to improve mitochondrial and cardiomyocyte function and reduce hypertrophy. 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, and ubiquitously expressed promoter. Importantly, this is all packaged within AAV rh10 vector, which appears to be an improved capsid for transduction in the heart. We believe this capsid allows us to produce clinical benefits at lower doses of vector, thereby reducing safety concerns. Before we jump into the data, I want to remind everyone that LX2006 is being evaluated in two parallel trials: one multicenter study sponsored by Lexeo and another investigator-initiated study run by Dr. Ron Crystal at Weill Cornell.
It is important to note that these two trials are very similar in that they are using the same drug product. While both studies evaluate safety and efficacy across cardiac and functional measures, the primary difference is that the cardiac biopsies are only performed in Lexeo's Sunrise FA trial, though protein expression is only evaluated in participants from the study. Finally, I want to share that we have reached alignment with the FDA on key elements of the pivotal trial for LX2006, including inclusion criteria and co-primary endpoints to support accelerated approval. The pivotal study will only enroll individuals with abnormal LVMI at baseline, which is defined as individuals that present with heart mass two standard deviations or greater above normal. Abnormal LVMI is a hallmark of hypertrophic cardiomyopathy and represents later stages of disease in FA.
Abnormal LVMI is also associated with an increased risk of death and poor cardiac outcomes in FA and in other cardiac conditions. This is a more targeted population than we enrolled in the phase I-II studies, and we estimate that it represents approximately 40% of adults with FA cardiomyopathy, providing a sizable group for enrollment in our registrational study. The co-primary registrational endpoints are LVMI and frataxin protein expression. The target threshold for LVMI improvement is at least a 10% reduction as measured by cardiac MRI at 12 months. As you will see this morning in our interim results, we exceeded this threshold with a mean reduction of 25% in LVMI at 12 months or sooner among participants with abnormal LVMI at baseline. With regards to frataxin expression, the target is any increase from baseline rather than a specific numerical threshold.
In the phase I-II study, we have observed an increase from baseline in all eight participants irrespective of dose, assessed using liquid chromatography mass spectrometry, or LCMS, which we also expect to use in the pivotal study. I will now turn it over to my colleague, Dr. Sandi See Tai, to review the interim data in more detail.
Thanks, Eric. On this slide, you can see the baseline characteristics of the 16 participants treated to date across the Sunrise FA and Weill Cornell Medicine trials. The dark pink shading represents an abnormal measure, or a value that is at least two standard deviations above the mean from healthy volunteers. The lighter pink shading represents a measure within the normal range, but greater than one standard deviation above the mean, which we are labeling high normal. At baseline, all participants had some evidence of cardiac dysfunction, and six participants had abnormal LVMI: three in cohort one, two in cohort two, and one in cohort three. We will focus much of our discussion today on this subset of patients with abnormal LVMI, given that they closely match the population we intend to enroll in our registrational study.
At the bottom of the table, you can see the latest visit for each individual and if they had a myocardial biopsy performed. As the primary objective of these studies is to evaluate the safety and tolerability of LX2006, we will start by sharing these data. LX2006 continues to be generally well tolerated to date. We've not observed any signs of complement activation or other immunogenicity, nor any signs of frataxin overexpression in the heart, and no participants have discontinued from either study. As we shared last year, there was one participant who was diagnosed with myocarditis one year after dosing. This individual had multiple comorbidities at enrollment, and their early treatment course was complicated by multiple pneumonias with required modifications to immunosuppression. At their 12-month visit, their laboratory tests were notable for elevated troponin, although the participant was otherwise asymptomatic.
Cardiac MRI taken at that time showed evidence of focal myocardial edema, increased LVMI, and increased wall thickness. All of these findings were consistent with myocarditis, and in discussions with the participant, they reported having a viral illness several weeks earlier. Of note, this event occurred one year after dosing, and there is no evidence of frataxin overexpression or transgene antibody response. We continue to monitor the participant very closely. It's important to note that this event occurred around this participant's most recent 12-month visit. You will see the 12-month results for this participant on subsequent slides, but we believe they are confounded by myocarditis. Looking now at cardiac biopsy data, all participants demonstrated an increase in frataxin expression at three months post-treatment, which we believe shows the potential of LX2006 to act as a disease-modifying treatment by introducing frataxin into the heart.
These results also meet the FDA-aligned thresholds for the future pivotal study, where protein expression will be evaluated for any increase in expression over baseline. Importantly, we are also seeing evidence of a dose response. The average increase over baseline at three months was 29% in cohort one, 69% in cohort two, and 115% in cohort three. Given the relatively low variability of LCMS, we expect to measure frataxin expression using this method in the future. We're very encouraged by these interim phase I-II results, particularly because increased frataxin expression appears to be correlated with evidence of clinical benefit, as reflected in multiple cardiac biomarkers you will see on subsequent slides. Here you can see cardiac biomarker data for the six participants with abnormal LVMI at baseline, which matches the inclusion criteria for the future pivotal study.
This group represents a segment of the FA population with more severe, later-stage cardiac disease, as evidenced by the baseline LVMI measurements that are significantly elevated, at least two standard deviations or more above the mean in healthy volunteers. This slide shows the change observed in clinical biomarkers between baseline and latest visit, and the dark green shading shows where treatment with LX2006 led to meaningful improvement from baseline. On average, these participants achieved a 25% reduction in LVMI at 12 months or sooner. Remember, the FDA-aligned threshold for a pivotal trial is at least a 10% improvement in LVMI at 12 months, which we believe is clearly achievable based on these phase I-II results. We also see signs of dose response in the cardiac biomarkers, as we are seeing greater response at earlier time points in the higher dose cohorts.
At their latest visit, five of these six participants had reached the normal range for LVMI, and LVMI improvement was associated with improvements in other biomarkers, including lateral wall thickness and troponin, as you can see in the chart. We believe these data are remarkable, and you can clearly see the potential of LX2006 to halt or even reverse disease progression evaluating these biomarkers. Looking holistically at this picture, we have great confidence that LX2006 is improving cardiac health in FA cardiomyopathy. Now, looking across time points, this chart visually demonstrates the dose response with a greater reduction in LVMI seen at earlier time points in cohorts two and three, showing a deeper and more rapid response to therapy in these participants. We are also pleased to see sustained or deepening LVMI improvement over time in cohort one, which suggests persistent transgene expression with an underlying disease-modifying impact.
We hope to see the same pattern emerge in the higher dose cohorts as these participants are followed further. Finally, looking now at the secondary endpoints for those with abnormal baseline LVMI, again, we observe a pattern of sustained or deepening improvement over time with potential dose response in cohorts two and three relative to cohort one. Lateral wall thickness is on the left, and high sensitivity troponin I is on the right. We know that elevated lateral wall thickness and troponin are each correlated with poor outcomes in other cardiovascular diseases. These improvements further highlight the potential of LX2006 to positively impact cardiac outcomes in FA. The directionally consistent improvement observed across cardiac measures from LVMI to lateral wall thickness and troponin gives us great confidence in the treatment effect.
To date, we are seeing a very compelling picture of the therapeutic potential looking at these consistent patterns of improvement in multiple distinct measures of cardiac health. We've reviewed the results for a subset of participants with abnormal baseline LVMI, matching the inclusion criteria for the registrational study. Now, I would like to share data for the other six participants who began the study with baseline LVMI measures within the normal range. Those with a baseline LVMI more than one standard deviation above the mean for healthy volunteers are noted in pink, which we are labeling high normal. In this population, we are still seeing signs of clinical improvement and disease stabilization across biomarkers.
Almost all participants remained within the normal range for LVMI at their latest visit, excluding participant 10, who, as I noted before, was diagnosed with myocarditis at 12 months after treatment, including myocardial edema, which is likely confounding these results. Participants four and eight, who began the study with higher baseline LVMI values, showed greater improvements. Almost all participants demonstrated stabilization of lateral wall thickness and meaningful reductions in high sensitivity troponin I, which we believe suggests the potential of LX2006 to positively impact cardiac status even at earlier stages of disease. This is, again, encouraging evidence that LX2006 has the potential to halt or reverse disease progression even before severe hypertrophy has emerged. Now, looking at the complete picture, on this slide, you can see the absolute change in LVMI across all 12 participants with six months or more of follow-up.
Men have slightly larger hearts than women on average, and the normal ranges for men and women differ. Here you can see men on the left and women on the right. As you can see, the majority of participants reach or remain within the normal range for LVMI at their latest visit. There is evidence of sustained or deepening response over time in cohort one at the low dose, which you can see in gray. There is also evidence of potential dose response in the mid and high dose cohorts relative to the low dose, with a greater response to therapy observed at earlier time points, which you can see in blue for cohort two and green for cohort three. Overall, 10 of 12 participants are in the normal range for LVMI at latest visit, including five of the six participants who had abnormal LVMI measurements at baseline.
The outlier on this slide is, again, participant 10 with measurements likely confounded by myocarditis diagnosed around 12 months. Looking at the secondary or supportive endpoints again, this time across all 12 patients, lateral wall thickness is shown on the left and troponin on the right. Overall, we are seeing consistent trends of improvement in hypertrophy or disease stabilization across most participants to date. The lateral wall thickness measurements are small in millimeters, so there is some measurement variation, but overall, the pattern of improvement is consistent with the LVMI data and with an underlying disease-modifying treatment effect. On the right, you can see that almost all participants experience large reductions in troponin, decreased anywhere from 25% to almost 100% from baseline. Elevated troponins are a marker of myocardial injury, so this reduction across the study population, regardless of baseline status or disease severity, is clinically meaningful.
Finally, I'd like to share the evidence of functional improvement observed across all participants to date, regardless of baseline LVMI. On the left, you can see change from baseline in the modified Friedreich Ataxia Rating Scale, or mFARS, where a reduction is positive and reflects less physical impairment. This scale measures function in people with FA across four subscales: bulbar function, upper limb coordination, lower limb coordination, and upright stability. A change of two points or more is generally considered clinically meaningful, and without treatment, individuals progress by approximately one point per year on average. Progression of neurological symptoms will impact the scale over time, but we are seeing evidence that treating the frataxin deficiency in the heart can improve functional outcomes specific to people with FA.
It's too early to say whether there is a dose response here, but we are seeing greater improvement in those participants that have 12 months or more of follow-up. There appears to be greater improvement over time following treatment with LX2006. On the right, the Kansas City Cardiomyopathy Questionnaire, or KCCQ, is a patient-reported outcome measure that assesses symptoms, function, and quality of life for individuals with heart failure. Here an increase over baseline is positive, and this scale is strongly associated with clinical events over time. Improvement could represent fewer reported symptoms of heart failure, like reduced shortness of breath or lower extremity swelling, or an increased ability to do activities of daily living or recreation and hobbies. A change of five points or more is generally considered clinically meaningful.
This measure is only collected in the Sunrise FA phase I-II clinical trial, but again, we are seeing early evidence of improvement over time. We continue to collect data to determine the confirmatory endpoint approach in the pivotal study, but we expect it could be one of these measures. Given the clinically meaningful impact observed from treatment with LX2006 thus far, we expect to initiate a pivotal study by early 2026, and I'll share some additional details about the anticipated study design now. Based on the frataxin expression and safety data to date, we expect to take forward the highest dose, or cohort three dose, of 1.2E12 vector genomes per kilogram. As mentioned previously, the study will be enriched based on LVMI, enrolling participants with abnormal LVMI at baseline. Efficacy will be assessed with two co-primary endpoints of LVMI and frataxin expression. We intend to evaluate these endpoints separately.
LVMI will be assessed at 12 months following treatment, and we will be looking for an average reduction of 10% or more. Cardiac frataxin expression will be assessed at three months following treatment, and we expect to evaluate expression with a responder analysis. Treatment effect in LVMI will be assessed against an external comparator arm, a concurrent natural history study called CLARITY-FA, which we expect to begin enrolling later this spring. Following safety assessment in the cohort of participants aged 16 and over, we also expect to enroll pediatric cohorts where the primary endpoint will be safety. We anticipate the 16+ adult cohort will include at least 12 participants with 90% power to detect a difference, and we can share more details on the statistical plan following final FDA alignment later this year. I will now turn it back to Nolan to close the call.
Thank you, Sandi.
I'm highly encouraged by these interim data and the potential of LX2006 to be a first and best-in-class treatment for FA cardiomyopathy. I'd like to talk for a moment about the commercial opportunity for this treatment candidate. Approximately 5,500 individuals globally have FA cardiomyopathy with abnormal LVMI, and 12,000 globally are estimated to have FA with some cardiac dysfunction. Importantly, children and adolescents with earlier onset of disease are more likely to have a severe phenotype and faster progression. This group has no disease-modifying treatments available today for either neurologic or cardiac symptoms, and the unmet need is significant given the earlier mortality facing these children. While the pivotal study will focus on those with abnormal LVMI or later stages of disease, the interim results shared today demonstrate the potential of LX2006 to positively impact cardiac health in those with earlier stages of disease as well.
Heart failure guidelines recommend intervention as soon as individuals present with structural or functional cardiac abnormality, even in the absence of symptomatic heart failure. We believe there is a clinical justification for early intervention in FACM. We have seen multiple examples of pivotal studies with more narrow inclusion criteria that go on to have broader commercial labels, especially in rare disease. This is what we expect to pursue for LX2006. In closing, we've observed increased frataxin protein expression in all participants, improvements in cardiac biomarkers and functional measures across a majority of participants, and a generally favorable safety profile. We are meeting or exceeding thresholds agreed by FDA to support accelerated approval for LX2006 in a registrational study, and we are looking to begin this study by early 2026.
I want to thank the participants, caregivers, and investigators who have helped us advance our development of LX2006 to this important milestone. Thank you for your time this morning, and we will now take questions.
Thank you. We will now hold a question-and-answer session. To ask a question, please press star followed by one one on your touch-tone phone. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Tessa Romero with JPMorgan.
Your line is now open. Good morning, team. This is Caroline Pocher on for Tessa Romero with JPMorgan. Thanks for taking our questions. Just a couple from us. Across the patients with abnormal LVMI at baseline, it looks like there is some heterogeneity in terms of the change in LVMI, LWT, and troponin.
Have you been able to identify any characteristics that might be able to predict a better response in these patients?
Thank you for the question. This is Nolan. I will ask Eric to comment on the patient profiles and the response rates. Sure. I think it's evident that the patients with the highest LVMI are the ones that respond most in terms of a percentage, but it is notable that as you increase the dose of the medicine, you also see a response that suggests, frankly, a dose response. For example, if you take patients with the same left ventricular mass, the patients in cohort two have a greater drop than the patients in cohort one, and even patients who have abnormal LVMI but not exceedingly abnormal, the patients in cohort three have a drop that's greater than in cohort one.
You are seeing evidence of a dose response, but clearly the higher the LVMI, the greater the response across biomarkers. I would suggest it's the same across the secondary endpoints as well. You could see a dose-dependent response in troponin, for example, the same in wall thickness. I think what you've mentioned as heterogeneity is actually just a response rate based on patients' pretreatment baselines, and what you're also layering in is a dose response across the cohorts as well.
Okay. Great. Then just one final question from us. Can you provide any more granularity around the timing of when you plan to gain final alignment with regulators around the registrational design, and has your team you have been interacting with at the agency changed at all?
Thanks. Yeah. Thank you for the question.
I'd say on the final alignment, there are some details on the statistical plan that we're working to align with on the FDA. That will be a 2025 event, and I think we'll have more guidance on the precise timing of that coming in the future, but I would guide to, at this moment, within 2025. In terms of the FDA itself, I know this is an important question at this moment. From our perspective, the team that we've been working with has not changed, and they continue to work in the same way. I think that this is the current state of affairs in respect to collaborating with the FDA at the moment.
Great. Thank you so much.
Thank you. Our next question comes from the line of Paul Matteis with Stifel. Your line is now open.
Hi there. This is Julian on for Paul.
Thanks so much for taking our question and congrats on all the progress. Just one from us. I guess, have you given any additional thought as to what LVMI cutoff specifically you would enroll in the study and what data you're looking at to inform that? I guess just in the one patient where you have LVMI data from cohort three, you sort of note that they have a lower baseline LVMI than a couple of the patients in cohort two. Just trying to get a better understanding of, are you looking to enroll patients with triple-digit LVMI, or can it be just sort of above 80 or something like that? Thank you.
All right. Thanks for the question. Maybe I'll ask Eric to comment on that.
Yeah. We're going to stick with two standard deviations above normal based on the sex of the patient.
I would note that even the patient who has an LVMI of 85 goes down to 74. That demonstrates they still have more than a 10% reduction, and that is at six months, and that is the dose we are going to be using. We think as long as we stick with above two standard deviations, we should be in good shape or exceeding the bar that we have agreed upon with the FDA. Importantly, as you have seen, five of those six patients reach normal left ventricular mass index, which means we are taking a patient with two standard deviations or more of cardiac hypertrophy, and we are normalizing that function, which is obviously a hallmark of FA cardiomyopathy. The patient profiles and the cutoff that you see in the slide in the deck is the inclusion criteria we will be taking forward into the registrational study.
Okay. Great.
One quick question, if you don't mind as well. Any consideration for a lower dose in the pediatric or adolescent cohorts, or are you confident enough in your safety profile that you'd go forward with this high dose for all of these patient populations? Thanks.
Yeah. We feel very comfortable about a therapeutic index, and so we anticipate going with the same dose in children as adults. We have a significant amount of safety data across all of the dose cohorts. Remember, this dose is a kilogram per kilogram dose. Obviously, that will be indexed to the patient's body weight. The pediatric patients will have obviously lower body weights than the adults. We're sitting at a 1E12 vector genomes per kilogram dose. This is a full two logs lower than doses where you would commonly see systemic AAV-related tox issues.
Typically, you would begin to observe those at 1E14 vector genomes per kilogram or higher, and this is substantially lower than that. Even our highest dose remains a very low dose for systemic gene therapy.
Thank you. Our next question comes from the line of Brian Skorney with Baird. Your line is now open.
Hey. Good morning, everyone, and thank you for taking my question, and congrats on the data. Maybe to start, I'm just trying to contextualize the frataxin expression levels on LCMS and wondering if you have any healthy control analysis. Just looking through historical publications, it seems like normal blood measurements are reported to be anywhere in the low teens to mid-20s nanogram per ml, but not sure what a normal measurement might be in cardiac tissue.
Second, just as a follow-up in terms of the FDA dialogue, just wondering if you need another formal RMAT type B meeting to confirm the design and the statistical plan, or is that an informal communication, just sort of trying to get a handle on the frequency of discussion with the agency given the RMAT designation and if those are generally in sort of a formal type B meeting setting? Thanks.
I'll ask Eric to comment on the first question, and maybe I'll take the second one.
Yeah. You're correct in that there's not a lot of published literature in measuring frataxin by LCMS in the heart. There's only peripheral tissue. We have done some work from autopsy analysis, which suggests variability, specifically anywhere from 20 nanograms- 100 nanograms in a patient per milligram.
I'll note those are almost certainly homozygous patients, so you can imagine heterozygous patients who are asymptomatic may have considerably less than that. I will pass on to Nolan for the second question.
On the RMAT designation frequency of interactions with the FDA, you're correct that it may not require an actual meeting to reach the final alignment on the protocol with the FDA. I think we'll just have to work through some of the details of the statistical methods and through the path we're progressing on today. Our expectation would be that we'd be in a position to give an update on the final design within 2025. The slide that you've seen represents assumptions that we've developed internally based on ongoing discussions with the FDA, and I think we'll be in a position to give more guidance on the finalized design within the year.
Great.
Thank you.
Thank you. As a reminder to ask a question at this time, please press star one one on your touch-tone telephone. Our next question comes from the line of Mani Forooha r with Leerink Partners. Your line is now open.
Hey, guys. Thanks for taking the question. A little more of an operational than a data-driven one. Presuming the timeline on final data—excuse me—on final pivotal design details is met in 2025 and no further disruption at the FDA beyond what we've already seen, what are the assumptions around enrollment pace and dosing timing for the pivotal that are baked into the commentary you've made about data timing?
Thanks, Mani, for the question. As we've guided to, we intend to start the registrational study by early 2026 at the latest.
What you can also see in the guidance is that we intend to start an external control natural history study within the second quarter of this year. I think there's an advantage to starting that study early because we're working with the same sites that we intend to work with for the registrational treatment study. We will be in progress of identifying patients for the natural history study, which has a very similar inclusion criteria to the treatment study. I think what this does is it de-risks enrollment in a pretty meaningful way in that we're getting the sites up and running. We have physicians that begin looking for patients of this abnormal LVMI profile, and we're doing that, call it, 6+ months ahead of the start of the actual treatment study.
By doing this and making this investment upfront, this de-risks enrollment on the back end and also obviously helps us accelerate timelines for enrollment and getting to data. The guidance we've given starting the study by the beginning of 2026 and guidance within 2027, you can assume we're at a 12-month endpoint for LVMI. I think you can back away from sort of the range of assumptions on enrollment that will be implied in that, but we would anticipate obviously having the study enroll within 2026 and then data in 2027.
Great. As a quick follow-up, the natural history study, how do we think about the patient population represented there? Is that going to be more representative of the abnormal LVMI population of pivotal, more representative of the broad population of FA cardiomyopathy patients in terms of the total end market?
How should we think about the patient mix in the natural history study versus the patient mix in the pivotal study versus the patient mix in kind of the TAM, if that makes sense?
Yeah. Let me just take that. I think, one, the patient profile in the natural history study will be identical to the treatment study. We will have an inclusion criteria that includes abnormal patients in the natural history study. We'll have an inclusion criteria that includes abnormals in the treatment study. Those two, from an inclusion criteria perspective, will be identical.
I think from a TAM perspective, if you think about that 5,500 patients globally that have abnormal LVMI, then the other 7,000 patients that have either normal or high normal, we think the data that we're generating out of this phase I study can help to support the case for the broader label and treating the entire population that has some form of cardiac involvement. As you saw from the data, we have improvements in LVMI for patients that are high normals, and you saw the two at about a 9% rate of improvement in LVMI. You see improvements in wall thickness, and you see sustained and very dramatic improvements in troponin.
We think this is the body of evidence that would support both for regulators, but ultimately for patients and physicians, a case for treating the broad population of up to 12,000 patients with Friedreich's ataxia that have some form of cardiac involvement. I'd also point to the functional data, the improvements in mFARS, the improvements in KCCQ. We observe these across patients that have both abnormal LVMI and normal LVMI. While the inclusion criteria of the study will be focused on abnormals, again, we think this is the fastest and, I'd say, most de-risked path to an accelerated approval. We think the body of evidence for normals and high normals and having that included in the label and then credibly treating that population commercially is being generated, and you've seen it in the data that we presented today.
Thanks. That's really helpful. Thank you.
Our next question comes from the line of Luca Issi with RBC. Your line is now open.
Oh, great. Thanks so much. And congrats on the data. Maybe just two quick ones here. Maybe Eric, I mean, it looks like the high sensitivity troponin data is actually pretty striking with actually all patients actually benefiting irrespectively of baseline LVMI, which I think is notable. Maybe why not using troponin as your go-to endpoint going forward? Maybe that will allow you to capture a broader patient population. That is one. Then second, on the pivotal, you did mention that you intend to evaluate the endpoint separately, and obviously there are different times as well, LVMI 12 months versus expression at three months. Can you just expand a little bit more on it?
I guess the question is, what happened if the pivotal trial maybe hits the stat on one endpoint but not the other? Any comment there? Much appreciated.
Thanks so much. Maybe I'll ask Eric a comment on the first question on troponin.
Sure. I think the troponin data gives a lot of credence to the biological effect of our medications. It's clear that we're having an impact on this important biomarker. It does can vary a fair amount. It's a bit noisy. I think using it as a primary for that reason is a bit problematic. I'll remind you that there's more precedent for using LVMI as an endpoint, whereas troponin hasn't been used as a primary endpoint in prior studies and more data for it in terms of a mortality marker in Friedreich's ataxia. I think it's an important endpoint.
I think it'll be a great secondary to confirm the impact of our medication and show that we're impacting disease even in those patients that don't have elevated LVMI in our first cohort.
In terms of the second question?
Yeah. I mean, it's a tough one to speculate on meeting one endpoint but not the other. I mean, I'd point to the data that we've reviewed today. We're clearing the performance threshold on LVMI by a pretty substantial margin, and the study will be powered against LVMI. That's an important factor is that that's the endpoint that the study will be powered against. The frataxin expression endpoint is binary. It's a yes/no. We've achieved that yes in 100% of the patients. I think we look at both endpoints as pretty materially de-risked.
The only question is how many patients are needed to power the appropriate endpoint. I think the other points I would make here is the two secondary endpoints, the supportive endpoints of troponin and wall thickness. We're seeing improvement across the patients there. We're also seeing improvement in the functional measures. I think it's difficult to comment on what if we don't meet one of those endpoints, but I think for every single endpoint that would be involved in this study, the data that you've seen we're exceeding the relevant threshold. We're seeing improvement across patients irrespective of where they start from a disease point of view. I think this should give some confidence that, one, the registrational study is pretty materially de-risked with the data that we've presented today, but we're also seeing improvement across a range of endpoints.
Even if something does happen where we don't achieve one, which, again, as I'm describing, I think is unlikely, we have a pretty robust body of supportive evidence across the patients that are really suffering from this disease that can drive towards an approval. I think that's the most we can sort of speculate on possible scenarios of not achieving one of the endpoints in a registrational study.
Got it. Super helpful. Congrats again.
Thank you. Our next question comes from the line of Mitchell Kapoor with H.C. Wainwright & Company. Your line is now open.
Good morning. This is Danan from Mitchell. Thanks for taking our questions and congratulations on the data. First, is there a correlation of high range of LVMI that would typically hit an LVEF of greater than or equal to 40%?
Then secondly, how homogenous is disease progression in the context of comparing the external cohort and the pivotal cohorts to ensure comparability? I'd like to ask a follow-up if I could.
I'll take the first one. The question was, is there a connection of ejection fraction to LVMI? Sure. They're not necessarily connected. In fact, by the time the EF is dropping in these patients, LVMI may be that indicates potential fibrosis, and LVMI may start to trail down at the very end stages. We're excluding those patients, so I don't think it's actually relevant for our trial. The second question, could you repeat it?
Yeah. He has not asked the second question yet. If you can go ahead. Oh.
No, the second question was in comparing the external cohort to the pivotal cohort, how homogenous is disease progression to ensure that those patients are comparable because they're not going to be in the same trial, if that makes sense?
Got it. No, there's a good amount of public data showing that disease progression is pretty homogenous, that people go through steady stages one through four of disease, and as their LVMI goes up, it continues to go up till, as I was mentioning, the very end stage of disease. On top of that, we'll propensity match to ensure that the patients in the natural history study are very similar to the ones that are in the trial.
Got it. Thank you. In characterizing safety, what was the most common adverse event? Particularly, I guess a lot of thoughts are on liver panel, if there's any liver panel data.
If there is, did liver enzymes elevate? If so, around what time after dosing did you see those elevations?
Thank you. We almost saw little to no elevation in liver AST or ALT. That is a reflection of the fact that our doses are still several logs below where you might see something like that or at least a log before in trials. We really had a very well-tolerated therapy, as we stated earlier. Almost really nothing. We are mentioning some little chest pain, things like that that went away, but nothing significant.
That is awesome. Thank you so much.
Thank you. I am currently showing no further questions at this time. I would like to hand the call back over to Nolan for closing remarks.
Thank you for taking the time to listen today. We are very excited about the clinical data that we have presented.
I think we are showing an important impact on the hallmark of FA cardiomyopathy, which is cardiac hypertrophy. We're seeing a 25% reduction for patients that have reached 12 months or earlier. We're seeing frataxin expression across 100% of the patients. That's greater post-dose than pre-dose. We're seeing improvements in wall thickness, troponin. We're seeing improvements in functional scales, the modified Friedreich Ataxia Rating Scale. We're seeing improvements in KCCQ. We are very excited to have both an impact on important biomarkers related to this disease. These are biomarkers that the FDA has aligned around for the purposes of a registrational study. Importantly, we're seeing improvements in functional measures as well. These are important to patients and physicians and obviously could be the focus of a full approval of the therapy.
With that, I will close the call and thank everyone for taking the time to listen today.
This concludes today's conference call. Thank you for your participation. You may now disconnect.