Welcome, everyone, to the 44th Annual J.P. Morgan Healthcare Conference. My name is Tessa Romero, and I'm one of the Senior Biotech Analysts here at J.P. Morgan. We're pleased to welcome our next presenting company, Lexeo Therapeutics, to kick off our Wednesday, and presenting on behalf of the company, we have CEO Nolan Townsend. Nolan, over to you.
Thank you, Tess. It's great to be here, and thanks to everyone for coming. We're going to start with a short video to give a flavor of the type of diseases that Lexeo Therapeutics is seeking to address.
Keith was a very typical little boy. He was taking a karate class. He was playing Wiffle Ball in the backyard, but he was beginning to stumble and fall a little more frequently. There were some indications that something might be up.
I joined the DeMatha swim team, but I could not get on the blocks. I would immediately fall off into the pool. At that point, I knew something had to be wrong.
At a certain point, we started noticing something was off, and therefore, we took him to a specialist to find out, okay, what is going on? Why is he falling off his skateboard so often compared to other kids?
Ja, dus eigenlijk op een tijdsperiode van drie maanden zijn we dan te weten gekomen dat eigenlijk twee van onze drie kinderen de ziekte hebben.
When the neurologist told me she suspected Keith had Friedreich's ataxia, like everyone else in this country, we think a prescription will take care of it and he'll be fine and go on with life. Her eyes started watering, and she said, "There is nothing he can take that's going to cure this.
As it turned out, Keith got all the symptoms of Friedreich's ataxia, including the neurological, the diabetes, and the heart condition, which was ultimately what took his life at age 24.
I came home that day and just sat in my room and stared at my ceiling for a while. I was thinking, "Why? Why is this happening to me?
We were Googling online about Friedreich's ataxia, and the most frightening thing that we read is that a thickening of the heart muscle itself was one of the most common features. If your heart fails, well, to be frank, life ends.
When most people think about Friedreich's ataxia, they don't think about the heart, and that is one of my biggest concerns. I'm 23 years old, and every day I'm afraid of heart failure.
As parents, our biggest fear was, who's going to be there when it happens? How can we help them?
Everything that you imagine for your child, at that moment, it just evaporated.
I was dreaming of getting married and moving down south and having a nice big house with a wraparound porch and a big family. And I knew that that was going to be a very hard future for me. And it feels like a part of me was just kind of ripped away very fast.
Mom, let me see your ass. Whoa!
We dream about the life a boy could have, but about growing up. Having families of our own, what we are most hopeful for is that there will be a treatment on the market that could take away the worries of those sleepless nights. That's what we're fighting for. That's our biggest hope.
We decided what we needed to do about this was to support the medical research into Friedreich's ataxia.
We knew it would probably not be in time for Keith, but even though it wasn't time for him, that it was going to help a lot of other people too.
In order for all of my dreams to be possible, we need more research. We need more funding. Until then, I'm going to keep advocating, going to keep staying positive. There's still life to be lived.
Keith was always the inspiration. Now it's clear that we have changed the hopelessness to hope and now confidence. We know that we're going to get this one.
You know, these are real patients struggling with a very difficult disease. And the mission of Lexeo Therapeutics is to deliver therapies to treat patients with challenging diseases exactly like this one. We're a company dedicated to reshaping heart health. Our first program is in Friedreich's ataxia, but we expect to have an impact on other diseases of a similar profile over time. We're doing this by building one of the leading cardiac genetic medicines platforms. The company has a deep expertise in cardiac genetic medicine, everything from clinical trials to manufacturing through to preclinical development. We have a differentiated delivery system in the AAVrh10 capsid. It's a highly cardiotropic vector. It's ideal for treating diseases of the heart. We have an innovative manufacturing platform that's able to supply both small and large indications with cardiac disease. And we have a strong financial position and operating experience behind that.
And we're advancing cardiac disease and cardiac treatments into a very interesting context for genetic medicines. There's a big white space in cardiovascular genetic medicines today. There's only 10 cardiac precision medicines approved, and several of these treat the same disease. Most of cardiac treatments are one-size-fits-all treatments. And if you look at oncology and the way that field has evolved over the past few decades, the approaches in oncology to precision medicine have made all the difference in the advances in cancer that we've seen. We see the cardiac disease area evolving in exactly the same direction, that we will take these large diseases, break them into their genetic components, and then apply precision therapies to treat them.
Lexeo is at the tip of the spear in advancing therapies for many of these diseases, and our pipeline reflects a range of treatments across a range of cardiac diseases, all of which can have a meaningful impact on patients' lives. We're advancing this first through novel technology in the capsid that we're utilizing. The AAVrh10 has demonstrated a very compelling cardiac tropism profile. This is about one and a half to two x greater biodistribution into the heart than many of the other commonly used capsids. We've seen this across murine models. We've seen this across large animal models. We've seen this trend in cardiac transduction across a range of conditions. And now we're also seeing it validated clinically in two different programs. But importantly, as many would know, safety in gene therapy is linked to dose.
So the ability to transduce the heart at relatively low doses for systemic gene therapy yields a very compelling safety profile coming out of our programs. So interestingly, there's a line above 1E14 or below, and notably below 1E14, there's almost an absence of safety events in gene therapy. Typically, Lexeo focuses on programs where we're able to transduce the heart safely, and the AAVrh10 is a tool which we utilize to achieve that. And our manufacturing process is fit for purpose. We designed this process to allow us to deliver vector against both large indications and small. We're achieving 1E15 vector genomes per liter in terms of our scale. We're doing this with low empty-capsid ratios, and our downstream recovery is greater than 55%.
So what this means is that we can supply vector against diseases like Friedreich ataxia with, let's say, 5,000 patients, or we can supply vector against the commercial demand of diseases like arrhythmogenic cardiomyopathy with 60,000 patients. We have a lot of flexibility into what we can deliver here for both clinical and commercial supply to allow us to address the demands of the cardiac genetic medicines market in general. So in review of our 2025, I think we've made a lot of progress as a company. We've announced positive data from our Friedreich ataxia cardiomyopathy program in the second half of the year. We received a breakthrough designation for our Friedreich ataxia program, and we initiated the natural history control for our registrational study called CLARITY-FA.
In our PKP2 arrhythmogenic cardiomyopathy program, LX2020, we've actually completed enrollment of the phase 1/2 study. We've shared interim data from this phase 1/2 study in the low-dose cohort in the first half of the year, and we'll talk today about recent data that we shared for this program in the beginning of 2026. On the corporate side, we've completed two financings totaling about $230 million of capital. This secures a runway into 2028. This also has allowed us to fund the registrational study for Friedreich ataxia through its conclusion. We've appointed a CFO with commercial finance experience as the company transitions to become a commercial stage company, and we've completed a partnership to advance novel non-viral cardiac RNA therapeutics in collaboration with two leading venture funds, so it's been a very busy 2025, and I think we've made a lot of progress as a company in achieving our mission.
I'll switch gears here to begin talking about the pipeline. I think it's evolved in a very compelling way over the past few years. Our FA cardiomyopathy program has completed its phase 1/2 study. We're now moving this program into a registrational study. We expect to have a regulatory update, finalizing the protocol and statistical plan for this registrational study in early 2026. We would expect to initiate SUNRISE-FA, which is a pivotal study for Friedreich's ataxia cardiomyopathy in the first half of 2026. For LX2020, our arrhythmogenic cardiomyopathy program, we've completed a data update at the high dose in the beginning of this year. We expect to have a regulatory update associated with this program within 2026. I think this will clarify the path from our phase 1/2 and the future registrational path, and we expect to have a data update associated with LX2020 in Q4 of this year.
From a preclinical perspective, we recently completed a partnership with Johnson & Johnson to explore cardiovascular delivery of AAV gene therapies. So I mentioned earlier, the safety in gene therapy is linked to dose. To date, most companies, including ourselves, have been utilizing systemically administered gene therapy to treat cardiovascular diseases, and there's a range of diseases we can treat with systemically administered vectors. However, there are also diseases that require more protein and likely require higher doses, potentially moving gene therapy into a less safe range. So localized delivery is the key to the future of addressing the range of cardiac diseases, even those that require higher doses and more protein. And we're excited to work with the leading company in the cardiovascular space, like Johnson & Johnson, to advance towards these goals.
And we also have IND-enabling studies that we're planning in 2026, which we'll give future updates on, associated with our two preclinical programs. So I'll switch gears to talk about LX2006 and Friedreich ataxia cardiomyopathy. This is really, for us, a beachhead in cardiac disease. It's a disease that many would know as a neurologic disease, but 80% of the patients in Friedreich ataxia , the cause of mortality, is cardiac disease. You heard earlier from patients, you know, they struggle with this disease. You could see the patients are neurologically impaired, and typically, the cardiac symptoms emerge in a subclinical manner initially. But patients advance towards heart failure typically, and as I mentioned, 80% of FA patients, the cause of death is cardiac disease. So you can really only address mortality in Friedreich's ataxia by addressing the cardiac component of the disease.
But interestingly, the therapy we're developing and advancing not only has benefits in cardiac, it is also showing benefits in the neurologic component of Friedreich ataxia as well. And I'll spend some time talking about that. So LX2020 is delivering a functional copy of the frataxin gene. This expresses the functional protein. We're utilizing a ubiquitous promoter, which means we're expressing frataxin in all organs, not only the heart. So we expect to see frataxin expression in skeletal muscle, potentially in dorsal root ganglia, and obviously in the heart as well. This is important because this is a multisystem disease. The cardiac disease is the cause of death. This is our initial target, but there are broader benefits to this ubiquitous promoter and the broad expression of our frataxin construct.
Our role in advancing research in FA, we initiated a phase 1/2 study called SUNRISE-FA. This study completed enrollment last year. We've read out data associated with this program in 2025. I think some very exciting data, which I'll spend some time discussing today. We initiated CLARITY-FA, which is a natural history study meant to support the registrational path for our Friedreich's ataxia program, and then we expect to initiate SUNRISE-FA2, our pivotal trial, in the first half of 2026. So we're moving quickly from phase 1/2 into registration and hopefully towards a BLA in the near term. So just spending a bit of time on the data, I think it's a very exciting data package that's really matured and advanced over time. On the top left, you can see the frataxin expression we have achieved in the heart. This is measured via cardiac biopsies. You see a dose-dependent response in frataxin expression with the highest dose achieving a 115% increase in frataxin.
Remember, this is the missing protein that is the cause of the disease. On the top right, you can see what this frataxin expression achieves in terms of cardiac benefit. Left ventricular mass index is a way that we measure cardiac hypertrophy or thickening of the heart wall. And you can see at the higher doses, at 12 months, we're achieving a 33% reduction in left ventricular mass index, meaning we are reducing the heart mass of these patients by 33%. But importantly, all of the patients are moving from abnormal heart mass into the normal range, which means we have reversed the cardiac disease pathology in these patients. We are achieving a 28% reduction in LVMI at the six-month time point.
These are very meaningful effect sizes relative to a 10% reduction in LVMI, which is viewed to be clinically meaningful and linked to a 20% risk of mortality. Also importantly, we're having an impact on the neurologic component of the disease, and I think this is also very exciting data. On the bottom left, you can see the improvements we're achieving on the modified Friedreich Ataxia Rating Scale relative to natural history. You can see a 2- 3 point improvement in the mFARS scale. This is roughly similar to what the commercially available treatment is achieving. You can see a deepening effect over time and improvement in mFARS. Not only are we reversing the cardiac disease pathology, we're also showing improvement on the neurologic scale simultaneously. This therapy has the potential to change the standard of care and treatment in Friedreich ataxia disease. This is the therapy we're excited to develop and take forward into registrational studies.
I'll switch gears to talk about PKP2 arrhythmogenic cardiomyopathy, our LX2020 program, and I know we'll spend some time talking more about this today in the Q&A. This disease is one of life-threatening arrhythmias. Typically, sudden death from an arrhythmia is the most common way that patients are diagnosed. This is a large rare disease in that roughly 60,000 patients in the U.S. are viewed to have the disease. Patients with the disease, 23% of the time, experience mortality. The standard of care is simply implanting an ICD in the patient's heart. That stops these sudden death events from becoming actual events of mortality. From a pathology of the disease perspective, the desmosome is the cell-cell junction that mediates this disease.
When plakophilin-2 is absent, we get fibrofatty infiltrates that enter the cell-cell junction, and the cells in effect become islands. This interrupts the electrical conduction. This is the cause of the arrhythmias that ultimately lead to these sudden death events. So our approach is to restore the plakophilin-2 gene, which restores the cell-cell junction or desmosomal function. This has been viewed in animal models to reduce these events of life-threatening arrhythmias, premature ventricular contractions, and ventricular tachycardia. So this is the gene therapy construct that we're advancing. This is also utilizing the AAVrh10 capsid, as I mentioned earlier, with the very compelling cardiac tropism profile that we'll discuss more in future slides. There are three ways that patients typically present with this disease or three ways which you can identify arrhythmogenic cardiomyopathy.
One is premature ventricular contractions, which I would describe as a surrogate for the disease. These are just extra heartbeats. The next is nonsustained VT. So this is a collection of PVCs, and these collection of PVCs are nonsustained VT. Ventricular tachycardia is a clinical endpoint in this disease. This is representative of arrhythmogenic cardiomyopathy. And then a longer sustainment of ventricular tachycardia is a sustained VT, and that ultimately typically leads to an ICD shock. So this is the continuum of endpoints that are relevant in arrhythmogenic cardiomyopathy, and we'd say ventricular tachycardia is probably the most relevant endpoint in this disease. We have two studies. One is an interventional study. One is a natural history study running in this disease. HEROIC-PKP2 is the phase 1/2 study. We have two doses we've studied in this program, a 2E13 dose and a 6E13 dose. They treated a total of 10 patients. The study is fully enrolled.
I'll describe some of the data to you today, and we'll spend some time talking about it. We also have, alongside this phase 1/2 study, a 15-patient natural history study evaluating untreated patients and the progression of the disease in that context, so we've advanced some very meaningful research in this disease. I think we're gaining a great understanding of the nature of the disease from an untreated context, but also the impact that our therapy can have in arrhythmogenic cardiomyopathy, and I'll describe some of the data that we presented earlier in the week to you with respect to a few different angles. One is in respect to protein expression. We've achieved protein expression at the lower dose on average of a 93% increase in plakophilin-2 protein expression as measured via cardiac biopsies. At the high dose, we've achieved a 162% increase in PKP2 expression.
So you can see a dose-dependent response of plakophilin-2 expression as measured by cardiac biopsies. We've also had some interesting results in patient-reported outcomes where four of five patients are reporting that they are feeling better after being treated with our PKP2 arrhythmogenic cardiomyopathy. We've achieved a mean change of 14% in reduction in premature ventricular contractions, and importantly, we've achieved a mean reduction of 22% at the high dose in nonsustained ventricular tachycardia. And for those that follow cardiac disease, you would know that a 22% reduction in a clinically meaningful endpoint that's linked to mortality, such as nonsustained VT, is a very interesting outcome. And we're achieving this for patients, many of which are at the earliest time point for follow-up. They're at six months, and we're seeing a deepening effect over time. So at nine months, we're achieving over 50% reduction in nonsustained ventricular tachycardia.
As this data set matures, we're excited to see the clinical impact that we're having across this very important endpoint. The treatment was generally well tolerated. We had a single grade three treatment-related SAE of sustained ventricular tachycardia. This SAE is consistent with the treatment history of this disease and of this patient, and we had no other SAEs associated, no other grade three SAEs associated with the program. We're also advancing two preclinical cardiac gene therapy programs. One is in desmoplakin-mediated cardiomyopathy, LX2021. This is another very challenging disease where we're delivering the connexin construct to treat desmoplakin-mediated cardiomyopathy. The second is in hypertrophic cardiomyopathy, the program LX2022. This is a program where we will be collaborating with J&J to deliver localized TNNI3 gene to the heart.
So our research collaboration efforts will certainly support the advancements of this preclinical pipeline and allow us to treat even more patients over time with very challenging cardiovascular diseases. So just to summarize, Lexeo, as we've advanced over the past six years, has become a leader in cardiac genetic medicines, addressing high unmet need diseases with no existing treatments ahead of them. We have a catalyst-rich 2026 across both our Friedreich ataxia and our arrhythmogenic cardiomyopathy program. We have a differentiated AAVrh10 capsid, which has now been validated for transduction of the heart, not only in the preclinical setting, but also in the clinical setting. We have an Sf9 manufacturing platform that can deliver vector for both large and small indications. We're advancing towards a pivotal stage for our Friedreich ataxia program.
We expect to have regulatory engagements associated with LX2020 within this year to move that program also forward into the next stages in its lifecycle. We have a very strong cash position with a cash runway into 2028, so more than enough capital to execute on the goals that I described today, so with that, I'd invite our Head of Research, Eric Adler, and our Chief Financial Officer, Louis Tamayo , to the stage to discuss the questions that Tessa has.
Wonderful. Thank you so much, Nolan, for the presentation. Let's see how much ground we can cover in about 16 minutes here, so I thought I might start our conversation with a little bit of a strategic question. The company went public in 2023, I believe. What is the strategic direction of the company that you are building? How do you see the portfolio evolving over the next several years?
Yeah. When we went public in 2023, the company was focused on two different disease areas, actually. We initially had a CNS pipeline and a cardiovascular pipeline. I think over the last couple of years with the capital markets environment, we decided to focus more so on the cardiovascular side of our pipeline, and we are seeking and in discussions with partners about the CNS component of the pipeline. I think we also saw the opportunity set in the cardiovascular genetic medicine space evolving in a very favorable direction, and we saw the capabilities that the company had built to be ideal for this space. I mentioned the vector supply, the CMC strategy, our ability to treat a range of diseases regardless of prevalence, but also just the expertise we built.
And I think we've gained even further confidence in the AAVrh10 capsid and its ability to deliver gene payloads to the heart and to do so efficiently. I think our foothold now in cardiac is very strong. I would envision that we are moving forward a range of programs across the years here. So we have our FA program, which we would expect to have a launch in the next couple of years. I think the PKP2 program may not be that far behind that. And then you see two other preclinical programs that can move into late-stage studies. So I think there's a picture here where we could have a deep substrate of late-stage assets and commercial assets by the end of the decade. And I think complementing this, we've begun to do discovery work in non-viral, allowing us to address gain-of-function cardiac diseases.
So today, gene therapy is purpose-fit for loss-of-function cardiac diseases, but it's not ideal for gain-of-function cardiac diseases. We've worked with two leading venture funds to form a new company that can address gain-of-function cardiac diseases as well. So between ourselves and the company that we're collaborating with, we think we can address almost all genetic cardiac diseases in existence today.
Yeah. And can you talk a little bit about how the J&J collaboration came about?
Yes. I think as we saw the picture, there's a range of cardiac diseases that are loss-of-function. There are, let's say, a dozen of them that are of any meaningful prevalence or size. But you look at that construct and say, how many of these diseases require a substantial amount of protein to be treated?
We're looking for solutions for a small set of diseases that require a substantial amount of protein that systemically administered gene therapy would not be appropriate due to the doses that would be required. So localized delivery is ideal for those conditions. And J&J is, in our view, an ideal partner to work with to explore localized delivery. There's only one other company that's focused on localized delivery today. So we're seeking to innovate in this space and allow us to treat these diseases more comprehensively. I know, Eric, if you want to say a few words about that as well.
Sure. I think to be able, as Nolan was saying, to treat the whole spectrum of loss-of-function cardiovascular disease, you need to be delivering sufficient amounts of protein in some of these sarcomeric diseases where there's extremely high protein deficiency and extremely high protein content.
By doing local delivery, you can deliver that amount, but do it in a way that you're diminishing the risk of toxicity by diminishing your total dose.
Okay. I thought next we might just dig into this latest cut of phase 1/2 HEROIC-PKP2 clinical data that I guess is kind of hot off the press. Nolan or Eric, maybe you can just drill down a little bit more on what the take-home messages were in terms of where these data fell relative to what you thought you would be able to achieve at this time point, and how much latitude do you believe you have to show deeper reductions with longer follow-up and on what measures of clinical effect?
Yeah. Thanks for the question, Tess. Maybe I'll ask.
This is a little loaded. Sorry.
No, no, no. It's fine.
Multiple parts.
Absolutely.
Maybe I'll ask Eric just to talk about the endpoints that we evaluated in the disease, some of the background biology, the effect size relative to what we typically see in cardiac disease and some of the other existing treatments.
Sure, so if you think of the driver of mortality in this disease, it's ventricular tachycardia, so front and center for us, the important measurement, the clinically relevant measurement that we can make in these patients is VT, and when we talk about VT, we include nonsustained VT when you have three or more PVCs or sustained VT when you have 30 seconds or more of VT.
And the first thing that came out and we saw this data coming out is that we had this significant impact in that measurement that's clinically relevant to providers and patients, a 22% reduction at six months, which is the earliest look into this. So getting to the second part of your question about do we believe this data can mature. Every program that you can look at in cardiac gene therapy in the last 10 years, you've seen that these things take time. Remodeling takes time. And in fact, in the FA program, it was the same thing. At six months, we saw these glimmers of things. It becomes deeper and deeper over time as you look.
So, A, I think we're affecting the most clinically relevant endpoint, one that the standard of care therapies, whether it's amiodarone or ablation, they're associated with modest treatment effect size and high toxicity. And two, I think we do, in fact, already see signals this is deepening over time. Very early data, but our two patients that are nine months had this closer to 60%, 40% reduction in VT. So none of these patients got shocks from the defibrillators. These are patients that have a history of shocks. So I encourage this as a very clinically meaningful early—we set it from the very early signal, but really excited about what we've seen.
Okay. And maybe we can just briefly touch on safety. And just a clarifying question for me, actually, from the slide. Can you speak to in a little bit more detail about these LFT elevations that you saw in five patients at the high dose? What level of elevations did you see, and how did you interpret these events?
Yeah. Eric, maybe you can take them.
Sure. So as we've already disclosed, these were LFT elevations that were not related to hospitalizations, did not require or did not observe any changes in whether it's bilirubin or platelets, the things that we associate with high LFT and mortality. None of these were grade three SAEs, again. So for me, before we started the trial, we adopted a clinical protocol expecting some change in LFTs as we see in clinical gene therapy. We used that protocol, never had to deviate from that protocol during the entire trial.
I would say, without getting into patient-level details, that we saw something that was not out of the ordinary for any even commercial gene therapies and no grade three SAEs.
Yeah. I would just follow, I think, across both programs. The classic gene therapy-related SAEs that you would see are SAEs like complement activation, or you'd see SAEs related to things like liver injury. Across both programs, we have had no gene therapy-related SAEs. We have had a case of asymptomatic myocarditis in the FA program that's viewed to be possibly treatment-related. We've had a case of sustained VT, which is also in the treatment history of this patient with this disease. So importantly, with the AAVrh10 capsid, we've not seen complement activation-related SAEs. We've not seen liver injury-related SAEs. So I think, in general, the capsid is meeting our expectations.
They're able to deliver between three to five vector copies per cell, and we're able to do so with no treatment-related SAEs. I think that is a great accomplishment for a capsid in gene therapy. It actually makes us ideal for treating the heart, and I'll note that for our patients nine and 10, which have been dosed, we've seen no LFT elevations in those patients to date, so again, I think we've met our standard for safety profile for this capsid, and at the same time, it's delivering a meaningful genetic payload to the heart.
Okay, and I'm assuming you've shown these data to your investigators and our physician colleagues at this point. What has been their early feedback on the data?
Maybe Eric, you want to take them?
Yeah. I mean, I think that physician investigators, other cardiologists, everyone, I think there's a consensus that this 20% reduction at an early time point in VT is striking. So people were excited about that. Clearly, everyone saw the safety profile, very excited about a clean safety profile in gene therapy. So the combination of treating the most important clinically relevant endpoint in a clean safety profile is exciting. And one of the other things to mention is that the safety profile is associated without any induction therapy. So we're using kind of standard immunotherapy, steroids, and sirolimus, having no grade three SAEs, and then having this significant impact on these clinically relevant endpoints. Obviously, they want to see the data mature, but everyone's been really excited.
Okay. Big picture here, how much more data do you think you need to collect to be able to design a registrational trial that has a high probability of success?
I think the study we have completed enrollment of will give sufficient substrate to allow us to design a registrational study. If you're asking about the maturity of that data, where does it need to sit, that's an answer we do not have today. I think sometime between now and the end of 2026, we will definitely have a sufficient maturity of data to support that conversation. I think you can hear the direction of travel from the endpoints that we're focused on for a future registrational study. We think ventricular tachycardia is not a surrogate. It is a clinical endpoint relevant for this disease. We'll continue to monitor the maturity of the data against that endpoint.
I think there's a discussion we can have with the FDA about the relevance of that endpoint for the disease, and I don't think it will be a very complex discussion given the nature of it, and then the only question left is, what is the final effect size that we're achieving in an endpoint like nonsustained VT, and how large of a study does that need to be to show an effect there.
And any comments on, I don't know, the ecosystem of a couple of other gene therapy-based approaches for PKP2? Where do you see the landscape kind of evolving over time?
Yeah, so the first thing I'd say, this is a large, rare disease, so it can support multiple commercial therapies, so I don't necessarily see if there ends up being three therapies in this market. These are all multi-billion-dollar treatments in their own right. But I think safety is going to be the most important aspect of this in terms of how this field evolves. I think that the treatment that's able to deliver improvements and clinically meaningful endpoints, but able to do so with the clean safety profile, is the treatment that will be preferred by patients and preferred by physicians.
We believe what we're achieving here with the modest elevations in LFTs relative to a 22% or greater reduction in nonsustained VT is a very good outcome. It's exactly the risk-benefit profile that we think an arrhythmogenic cardiomyopathy patient would be excited to consider. So we think we're headed in the right direction with our program. And I think we'll need to see more data from some of the other programs and understand how this picture all fits together from a competitive landscape point of view.
Okay. So maybe we'll just pivot now to your FA cardiomyopathy program. The video made me and my team tear up, so thank you for that. Maybe you could just talk a little bit more about the gating factors at this point kicking off your study. And from our perspective, your trial design seems very de-risked. So what are you thinking about on your end just in terms of how do you set this trial up to maximize its chance for success?
Yeah. So I think we've communicated quite a bit about the structure, size, and sort of timelines of the study that we're working towards. I think all of that guidance remains consistent with what we've previously discussed in terms of the FDA's open to considering time points less than 12 months. We're looking at a relatively modest size study.
We have a natural history study that's already running alongside the single-arm treatment study. So I think all of that guidance remains in place. And what we're doing now is working to finalize the statistical analysis plan associated with that study ahead of dosing the first patient. But importantly, our natural history study is in progress. So we have sites up and running. We're screening patients. The natural history study has an identical inclusion criteria to the treatment study. So we are able to do work even now to find patients that could ultimately cross over into the treatment study. So while we're finalizing this work with the FDA, we are operationalizing the natural history study, and we're finding patients with the exact profile that we would have in the treatment study.
Okay. You're guessing that the profile across these patients is going to be pretty consistent from a baseline perspective, or how are you thinking about that?
Yeah. So the inclusion criteria, we're focused on patients with abnormal left ventricular mass, which in our definition is two standard deviations above normal. So they need to present with cardiac hypertrophy in order for us to show an improvement in that endpoint. And that's the profile of patient that we're focused on in the disease. We're looking at other secondary endpoints like troponin, where we saw a very meaningful improvement in troponin across the patients in our study. So that'll be another important endpoint. We're also evaluating lateral wall thickness, which is a two-dimensional measure of hypertrophy. And we're also going to be continuing to evaluate the modified Friedreich Ataxia Rating Scale , or mFARS, which is a neurologic scale.
The ability to show an improvement in the cardiac disease, the hallmark of the cardiac disease, which is hypertrophy, but also continue to show sustained improvements in the modified Friedreich Ataxia Rating Scale is what we think will make this, in totality, a very compelling treatment for patients with this disease. So the patients that you saw in the video, we've met many of them. They've come to meet our colleagues in our company. We're passionate and motivated to deliver a treatment for those patients as well. We hope to be able to save their lives as well with this treatment.
And just how do you think about the patient funnel in terms of the patients you think that would be most likely to adopt?
Yeah. I think the early adopters, in our view, most clearly will be the patients with abnormal left ventricular mass, so those that are the furthest and closest to latest stages of cardiac disease. As I mentioned, 80% of patients, the cause of death is heart failure or cardiomyopathy. So those patients would be most urgently seeking treatment because they're the closest to that type of event. I think as we get more treatment experience and treatment history, I think we'll move towards earlier patients that are earlier in the cardiac disease continuum, and obviously, those without cardiac disease but can benefit from some of the neurologic benefits that we're showing would be sort of the third-tier patients that we'd be focused on.
So that tier of later-stage heart disease, earlier patients with earlier heart disease from a prevention standpoint, and then those patients that are benefiting from the neurologic benefit that we're showing is sort of the cadence of uptake that we'd expect in the commercial market.
Okay. All right. Great. Nolan and the entire Lexeo team, I want to thank you so much for being here, and thanks for all the listeners for joining in as well.
All right. Thank you.