Lexeo Therapeutics Stock

Good morning, and welcome to Lexeo Therapeutics webcast presentation. [Operator Instructions] As a reminder, this call is being recorded.

I would now like to turn the conference call over to Ashley Kaplowitz, Head of Capital Markets at Lexeo Therapeutics. Ashley, please go ahead.

Thank you, and good morning. Earlier today, we issued a press release announcing the signing of an agreement to acquire Mantle Therapeutics and 3 new research collaborations focused on CNS-targeted gene therapy strategies in Friedreich's ataxia or FA. A copy of the press release and slides to today's call can be found on our website at lexeotx.com. Joining us on today's call are Nolan Townsend, Chief Executive Officer; Nani Bhalla, Chief Medical Officer; and Louis Tamayo, Chief Financial Officer.

Before I 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 purpose 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.

Thanks, Ashley, and thank you all for joining us this morning. Today, we are excited to announce that we have entered into an agreement to acquire Mantle Therapeutics alongside several new research collaborations, significantly expanding our presence in FA. Over the past several years, we have established a strong foundation in FA cardiomyopathy through the development of LX2006. Our initial area of focus was cardiomyopathy because it remains the leading cause of mortality in FA, and we believe that addressing that burden represented the greatest opportunity to improve outcomes for patients.

Today, we are building on that foundation by adding complementary therapeutic modalities and CNS-targeted gene therapy strategies, advancing our objective of building a best-in-class platform that comprehensively addresses both the cardiac and neurologic manifestations of FA. As the field has evolved, it has become increasingly clear that patients and families value a comprehensive approach that addresses both the cardiac and neurologic aspects of disease burden.

As we walk through today's announcement, you will see how this strategy will meaningfully expand our FA platform without changing our near-term priorities. LX2006 remains the backbone of our FA disease area strategy, and we believe it has the potential to become the best-in-class therapeutic for treating FA cardiomyopathy. SUNRISE-FA 2 remains our highest operational and capital allocation priority. These new assets and collaborations are designed to complement that foundation and maximize our overall benefit in the neurologic pathology of FA.

In addition to gene therapy, we will soon have small molecule, protein replacement and RNA-based strategies, providing multiple differentiated approaches to increase or replace frataxin in the brain and address the neurologic burden of FA. This broader toolkit will allow us to pursue multiple biologic theses for successfully treating the components of FA mediated by the central nervous system, while leveraging the infrastructure and expertise we have already built around LX2006 to extend our leadership in FA and create additional long-term value.

Importantly, achieving a compelling return on investment for this acquisition does not depend on advancing every program. Upon closing, we intend to evaluate the acquired programs against predefined scientific, clinical, strategic and financial criteria and prioritize investment in the opportunities demonstrating the strongest potential for clinical patient impact, regulatory success and shareholder value creation. Our cash runway guidance into 2028, which remains unchanged, includes plans to advance one acquired program into clinical development. We expect to provide a program prioritization update in early 2027 and submit an IND for our next FA development candidate in 2027.

FA is a progressive multisystem disease with substantial unmet need. Cardiac complications remain the leading cause of mortality and is the reason LX2006 continues to be such an important potential therapy for patients and providers. At the same time, neurologic manifestations affect patients throughout the course of the disease and contribute significantly to long-term disability and reduced quality of life. We are already observing a statistically significant improvement in the neurologic component of FA with LX2006, and we believe this benefit could be further expanded with therapeutics specifically designed to target the brain, a key organ to address in order to maximize patient benefit and achieve a best-in-class treatment for patients with FA.

Let me spend a moment on the transaction itself. Lexeo will acquire Mantle Therapeutics for $8.3 million in upfront consideration, gaining access to a differentiated FA portfolio that includes a clinical stage asset with early functional and biologic signals. The agreement also includes up to $13 million in success-based clinical and regulatory milestone payments, bringing the total potential consideration to $21.3 million. This transaction is complemented by 3 new research collaborations with Weill Cornell Medicine, Vivet Therapeutics and Apertura Gene Therapy. These collaborations are designed to evaluate cerebellum-targeted sequential dosing of frataxin gene therapy, alternative CNS delivery and strategies that may support repeat dosing of LX2006.

With that, I will turn it over to Nani Bhalla to walk through the Mantle programs and research collaborations in greater detail.

Thank you, Nolan, and good morning, everyone. As you can see on Slide 7, the Mantle portfolio includes 4 programs, which I will highlight in more detail on the next 2 slides. Starting with LX3010. This is a clinical stage oral combination therapy designed to increase frataxin expression while addressing mitochondrial function and oxidative stress through complementary mechanisms, including HDAC inhibition and Nrf2. What we find particularly interesting is that the early data include both a functional signal and direct evidence of increased frataxin protein. Early clinical data include an approximately 6-point improvement in mFARS scores at 16 weeks and a mean ninefold increase in frataxin protein levels from baseline in muscle biopsies across 11 Friedreich's ataxia patients. We plan to further evaluate the durability and reproducibility of these findings, but we believe the data generated to date support continued evaluation of the program.

LX3030 is a preclinical stage oral, tissue-penetrant small molecule designed to increase production of endogenous frataxin in the central nervous system. It is a third-generation benzamide HDAC inhibitor that builds on published clinical work demonstrating that oral benzamide HDACs can increase frataxin in patients with Friedreich's ataxia through epigenetic modulation and acetylation of chromatin. Preclinical studies have demonstrated robust increases in frataxin supporting continued evaluation of LX3030 as a differentiated oral therapy.

As we think about the unmet need in Friedreich's ataxia, neurological manifestations remain a major challenge. An oral therapy designed to reach the CNS and meaningfully increase frataxin could represent an important opportunity, particularly if it improves upon earlier approaches in this class. While still preclinical, we believe LX3030 has the potential to be a highly differentiated asset within the FA landscape.

What excites us about LX3050 is the opportunity to test a fundamentally different biological thesis of directly replacing deficient frataxin. LX3050 is a preclinical stage recombinant human frataxin fused to a proprietary anti-TfR1 Fab. It is intended to directly replace deficient frataxin and uses a TfR1 targeting brain shuttle designed to cross the blood-brain barrier and increase delivery of frataxin to the brain. In vitro studies have demonstrated dose-responsive improvements in measures of mitochondrial function, providing early support for the program's proposed mechanism. We believe that diversification of mechanism is important in a disease as complex as FA, and this program uses a potentially differentiated protein replacement strategy designed to reach disease-relevant tissues, including the CNS.

Finally, LX3070 is a discovery stage ASO Fab conjugate program designed to stabilize frataxin messenger RNA and thereby increase translation of endogenous frataxin protein. The program combines an RNA-targeted mechanism with a proprietary anti-TfR1 Fab intended to support delivery to disease-relevant tissues. In vitro studies have demonstrated dose-responsive increases in frataxin. What we found particularly attractive here is the combination of a novel mechanism and a delivery strategy intended to reach the central nervous system.

Together, the 4 programs will give us distinct approaches to either increase endogenous frataxin production or directly replacing the deficient protein. As these programs progress, Lexeo will have the opportunity to identify a differentiated lead neurologic program with the potential to deliver meaningful clinical benefit.

We have also established 3 new collaborations to evaluate cerebellar targeted sequential dosing of frataxin gene therapy. Each collaboration is designed to complement systemically administered LX2006. Starting with Weill Cornell Medicine, we are particularly excited as this collaboration builds on encouraging large animal data that were previously presented at ASGCT earlier this year. In those studies, animals received systemic intravenous LX2006, followed by a second intracisternal administration into the CSF and directly to the cerebellum 8 weeks later. Despite preexisting immunity to the vector, potentially therapeutic levels of vector genomes were detected in the cerebellum through both approaches. We believe these findings provide early support for the feasibility of sequential dosing strategies and reinforce the opportunity to explore broader neurological applications of LX2006 in the future.

With Apertura, we are excited to gain access to novel blood-brain barrier crossing capsids. One of the key challenges in neurological disease is achieving effective CNS delivery while maintaining a practical patient experience. This partnership gives us access to technology that may enable an intravenous route of administration to target the CNS, enabling a less invasive approach following initial systemic administration of LX2006.

And with Vivet, we are evaluating technology that may help address one of the fundamental challenges associated with repeat administration. If successful, novel immune modulation strategies could play an important role in enabling future sequential dosing approaches and expanding long-term flexibility for gene therapy. Importantly, these collaborations provide opportunities to explore broader neurological applications, alternative delivery approaches and future sequential dosing strategies, all while maintaining our focus on successful execution of SUNRISE-FA 2.

I will now turn it back over to Nolan.

Thank you, Nani. What these programs and collaborations provide is the potential to expand Lexeo's opportunity beyond FA cardiomyopathy and address a broader portion of the FA population over time. Today, LX2006 is focused on patients with Friedreich's ataxia cardiomyopathy with the potential to expand the opportunity to additional FA patients based on future mFARS data from our ongoing studies. The complementary modalities and CNS-targeted gene therapy strategies we have discussed today may further broaden our reach, including the patients with predominantly neurological disease and those across different stages of cardiac involvement.

Slide 12 shows how we intend to pursue the broader opportunity. We believe the clinical and biological rationale for LX2006 as a treatment for FA cardiomyopathy is strong, positioning it to serve as the backbone of a broader FA treatment platform. Each of the Mantle programs has the potential to complement LX2006, whether as a stand-alone sequential or combination therapy. While targeting the heart is central to addressing mortality in FA, safely and effectively transducing the brain has historically been a significant challenge for the field. The Mantle programs and research collaborations will provide multiple approaches to addressing that challenge, including strategies that increase or replace frataxin and extend the potential of gene therapy into the CNS.

To conclude, today's announcement significantly advances our long-term vision for Friedreich's ataxia. LX2006 remains our highest priority development program and SUNRISE-FA 2 remains our top operational and capital allocation priority. We are particularly encouraged by the continued momentum in CLARITY-FA, our natural history study, with 22 participants enrolled or imminently enrolling in the study to date. This provides an important pool of potential participants who may transition into SUNRISE-FA 2 pending eligibility. In parallel, we continue to work on clinical site activation for SUNRISE-FA 2 to support continued enrollment. The transactions announced today will strengthen our leadership position in FA and establish a differentiated platform with meaningful potential for patients and long-term shareholder value.

I will now turn the call over to the operator for Q&A.

[Operator Instructions] Our first question comes from Roanna Ruiz with Leerink Partners.

A couple from me. One big picture question. Can you talk a bit more about your strategy to prioritize the multiple acquired programs and strategic collaborations? What might be the go/no-go decision process that might happen before you file an IND, et cetera?

Sure. So thank you for the question. So I think we intend to and have been prioritizing the programs against predefined patient impact, regulatory probability of success and overall return profile characteristics. And what I mean by return profile is the cost of development to get to meaningful milestones and progress the program through the clinic. I think each program has its advantages. I think there's some very interesting therapeutic approaches here, and we intend to evaluate all of the existing data and add some additional studies to what exists today out of the Mantle portfolio to make a fully informed decision about which is the program we intend to progress most rapidly.

But I think what's interesting here is this portfolio allows us to evaluate multiple biologic thesis around treating FA in the brain. And obviously, we can do this in the context of other programs outside of our walls that are progressing alongside and the regulatory developments that occur around those programs as well. So I think we're both looking at the internal data and internal data we intend to create, but also looking at the regulatory landscape as it evolves in FA around us as well.

That makes sense. And could you elaborate a bit more on some of the early data and discovery work that got you excited about the Mantle programs above others that you might have looked at? And any other nuances or information that you think we should know about these programs?

Well, so first off, I think that what's exciting about this and certainly including the research collaborations is that every one of these approaches is fundamentally complementary to LX2006. LX2006 remains the top development priority. As was mentioned, we have 22 patients in CLARITY-FA. So we're progressing well towards fully enrolling these studies, getting to the pivotal study readout, moving this program into a BLA. So we are thinking about life cycle here. And obviously, we believe we have the best-in-class cardiovascular therapy for achieving a 2- to 3-point improvement in the mFARS scale. And the question is, can we do more for patients by adding an additional therapy on top of that in the future.

So first off, I'd say all are complementary. I think for the HDAC program, what was interesting for us is obviously the muscle biopsies, increases in frataxin there. We've not seen that across programs that are out there today. So I think that's what was interesting for us. But what's interesting as well is that, that strategy could also be benefited by a second-generation or third-generation HDAC program as well. Obviously, a protein therapy that has a brain shuttle that can maximize the biodistribution into the brain is also interesting. So I think we have a lot of interesting candidates here, and we intend to evaluate all of the data to make a decision about what's the best program to take forward as we advance LX2006 into its pivotal study data in the second half of the year.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

This is Ayan on the line for Kristen. Congratulations on the announcement here. I guess first, what are some of the best ways to truly understand the potential of the neurological benefit from these CNS-directed programs? Just anything beyond mFARS given that you've already seen some benefit here from LX2006?

So I think the question was how to best understand the potential of the pipeline. I think that, one, from our perspective, from a commercial standpoint, obviously, LX2006 as we're working towards the best-in-class treatment for FA cardiomyopathy. There's a meaningful percentage of the FA population that has existing cardiomyopathy, whether it's via cardiac hypertrophy or earlier components of the disease, such as elevated troponin and wall thickness. So there's certainly commercial market opportunity associated with that. But I think what LX2006 is probably not addressing as well as patients that do not yet have cardiovascular involvement in the disease. And I think that this is where the pipeline we're adding could have a meaningful benefit for patients, those that have primarily or only the neurologic component of the disease at current.

So I think in terms of potential, one could look at the other side of the disease, patients that are only challenged with the neurologic symptoms and think about the commercial market potential associated with treating the brain. I also think the addition of a therapy to patients that were previously treated with LX2006 really strengthens even the profile of LX2006 commercially that patients don't need to choose between a cardiac therapy and something else that as we have treatment arms in our future trials that include previously treated patients with LX2006, we can demonstrate the maximal effect size in the components of the disease that are mediated by the brain. So I think it both strengthens the LX2006 commercial opportunity, but also expands to patients that do not yet have cardiac involvement in the disease as well.

Great. Makes a lot of sense. And I guess sort of touched on my second question, which was on how you envision the IV infusion and the CNS-directed therapy ultimately being given together. And from the answer, it sounds like there's some rationale here for sequencing these treatments.

Yes, absolutely. If you're talking about gene therapy for the brain, we had a poster at ASGCT demonstrating the potential of sequential dosing. So nonhuman primates that were previously treated with LX2006 systemically were subsequently treated with an intracisternally administered gene therapy to the brain. We demonstrated that, that gene therapy reached its target in terms of transducing the cerebellum. So it showed what's possible for sequentially dosed gene therapy. And I think the gene therapy research collaborations really expand on that proof-of-concept work.

So whether you look at non-gene therapy approaches that come through the Mantle portfolio or the potential gene therapy -- the gene therapy research collaborations and the potential there, both are designed to being complementary to what we view to be the backbone of FA treatment for cardiomyopathy being LX2006.

Our next question comes from Tessa Romero with JPMorgan.

This is Caroline Pocher on for Tessa Romero with JPMorgan. Just a few from us. So acknowledging that your cash runway includes plans to advance one acquired program into clinical development, how do you see each of these opportunities from Mantle's portfolio stacking up in your view in terms of relative risk? And which asset do you think has the largest potential reward?

Well, I'd say, early for us to draw a formal conclusion on that. We guided to provide a pipeline prioritization update in early 2027, and that's where we'd intend to sort of communicate which of the programs we intend to take forward most rapidly. I would say each has their own advantages. All of them are complementary to LX2006. So we'll communicate in early '27, which one we've prioritized and sort of the rationale behind that prioritization. But we're certainly considering which program is positioned to move forward into the clinic the fastest, which program can demonstrate clinical proof of concept fastest, but also looking at the regulatory landscape and the types of approaches one can utilize to consider an accelerated approval for certain of these assets behind LX2006 is certainly some of the considerations here. So that's something we will be able to guide to early next year.

Okay. Great. And if I could just squeeze one last one in here. Of the 22 participants that you noted are enrolled or imminently enrolled in CLARITY-FA, how many do you think will be eligible to feed into SUNRISE-FA 2?

That's a number we don't yet have and that many are undergoing neutralizing antibody screens. But I think we'll give an enrollment update at a major milestone when it comes to SUNRISE-FA. But we are very encouraged by the number of patients that we have in CLARITY. Obviously, all of the patients in CLARITY aside from neutralizing antibodies meet the inclusion criteria of SUNRISE-FA 2. So it demonstrates that we are able to rapidly find patients that represent the phenotype that we would enroll in CLARITY-FA. So things are moving well there, and we're excited to see this number of patients that are in the CLARITY side of the study.

Our next question comes from Leland Gershell with Oppenheimer.

It looks like some interesting opportunities for Lexeo here. Nolan, just wondering with 2 of the more advanced Mantle programs focused on HDAC, just wondering if you could share with us what we know about kind of HDAC inhibition and its potential in FA and what the consistency and breadth of maybe HDAC inhibition across various patients with FA might be?

I would ask Nani, our Chief Medical Officer, to say a few words just about the broader strategy.

Yes. So certainly, there's data on HDAC inhibition, looking at frataxin and looking at the mechanism of action that we described. So as far as -- when we look at our programs and the programs that we have acquired from Mantle, again, the idea here is how do you get HDAC inhibition to the brain preferentially. And that's where the fusion and the binding with the Fab and everything becomes really important as we think through the approaches that we have. So I think from an HDAC inhibition perspective, from a mechanism perspective, there's data -- clinical data on the HDAC component of the combo that we talked about, the 3010 in the clinic, and we are leveraging that. There's earlier data from other companies on HDAC as well inhibition.

So when we look at all those data sets, we're encouraged by what we see. And this is also a third generation, the one that's in clinical development right now, third-generation benzamide HDAC inhibitor. So we feel that, again -- and that's designed to be a little bit more potent, have more preferential drug crossing. So those are all the things that we feel are complementary to the backbone of 2006 for the cardiomyopathy side of things.

You'll be able to find scientific literature on HDAC for Friedreich's ataxia and improving frataxin. I think the third-generation HDAC program represents a lot of the principles of what you may find in scientific literature, but includes some elements that will make it a safer -- clinically safer treatment than what you may see out there. So I think more to come on this as we work towards the prioritization. But I think the most advanced program shows the potential of that approach. And obviously, the increase in frataxin and muscle is something that is notable.

And the question is, can the next program achieve an even greater benefit? Or is the current clinical program the best one to take into future development? So these are a lot of the decisions we'll be working through here. But I do think we have a really interesting opportunity to get one of the programs into the clinic pretty rapidly to generate data in the near term, and we're excited about the potential benefit for patients.

Great. We look forward to learning more when you have your program prioritization review with us down the road.

Our next question comes from Brian Skorney with Baird.

Congrats on the deal. Really nice to see the company really leveraging into a really horrible disease without a lot out there to meaningfully move the needle. I'm just kind of curious in sort of broad strokes about the sequential dosing strategy and just sort of overcoming baseline antibody titers that would be predictive for immunological reaction and rejection of AAV-based therapy. You have baseline entry criteria for maximum titers in SUNRISE-FA, but maybe based on the Cornell data for intracisternal administration, at least in terms of some specific time line of dosing that titer may not be as relevant. You also have this imlifidase license.

And I know there are other companies out there looking to, kind of, crack this immunological egg that limits dosing and redosing. And in particular, Sarepta, I believe still has an ownership stake in Lexeo. And I would be interested to know how much dialogue there is there because they, I believe, also have a license for a different imlifidase through Hansa that they terminated. So I don't know how much insight you have into what happened there. But just sort of how do you kind of think about a target for antibody titers for systemic administration versus intracisternal and sort of the stepwise process of sort of increasing the ability to target higher and higher titers and eventually redosing on a sequential basis in patients or even redosing systemically in patients?

Yes. Thanks, Brian. So thanks for the question. And I think we're -- the first thing I'd say is I think we're really charting new ground here. I think when most companies talk about redosing, they're referring to redosing the same compartment. So a systemically administered therapy and then redosing it with another systemically administered therapy. I think what has not been explored is dosing one, let's say, compartment, let's call it systemic dosing and then sequentially dosing, for example, the brain, which is a different compartment, which many would believe to be immune privileged. So as you dose a patient systemically, you may not create immunity in the brain.

And I think that that's what we understood and that's the conclusion we reached from the nonhuman primate studies that were part of our ASGCT presentation where we demonstrated that despite a patient -- sorry, despite a primate being treated systemically, they were sequentially dosed with intracisternally administered vector and that vector reached this target in the cerebellum. So we know therapeutically that sequential dosing is very much feasible.

The question as you're raising is then the subsequent antibody response from the systemic leak of the vector. And I think that's where the IgG approaches really come in to manage that safety risk. So that's where we would be focused is on ensuring that the IgG approach manages the safety risk associated with the systemic leak of the vector following the CNS portion of the administration.

In terms of specific titers, I don't think we have a cutoff predefined. And then in looking at the capsid from Apertura, we're also evaluating even the cross-reactivity between AAVrh10 and that capsid and it may be that they're sufficiently different from one another that there's not even a systemic immunity question that emerges there. So I think that's all of what we intend to explore in these research collaborations. I think each one of the sequentially dosed gene therapies has its own potential advantages.

The Apertura capsid is IV administered. Obviously, that will be the most convenient from a treatment approach. However, the intracisternal approach has already demonstrated in primates that it can reach its target in, I'd say, at a reasonable dose. So we'll intend to explore both. The goal here across, again, the entire opportunity set is to find the best-in-class treatment option for patients. As I said -- as we said, LX2006, we believe will be the best-in-class treatment option for the cardiac disease, and we'd like to pair that with the brain-focused treatment option that's best for patients in, let's say, in combination with that in the future. So we'll be looking at all of this as part of the research plans going forward.

Our next question comes from Chris Raymond with Raymond James.

This is Sam Leach on for Chris Raymond. Just a follow-up to one of the earlier questions on LX3010 specifically. So I think there's been a few studies exploring HDAC inhibition in FA and then obviously, the same for NRf2. But has there been any mechanistic studies on combining these approaches? Do you expect the effects to be purely additive? Or do you think there's some synergy that could happen combining these mechanisms?

I think there is existing literature out there on the combining of the mechanisms. Maybe I'll ask our Chief Medical Officer to speak to this in...

Yes. So there is -- obviously, there's preclinical data in the combination from what Mantle use. But previous to that, the data is mostly on the isolated components. It's on the HDAC component of this combo and on the, as you said, the NRf2 to the KEAP pathway. So those data exist. I mean I think it's hard to know whether we would expect a synergistic or additional type of interaction. And that's why as we look at this early data and what we've seen in it, as I said, as Nolan said, it's encouraging, but we want to make sure that there's durability to this data and long-term efficiency to this data. So we'll continue to follow that and see where that leads. But most of the data that exists is actually on the individual components on the clinic side of things.

Our next question comes from Paul Matteis with Stifel.

I had 2 questions on the HDAC program and then just one on the FA pivotal for 2006. On the HDAC program, can you talk a little bit more about safety? HDAC inhibitors, I know not -- all aren't the same, but there's been some historical safety tolerability issues at this class in oncology? And just how comfortable are you with the therapeutic index? And then on the frataxin biopsy data, what did you find in these patients for baseline frataxin levels? And with a ninefold increase, how high are you getting them?

And then lastly, on SUNRISE-FA, maybe just talk about the 22 patients that are in this natural history study and could be enrolled soon? And what are you seeing in terms of LBMI and maybe like the proportion of those patients that are greater than 3 standard deviations?

Okay. Maybe we'll take those in reverse order in respect to the last question on the pivotal study. So as we mentioned, there's 22 patients in CLARITY-FA. I won't go into specifics on the baseline, but I'd say we have a number of patients with very meaningful starting disease, certainly so much so that I think we're very confident in the effect size that we're targeting in CLARITY-FA. That's probably all I can say about the patients' baseline today, but I think we're very comfortable with the disease burden that we're observing in CLARITY-FA.

In terms of your question on the muscle biopsies, again, we're not at a point to get into specific numbers here, but I can say that the patients are getting to a percent of normal in muscle that one would believe to be therapeutic in this disease. So it is a meaningful percent of normal that the patients are getting to that with respect to the muscle biopsies. And I think that, that was probably one of the highlights of that HDAC approach is that increase in frataxin in muscle, which we've not seen across many of the therapies that are being developed today in FA.

Lastly, on the HDAC, I don't know if there's some more that you'd like to say.

Yes, sure. So yes, your point is well taken. I mean, certainly, there's been a lot of data on the HDAC side, which has talked about some of the safety stuff. And I will say that, that's the whole reason with this third-generation molecule, the way it's being designed and how we're looking at this molecule is to actually avoid some of those issues. And that's part of the work that we will be doing as we go forward in the -- on the development -- early development side. So -- but yes, we're cognizant of that. And -- but this is -- just the way this molecule has been designed, it is taking all that into account to improve the safety profile and the blood-brain barrier penetration.

Our next question comes from Luca Issi with RBC Capital Markets.

Congratulations on the announcement. We would like to ask a question about the landscape of the neurological aspect of FA. We already have an NRf2 activator may have a frataxin protein replacement therapy as soon as next year. And then there's also mitochondrial antioxidants behind. How do you think about the neurological space becoming increasingly competitive here? And does LX2006 cardiac differentiation remains sufficient to anchor the platform's commercial thesis even if the CNS program for Mantle would take several years to reach proof of concept? Any color there much appreciated.

The second question, we couldn't hear was a little bit quiet. What I understood you asked in the first question was just about the neurologic side of the disease and the existing treatments that are out there. I think the way we think about this is each of these therapeutics that are in the -- coming to Lexeo via the Mantle pipeline have the potential to be a best-in-class treatment for targeting the brain.

If I were to think about, for example, the protein replacement therapy, it has a transferrin brain shuttle designed to maximize its biodistribution into the brain. And this is obviously highly complementary with LX2006, which is transducing the heart, transducing dorsal root ganglia, transducing skeletal muscle, transducing the peripheral nervous system, but it's unlikely that we're seeing substantial uptake of LX2006 into the brain. So this is where I think the potential of adding a therapy on to LX2006 as the best-in-class cardiovascular treatment that specifically targets the brain could have substantial benefit.

I think the fact that the landscape in FA is developing, we will begin to see what regulatory strategies have been the most effective at achieving approvals. And we have here what will be -- could be fast follower programs behind those that could represent a best-in-class profile. So I think that actually the landscape evolving in the way that you described could be, in a way, advantageous to derisk the regulatory picture and then allow for therapies like these to come very rapidly thereafter.

The second question, we could not hear as clearly. Could -- do you mind repeating it?

I appreciate the color on the first part of the question. The second part was mostly trying to ask about the cardiac differentiation from LX2006. And given the rest of the platform might be a couple of years behind, how do you see these 2 still go hand in hand in terms of the commercial thesis of treating the systemic disease?

Yes. Look, I think the commercial thesis is strong here. We're striving for, call it, category leadership treating the cardiovascular component of the disease through LX2006. We have seen a 28% reduction in left ventricular mass. The -- not only did we see that, but we also saw patients that were abnormal via LBMI return to the normal range. We saw these meaningful reductions in troponin. So we think we're looking at the best-in-class treatment for FA cardiomyopathy in LX2006. And we're already thinking about what to add to that to maximize the effect in the brain to achieve an overall best-in-class therapeutic profile.

And the other thing I'd note is that these therapies may not be years away. We may be in a position to have clinical proof of concept in the relatively near term, given some of the time lines that we've communicated. So I think these could be very much fast followers to an LX2006 BLA approval. We could see the additional therapeutic added to that for patients previously treated with LX2006 and really go from first-in-class with LX2006 to best-in-class with the addition of a brain-focused treatment with the goal from a commercial standpoint would be kind of category leadership in this area.

This concludes the question-and-answer session. Thank you for your participation. You may now disconnect. Good day.

All right. Great. Thanks, everyone. Good afternoon. Happy to be here moderating a chat with the Lexeo Therapeutics team. Super topical time for the company after coming off solidifying their plans for their Phase III program in FA-CM, and we'll talk a lot about that, and then we'll talk a little bit about probably PKP2 later. But maybe I think we're going to get in the weeds fairly quickly on the regulatory stuff and the design of the pivotal and the Lexeo team's thoughts.

But I thought it would be helpful, Nolan, if maybe you could just start off with some brief -- I don't -- just brief opening remarks on kind of where things are at with Lexeo and maybe also level set and just talk about the data you've generated to date in FA-CM, and include some of the nuances we've talked about that I think will kind of help inform your thinking on the pivotal and the patient selection for Phase III and then we can do follow-up. So thanks again for joining. Appreciate it.

Right. Well, thanks for having us, Paul, and we appreciate it. So as many know, Lexeo is a company focused on cardiac genetic medicines. Our most advanced program is treating Friedreich's ataxia, where we're having both an improvement in the cardiovascular component of the disease and the neurologic component of the disease coming out of data from our Phase I/II study.

We've undertaken an effort over the last several months to complete the protocol for our registrational study focused on an accelerated approval. This study is going to evaluate patients that have left ventricular mass index disease burden at 2 standard deviations or greater at a 6-month time point initially for accelerated approval. We'll talk a little bit more about the data that we demonstrated in the Phase I/II study because I think this is an important aspect of how we design the pivotal, both around effect size, endpoint profile, patient profile and so on.

Maybe, Nani, I'll just pass it to you to speak to the data we've generated to date across the patients, in particular, with abnormal LVMI.

Yes. Thanks, Nolan. Happy to discuss that. So the data that we've generated to date have really shown clinically meaningful and durable improvements in cardiac structure. And this is particularly in patients with an elevated LVMI at baseline. And this is the population that's most relevant to our pivotal study. So if you look at the patients with the elevated LVMI, we saw an 18% reduction in LVMI at 6 months and 23% at 12 months and with even greater reductions of 28% and 33%, respectively, in the high-dose cohort at 6 and 12 months.

So these are the effects that we've been seeing, and they are really durable because many of these patients have normalized their LVMI and some are maintaining this benefit out to 3 years. So really a durable effect on disease modification.

And we're also seeing a strong indication on the biomarkers. 6 of 17 patients showed either stabilization or reduced troponin in the study. And this is a pretty favorable impact when you think about the troponin representing a sign of cardiac injury. And alongside, we've shown and demonstrated a good safety and well-tolerated safety profile for LX2006.

So as we think about this, I think there's one patient that really stands out in the Phase I, Phase II data. This is a patient who had quite advanced cardiomyopathy. Their ejection fraction was 35%, and following LX2006 treatment, substantial improvement was noticed in this patient of multiple measures. An 83% reduction in troponin, a 48% reduction in LVMI and an increase, I think the most importantly, from ejection fraction of 35% to 74% at 18 months.

Now, this is a single patient, but it really illustrates the potential LX2006 has to meaningfully improve patients who may be even at a later stage of their FA cardiomyopathy disease. And beyond the heart, we've also seen a benefit on the mFARS scores in the 2006 treated participants in the Phase I/II studies. And if you think of this and look at the patients that we've published now in a propensity-matched analysis from the UNIFAI registry, we're showing a difference -- annualized progression difference of 2.3 points per year. So this is very encouraging to see this data and support the potential broader use for LX2006 and hopefully even a more comprehensive label down the road.

Awesome. Great. Thank you so much. So yes, maybe to that point, level set too, and talk about the recent regulatory update. I think it also would be helpful to maybe also just talk about when you started engaging with CBER and how that dialogue evolved also as the leadership has changed?

Yes. So we started discussions about the accelerated approval path in late 2024. This is when we determined that left ventricular mass index was an appropriate surrogate endpoint for this disease. We then had subsequent meetings in early 2025 and then in late 2025, really beginning to narrow on study design, patient population, structure of the approach.

We had another meeting with the FDA in late 2025 and ultimately submitted a protocol out of that meeting to the FDA in Q1 of 2026. We -- it probably took a bit longer from a response perspective than what we originally anticipated, but we ultimately did have quite a bit of back and forth with the FDA over the last few months, and we're able to finalize the protocol, and we've been able to enroll the first patient in this registrational study within this month. They were enrolled last week. So we've made quite a bit of progress despite, let's say, some delay in response from the FDA, we're still able to meet our guidance on having the first patient enrolled in the study by the end of the second quarter.

Awesome. Okay. Great. So maybe let's talk a little bit about just like the threshold for clinical meaningfulness and statistical meaningfulness. So maybe to start, you guys have historically talked about a 10% reduction in LVMI is clinically meaningful. So maybe one, like to clarify, where does that come from? Is that Lexeo's work? Is that something that you presented to the FDA that they've agreed upon? And then what was involved in the decision to power the study at a 15% effect size? And was this driven by FDA feedback? Or again, what's the thought?

Yes. Maybe I'll say a few words about the 10% versus 15%, and then I'll pass it to Nani to talk about the study design and the statistical picture. So the 10% effect size was the focus of several conversations and document exchanges with the FDA. There is a publication and really one of the seminal publications for mortality in FA, demonstrating that a 10% increase in left ventricular mass index is linked to a 20% increase in the likelihood of mortality from FA-CM.

So this was really the basis of the conversation on the 10% effect size with the FDA. There's never been a different number discussed with them because 10% remains the target number from a treatment effect perspective. So that's really the clinically meaningful threshold in FA and nothing has changed with respect to that.

Now with regards to how we design the study, I will pass it to Nani, our CMO, to speak to the 15% and how we thought about that. And I would note, obviously, he just spoke through, we're at a 28% improvement on LVMI at 6 months. And so from our perspective, a 15% number really looks like a slam dunk study. I mean there's a few factors that go into this that we can talk through some nuances, but I would argue that the 28% could even be an underestimate of the effect size at 6 months given some of the dynamics we'll talk about on an individual patient basis. And so maybe, Nani can just talk to some of the stats and effect size parts of this.

So the rationale Nolan kind of started the conversation that if you look at just our Phase I/II data and you look at the -- on average, patients with an abnormal baseline LVMI, and I think that's one of the key things here, achieved an 18% reduction in LVMI at 6 months. And the higher dose cohorts, if you look at the dose -- the 2 and 3 cohorts, we saw even a greater reduction of 28% at 6 months. And that's the dose that we're taking into our pivotal study.

And again, making sure that these patients are greater than 2 standard deviations above the mean when it comes to the enrollment criteria. And even though we've seen some deepening later on, it's very, very minimal. And really, the 6-month endpoint remains a changeable endpoint. And I think there's been also some discussion about responder analysis. And I think it's important to understand that this is the mean population, a continuous variable as a mean change of the population from baseline compared to the comparator group.

So I think it's important to recognize those. And then when we think about how we look at the Phase I, Phase II data, I think there is a missed fact of this patient -- one of the patients, patient #11, where the data was missing for 6 months because the patient missed their appointment for their imaging because of a hurricane. And we -- and as a result, we assumed the 3-month endpoint, which was about -- just about 10% as their carry forward.

But if you look at what they then did at 9 months and you kind of start from baseline to 3 months to 9 months, it's pretty much a straight line going down. And if you reestimate that patient on that line to suggest that, hey, what would that look like? That would be closer to -- much closer to 20% to 25%. And at that point, that's where we get the 28% from for the 6-month overarching reduction.

So when you take that into account, and then after that, we looked at all the different variability that we've seen in not just our study, but also in published data, one of the data sets that Nolan just mentioned actually and some of the other studies that have documented LVMI distributions. And when we take a look at all that variability, we then ran a number of Monte Carlo simulations, actually about 10,000 Monte Carlo simulations.

And Nolan, if you want -- I mean, Lou, if you want to go to that slide, you can -- and if you look at it, we -- basically, if we take that threshold of 15%, assuming that 28% reduction that I talked about, 99% of the time, you land pretty much at hitting the 15% LVMI reduction in the threshold. So we feel that given those simulations, the variability that we have seen in our data, in other published data, there's a consistency to the assumptions that we've made that we feel very confident after running these simulations that we can match and get the distribution we need to get to that 15% threshold.

And we've also seen initially the patients coming into CLARITY and where they stand when it comes to their overall baseline LVMI. So again, inducing confidence in us that we can bring that distribution to life, which will get us to that 15% LVMI reduction.

If I can just punctuate another point. I mean, look, we're at almost double the effect size that we need to achieve in the trial, and that's with an imputed, therefore, underestimated value in one of the patients. So we'd be at more than double the needed effect size. So I think from our point of view, the trade-off of designing a study around 15% relative to the size of the study that we're going to be running.

I mean, again, this looks to us like a slam dunk study here. Again, we're at 28% with a underestimated value in one of the patients. I mean it really looks like an effect size here that we can be very confident in. The other factor I would note is, as we come into this study, we have patients that will be crossing over from CLARITY-FA, which is our natural history study. So we also have an understanding of the existing LVMI disease burden that's likely to find its way into the treatment study.

And we know that those patients do have meaningful LVMI burden. We know they have enough disease burden to improve by more than 15%. So I think the combination of the effect size that we're observing, combined with an understanding of the baseline characteristics of the patients that are likely to enroll in this clinical trial. The 2 together, I think, give us a lot of confidence that this is a slam dunk study for us at 6 months.

Yes. Okay. Makes sense, Nolan. And so when you guys are powering at 15%, what are like the key assumptions in that? What are you assuming for like the severity of the population that you end up with in the pivotal versus the Phase I/II? And do you feel like you have enough information here given the kind of small Ns and subsets to sort of make a good assumption around variance or other key variables?

Yes. So I think if you look at the assumptions that we just talked about, it's really the distribution at the end of the day, Paul. That's what you would have to strike to get that similar effect size that we have seen in the Phase I/II trials and also in the simulations and the assumptions we've made in the simulations. And certainly, given what we are enrolling into CLARITY, because remember that we have patients that were coming into CLARITY that were then going to feed into SUNRISE-FA 2, and they had the same inclusion criteria as the pivotal study.

So as we look at the initial data set that's in CLARITY currently and those patients, when we look at those distributions, we're pretty comfortable that -- and confident that those patients that are coming in are already starting to represent these LVMIs that we have seen in our Phase I, Phase II and at least similar or in some cases, actually even worse. And that's important because these are the patients who are going to have the room to give benefit, so to speak, on the therapy because we know that the greater LVMI and the greater the starting point, the greater the chance that you will have that benefit down the road. And we're already starting to see that population coming in. So that's actually the driver of the confidence that we can meet this 15% endpoint.

Yes. Okay. Makes a lot of sense, guys. On the assumptions for the control arm, maybe before we even kind of get into the -- just sort of what we know about LVMI test retest variability, if there should be any change in control. Do you want to just give a little bit of context around the FDA dialogue here and how you went from like a pure single-arm study to study now with 2 arms with this concurrent untreated control. Like what was -- what's the rationale there? Yes.

Yes. So I think there are some concepts that evolved a bit during our conversation with the FDA. But from our point of view, there wasn't a wholesale or fundamental change in their position. We always were running a -- there was a single-arm study we discussed, but it was always relative to a natural history control. In fact, CLARITY-FA, the study that we're describing that's now in effect, the feeder study was launched originally as a natural history control to the single-arm study.

I think as the conversation advanced with the FDA, they wanted to find ways to reduce sources of bias -- so having an untreated arm of the study that had the same approach to assessments, the same assessor practices and so on at the same sites would effectively reduce -- sitting in the same protocol would reduce sources of bias and how the patients were being evaluated.

The other difference is, obviously, with the separate studies that the PI could choose which patient goes into the treatment study, which patient goes into the natural history. With this approach, we have -- that we have in this trial, we have a random allocation. So it removes the PI choice of which patient goes into which aspect of the study.

Therefore, ideally reducing bias in that regard, but also potentially resulting in a balance of patients across the untreated and the treated arm, so we can have the most confidence in -- everyone can have the most confidence in the effect across the disease that there, for example, aren't sicker patients in the treatment arm than in the natural history arm.

So I think those are a few of the factors that went into this. From our point of view, that was a design change that we were comfortable with. Functionally, the external natural history relative to the untreated arm is not materially different, did not result in a materially larger or more complex study -- we still have patients that did not have a sham procedure or placebo or anything of that type in the trial, which was important to the -- very important to the patient community. I think we landed in a good place with regards to bridging the gap between the FDA's comments on needing to reduce sources of bias, but also not having a placebo or a sham procedure included in the trial.

Yes. Okay. And yes, going back to the powering discussion, like what do you assume from that sham group? And what evidence can you point to people that sort of shows that the test retest for LVMI measurements in this population should have a little noise or I don't know. I mean it seems silly because this should be objective, right? But like is there any chance that someone could scan with a very high number and then kind of randomly go down 10% the next time? What data can we look at...

I don't know. Nani, do you want to say a few words about that?

Yes, sure. So there is certainly a natural history observational data, that suggests that there is no change, especially in the 6-month period. And when you do see some change, and it never really reaches that 10% threshold, even actually in some of the published data, when you see it even change to some degree, it's because either imaging technology is different. You've gone from MRI to echo, or there are different MRIs being done, different interobserver variability plays into it.

So all of that, but it's never a significant "morphologic change" that's actually occurring in the LVMI. And in our study, we're making sure that we avoid such a thing because we have a core lab that's reading our MR, and they're all on MRI, by the way. So it's not echo or MRI. It's all MRI. It's a core lab that uses a very advanced technology to make sure that there's consistency in measurements across the various measures, the same patient and across all the different patients. And it also then controls for interobserver variability.

Makes sense. Okay. Very good. And just to clarify one more thing on the primary analysis. So does the responder rate no longer matter? I mean, obviously, you want as many patients as possible, if not all to respond, but like from a regulatory perspective?

Yes. So that was a misunderstanding of some kind. There was a discussion of a responder rate for a prior frataxin expression endpoint. And it was binary, either you had more frataxin post treatment, or you had less. That was discussed as a responder rate. But the LVMI was always a continuous variable. We are always working towards an average, and that has never changed. So the design of this study with respect to LVMI and the approach to evaluate it numerically has been consistent throughout our discussion, both with the agency and with Wall Street.

Yes. Yes. Okay. Thank you, Nolan. Appreciate it. Yes. Maybe you've already sort of alluded to this, but do you want to talk a little bit more about enrollment in CLARITY? And I guess, what have you seen so far? And what is your confidence that you can find enough of these very high LVMI patients? And meet your guidance on data timelines?

Yes. Okay. So look, we have a meaningful double-digit number of patients enrolled in CLARITY-FA. I think we have to go through the process of those patients having their neutralizing antibody tests and then consent them into the registrational trial. But I think you can see just from the timing at which we announced our regulatory update and the trial design to which within, I think it's a week or 2, we have the first patient enrolled.

You can see that we have made a lot of progress on the enrollment front with the sites that are ultimately in our treatment study. So I think we're progressing well there and have a lot of confidence. What that also means is we have -- because it's a natural history study, we have visibility into the baseline characteristics of the patients in that natural history study.

So as we agreed on this approach, as we work towards the 15% we had an understanding of the underlying disease burden from an LVMI perspective. So the understanding that patients have enough LVMI disease burden to improve by more than 15%. And I think we can confidently say, let's say, on average, the patient profiles in LVMI that are reflected in our -- at least in CLARITY-FA appear to be even further along from an LVMI perspective than in our Phase I/II study from a disease burden point of view.

So I think from an ability to improve substantially, we have a good understanding of that picture as it sits today, and we'll be working to move as many of those patients over to the treatment study that we can in the near term. We're working across 19 sites in various countries. These are some of the top FA treatment centers globally. But many of these centers, especially outside of the U.S., they've not had they've not had clinical trials there yet. So there's a substantial interest for a lot of those patients, both in the U.S. but also outside of the U.S. to access a treatment like this, and we're seeing that in terms of our enrollment progress and speed as well.

Yes. Yes. Okay. Great. Good stuff. Do you want to briefly just talk about the competitive landscape in FA? There's other players talking about disease modification like Larimar had an update today, design and -- just what's your thought there? And how does that sort of shape where ataxia fits in over time?

Yes. So look, I think there -- obviously, one of the challenges in Friedreich's ataxia as a disease has always been that the different components of the disease have different levels of technical complexity associated with addressing them. And from our point of view, the cause of death in the disease is the cardiac disease. We want to first focus there, prevent patients from progressing in later stages of heart failure that the patients live long enough to benefit from future cerebellum-focused treatments, which we knew would take a lot longer to advance because of the technical complexity.

So I think that, that's the picture that's playing out now. We have the most advanced therapy treating the cardiac disease at a very meaningful effect size whether you look at LVMI, you look at, for example, ejection fraction, troponin, you look across these endpoints, we think we're having a very meaningful impact on this disease. And I think ultimately, you'll see, obviously, with the abnormal patients all returning into the normal range, you're seeing an ability to correct the cardiac disease from a biomarker perspective.

But I hope over time, we also see this improvement in mortality and so on. Now our therapy was designed with a ubiquitous promoter where we're expressing frataxin not only in the heart, but in skeletal muscle, likely in dorsal root ganglia as well. And it was designed that way purposefully so that we could have a broader impact on other aspects of the disease than just the heart.

And so as a result, we're seeing about a 2.5% -- 2.5 point improvement in mFARS, which is a neurologic scale, which is roughly equivalent to the commercially approved treatment today.

So I think we're impacting both the cardiac and aspects of the neurologic disease. But I would say that admittedly, it's not a cerebellum targeted treatment option today. So we have started to look at other approaches. Notably, we presented data at ASGCT this year, showing that sequential dosing of a gene therapy is possible. And what I mean by that is a systemically administered vector followed by a brain-targeted vector, and we evaluated both intracisternal administration and we evaluated intraparenchymal administration.

In both cases, the gene therapy reached its target of transducing the cerebellum. So the point I'm making is that the introduction of LX2006 can be complemented with other CNS-focused approaches in the future. So I would argue that we're advancing the best-in-class cardiac treatment, and this would need to potentially in the future to the extent this is derisked in the right way, can be paired with a best-in-class neurologic option, whether it's one of the gene therapy solutions or one of the non-gene therapy solutions.

It's not necessarily my understanding that every therapeutic option out there that's treating FA is a direct competitor to one another. There's nothing to prevent a patient that's been treated with the gene therapy from receiving one of the other modalities. And even as I described, a patient treated with LX2006 may still be able to benefit from an interdentate nucleus approach as a stand-alone thereafter.

So I think there's still a lot to play out here in the competitive landscape. To my knowledge, we have a handful of patients that have been dosed with any other gene therapy. I think from an efficacy signal perspective, I think there's still more to look for here with some of the other treatments. And so I think we're just going to be waiting to see how the competitive landscape plays out. I think it's always great to have more options for patients, particularly where they're complementary to one another, and they can address different components of the disease in combination.

Yes. Okay. Great. One last question on FA that I missed and then we can briefly talk about PKP2. But just as it relates to the pivotal study, I think you've talked about 2 dynamics I wanted to just kind of get into. One was that there's this opportunity for a blinded interim sample size reestimation if needed. So maybe talk about just when that happens and like the mechanics and scenarios around that.

And then second, I think you're allowing patients to cross over from the untreated arm to drug at 6 months. Yes, I mean, maybe not connected, but comment on that as well. Does that like influence your ability to like sort of look at the 12-month data as a backup option if the 6-month data was less robust than expected? So I realize there's 2 questions in there, but just around that discussion.

Do you want to take the first one, and maybe I'll try to take the second.

Yes, sure. So if you look at the question you asked about sample size reestimation of blinded fashion, so that would occur when half the population has reached 6 months, their 6-month endpoint. So basically, we would have looked at half the population a blinded way to understand what kind of blinded change we're seeing, and that's where the DMC will assess the data and make a recommendation regarding a sample size reestimation.

What I'll say is that given where we are right now and given the standard deviations that we have thus far assumed in our simulations and what we have seen in our trial, if those assumptions hold up and those standard deviation across the measurements hold up, the chance that we will require a sample size reestimation to occur is extremely small.

So that's, I think, the punchline there that it just -- it's -- if everything holds up that we have talked about, it is an incredibly small probability that we will need to reestimate or change the sample size in any way. So that's the big thing there.

And what I'd say on -- I mean, the question that you're asking is the patients that are crossing over. I think, one, from an ethics perspective, to have patients stay in an untreated sort of setup for a meaningful amount of time, there are some questions there. But I think more importantly is this, the untreated arm is designed to show that LVMI does not spontaneously change.

And we're going to be pulling data in support of that, both from our own study, those untreated patients. There are untreated patients in CLARITY-FA, some of which have been in the study for quite a long time. We have data, therefore, in CLARITY-FA supporting the idea that LVMI does not spontaneously improve. And obviously, there are other outside natural history databases. We have access to natural history data from Cornell.

We have access to a study in Australia. We have access to a natural history registry at CHOP, so on and so on. So there's quite a bit of data out there with cardiac MRI that we can utilize to support the case that it does not spontaneously improve. So I just mentioned up to 5 data sources. So to the extent we have patients that have crossed over and we're able to look at the longer time points, we have several different sources to utilize to support the case that even without those patients still on control at 12 months that LVMI should not spontaneously improve so that the effect size that we see across all 26 patients is credible relative to that. These are not -- it's not an efforts-based endpoint -- and it's one that's very objective in its measurement approach.

Yes. Yes. Okay. All great. Makes sense. Thank you guys for all the added the detail. Yes, maybe we can briefly just talk about PKP2 and you had some preliminary data this year on JPMorgan. How much additional data are we going to get next? And what's your expectation for how that data might mature? Is this the type of disease where you think the effect could sort of expand over time? Or is just durability sort of good enough to remain excited?

Yes. So maybe I'll say a few words, and I'll ask Nani to add. So we showed at the JPMorgan conference this year, I believe, roughly 14% improvement in premature ventricular contractions versus the pretreatment baseline. We showed about a 22% improvement in non-sustained ventricular tachycardia at the same time point.

This is with most of the patients at 6 months of treatment follow-up at the highest dose, which is the earliest time point where we can evaluate efficacy. We also have a natural history study running along that -- alongside that trial. We saw about a 20% worsening in non-sustained ventricular tachycardia across that same time point. So if you look at the delta between the 22% improvement and the 20% worsening, we're at about a 42% effect size on non-sustained ventricular tachycardia, which there's a discussion we're having about whether this is a surrogate or this is even just a real clinical endpoint that we're evaluating that's very central to this disease.

So we're having about a 40% improvement in an endpoint that's highly clinically meaningful. We think that, that's an interesting early signal. And what we saw for the patients that were at longer follow-up, so there are patients at 9 months of treatment follow-up in that high-dose cohort, we saw about a 65% reduction in non-sustained ventricular tachycardia, which is a very meaningful effect size there.

So I think we are seeing that deepening over time. I think we're at a pretty meaningful effect size already. What we should have later this year is all of the patients at least 12 months of treatment follow-up, maybe one will be short of that, but we'll have the vast majority of the data set at 12 months or greater of treatment follow-up. So I think we'll really get a sense of where the effect size is trending.

I think to expect that all of the processes in respect to biology have all concluded themselves at 6 months and especially in a disease like this would be very optimistic. I think we can continue to expect a deepening effect. And I think the other thing we're looking for is consistency of effect across the patients that we see improvement across the majority of patients in the disease.

So I think we're looking at data of all 10 patients -- all of them should be at 12 months. And we also have 2 patients that we've treated since the last data readout that there has not been 6-month data seen for those patients yet either. And those last 2 patients are in our commercial manufacturing process. So it's our highest potency process that those patients were dosed with as well. So I think we're in good shape on the safety front as well. Obviously, no new safety updates either.

Yes. That's great, Nolan. What additional work needs to be done on endpoints and effect size on something like NSVT to get the FDA comfortable with the measure and comfortable with what constitutes a clinically meaningful benefit.

I don't know, Nani, do you want to say a few words about that?

Yes, sure. So yes, so the NSVT reduction we've seen so far, as Nolan said, is very, very compelling. And I think that's a more important endpoint if we think about relative to PVCs. PVCs are incredibly variable. There's much more to PVCs than just maybe even a drug effect. There's a lot of patient variability. There's a lot of other things that can induce PVCs, just exercising, walking up the stairs, drinking a couple of cups of coffee, et cetera. So there's a lot of variability that can occur.

So NSVT reduction really remains the main endpoint, and we think that's the compelling endpoint that we have to go after. And as Nolan said, it's not just that maybe it's a surrogate, but even thinking about it as the formal confirmatory endpoint for a trial like this. And from an efficacy and what we think is a compelling efficacy, 20% is a good bar. That's -- we've shown that bar currently in our data set.

And if you think about where the current standards of care are, they're nowhere -- they're kind of around that 20% or lower than that. And those are drugs like amiodarone, which are usually given high dose in these patients. They have -- they don't -- they're not without their side effect issues, and it makes it very difficult for patients to stay on these types of drugs for long term.

So really, we think that given to where the standard is currently, we can beat that and improve on that if we shoot for that 20% type of therapy with just one injection and hopefully getting beyond what the patients will need from the current standard of care.

Yes. Okay. Great. And so is the plan to engage the FDA soon after this next data cut?

Well, we have guided to a regulatory update this year. We expect to have one. We've not guided to the timing of that update yet. Obviously, we're describing a meaningful body of work to first validate the endpoint, the clinical meaningfulness of the endpoint. I have this question, is it a surrogate or is it just a clinical endpoint? So we're actually working towards full approval instead of accelerated approval.

So topics like that will take some time, but we can commit -- reconfirm our guidance that we will have a regulatory update this year, and we will have the data update this year. So I think it's an important year for PKP2 for us, obviously, with the 12-month data. We're already seeing an effect size that's similar to the standard of care. And this is without even the later time points yet. So we're really looking forward to progressing this discussion with the FDA and working towards this data readout later in the year.

Okay. Great. Well, thank you. This was all super interesting, helpful and clarifying, I think, to me and others listening in here. Maybe just to wrap things up, do you want to talk a little bit about your cash runway, your comfort that you can get through the PKP2 readout and obviously, the FA-CM readout more importantly? And then just any other sort of closing remarks you'd like to make, Nolan or the team, I think, would be.

Yes. From a cash perspective, our last disclosed cash balance at the end of Q1 was $227 million. We're in very good shape. We're burning -- we anticipate to burn in the range of $25 million to $30 million per quarter, and we're very carefully managing that to make sure we get at least through the completion of the BLA filing. So no immediate needs for a cash raise, and I think we're well-funded to ensure that we get through the BLA.

Yes. On closing remarks, I think we're seeing a regulator in CBER that is beginning to shift itself back to a more moderate position. The fact that they're reopening the discussion with companies like uniQure and REGENX and Replimune and others, I think, is a good sign. So I think we're seeing some just overall derisking on the regulatory front that's positive.

I think we have a study design that we can execute given the size of the study, given the number of patients we already have in our natural history study. And I think this 28% effect size that's even underestimated given that imputed time point from that patient we're at a dramatic effect size of the therapy relative to the 15% that we need to achieve. And that's even with patient baselines that patients that are less severe from an LVMI perspective than the ones that we can see are coming into the trial.

So from our perspective, this looks like a slam dunk picture here, both from the type of patients we will ultimately have in the trial, the effect size of the drug, the executability of the trial. And then we have a regulator in CBER that's becoming obviously more flexible or let's say, more open to rare disease gene therapies as we're seeing with these couple of examples that are advancing here.

So I think in general, this picture from our perspective is shaping up very positively. We think there's a lot of great tailwinds behind us from a regulatory point of view and other factors and we look forward to working towards this top line readout and reporting the results next year.

Yes. Okay. Awesome. Well, thank you, guys, very much. Really appreciate the time and all the detail. And yes, thanks, everyone, for joining the call today. And if you have any follow-ups, feel free to shoot me a note.

Thanks, Paul. Appreciate it.

Thanks, guys.

Thank you.

Thank you, Paul.

Good morning, and welcome to Lexeo Therapeutics webcast presentation. [Operator Instructions] As a reminder, this call is being recorded. I would now like to turn the conference call over to Ashley Kaplowitz, Head of Capital Markets at Lexeo Therapeutics. Ashley, please go ahead.

Thank you, and good morning. Earlier today, we issued a press release announcing the finalized registrational trial design for LX2006 for the treatment of Friedreich's ataxia or FA. A copy of the press release and slides related to today's call can be found on our website at lexeotx.com. Joining us in today's call will be Nolan Townsend, Chief Executive Officer; and Nani Bhalla, Chief Medical Officer. Louis Tamayo, Chief Financial Officer, will also be available for Q&A.

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.

Thanks, Ashley, and thank you all for joining us today. At Lexeo, we are committed to pioneering meaningful genetic medicines for individuals living with rare and serious diseases, particularly where treatment options remain limited. Today, we're excited to share important progress on our LX2006 program, which we believe has the potential to make a meaningful difference for individuals living with Friedreich's ataxia.

As announced in our press release this morning, we have now finalized the pivotal study protocol and statistical analysis plan in support of an accelerated approval pathway for LX2006, establishing a clear framework for execution as we advance the program. SUNRISE-FA 2 is an open-label trial in which at least 13 participants aged 16 and older will receive a single IV administration of LX2006 compared with an untreated control group of at least 13 participants who will not receive LX2006. There will be no placebo or sham procedures for participants in the untreated control group. The inclusion of a concurrent untreated control arm was in response to feedback from the FDA aimed at reducing potential source of bias in the study. We designed this control arm to essentially mirror an external natural history control while being implemented prospectively within the same protocol.

This will ensure consistency in study assessments and evaluation methods across both arms. And, importantly, it does not impact key study parameters, including size and duration of the study. In fact, we will now enroll fewer patients in total than the previously guided pivotal study in external natural history control combined. The primary endpoint is LVMI, which will be used to power the study.

We are also evaluating several important secondary endpoints, including mFARS, KCCQ, high-sensitivity troponin I, and lateral wall thickness to provide a more comprehensive view of both cardiac and neurologic benefits of LX2006. We believe this study design best positions us to demonstrate meaningful impact on cardiac disease while also aiming to capture broader functional benefit, supporting the potential overall value of LX2006 for Friedreich's ataxia patients.

We also continue to engage with the FDA on a confirmatory evidence strategy. To date, discussions have focused on the potential use of certain secondary endpoints at the 12-month time point to support a full approval. After we complete those discussions with the agency, we will provide an update.

Turning to CLARITY-FA. Our ongoing natural history study will be used to provide supportive evidence on the untreated disease course for both accelerated and full approval. Enrollment is progressing well with a double-digit number of participants enrolled or imminently enrolling into the study to date. The patients enrolled in CLARITY-FA are eligible to participate in SUNRISE-FA 2 as both studies have identical inclusion criteria.

As a result, we have made a strong start identifying potential participants for the pivotal study while finalizing its study design over the past several months. And as noted in our press release this morning, we expect the first patient to enroll from CLARITY-FA into the SUNRISE-FA 2 study by the end of the month.

With the protocol in support of accelerated approval in place, we are confident in the trajectory of enrollment going forward. And we have seen acceleration more recently as we've activated additional sites for CLARITY-FA, with greater than 60% of participants coming in over the last 2 months. We currently have 19 sites active across 8 countries with more than half of those sites activated in the last 6 months. We know these are the right centers as they represent leading institutions in FA care and also bring deep experience in gene therapy. Further, as we think about the broader potential of LX2006, we are establishing multidisciplinary teams across these centers, integrating both cardiac and neurologic expertise to ensure we are well positioned to address the full spectrum of disease even as our initial focus remains on the cardiac component.

Overall, we are very pleased with the progress to date, and we'll provide enrollment updates at key future milestones. Turning to Slide 5, we are excited to initiate the study later this month. We are targeting a top line data readout in the second half of 2027 and a BLA submission in the first half of 2028. Given the significant urgent unmet need in this patient population, we are taking every possible step to pursue the most expedited path to approval.

Overall, this regulatory update reflects many years of work behind LX2006, and we're focused on executing the next phase of development to advance this program forward, including building the commercial foundation needed to support a successful launch. With that, let me now turn it over to our Chief Medical Officer, Nani Bhalla, who will begin by highlighting the significant unmet need in FA, summarize the latest safety and efficacy data for LX2006 and then provide more detail around the finalized study design and statistical plan for the SUNRISE-FA 2 pivotal study.

Thank you, Nolan, and good morning, everyone. Friedreich's ataxia is a rare progressive multisystem disorder affecting approximately 5,000 people in the United States and about 15,000 globally. While it is often thought of as a neurologic condition, cardiac complications are the most common cause of mortality in FA, and there are currently no approved treatments focused on the cardiac aspects of this disease.

Nearly all people with FA will develop some degree of cardiac complications over time and up to 40% have left ventricular hypertrophy as defined by an abnormal left ventricular mass index or LVMI. This population represents the key target group for the LX2006 pivotal study, although a broader population has been studied in the Phase I/II trials. Individuals with FA have very low levels of frataxin protein. That deficiency disrupts normal mitochondrial function in the heart and in other tissues involved in the disease.

LX2006 has been designed to address the root cause of disease by restoring frataxin. It delivers a functional full-length copy of the frataxin gene using an AAVrh10 vector. This vector has a natural affinity for cardiomyocytes, which allows us to efficiently target the heart and use relatively lower doses, which we believe is differentiating from both an efficacy and safety standpoint. We also designed LX2006 with a CAG promoter, a strong and clinically validated promoter that could drive expression more broadly.

While the heart is our primary focus, given its role in mortality, this approach allows for frataxin expression beyond the heart, including in skeletal muscle and potentially in the dorsal root ganglia. On Slide 9, you'll see a snapshot of the data that has been generated to date. I'll start with the cardiac MRI data, focusing on the 6 participants with abnormal LVMI at baseline, which aligns directly with the inclusion criteria for our pivotal study.

On average, these patients achieved an 18% reduction in LVMI at 6 months and 23% reduction in 12 months. And looking at the higher dose cohorts 2 and 3, we saw even greater reductions of 28% and 33% at 6 and 12 months, respectively. We are advancing the dose used in cohort 3 into the pivotal study. Just as important, these improvements are durable and, in many cases, deepen over time. A majority of participants reach or remain within the normal LVMI range at their most recent visit with some patients maintaining this benefit out to 3 years post treatment, which we believe is a strong evidence of sustained disease modification. Looking at supportive biomarkers, 16 of 17 participants show reduced or stable troponin I levels, supporting a favorable effect on cardiac injury.

And importantly, from a safety perspective, LX2006 continues to be generally well tolerated with no new signals of concern. Overall, these data demonstrate durable, clinically meaningful improvements in cardiac structure and biomarkers, providing strong support for our pivotal study design and the broader development strategy for LX2006. I want to highlight recent data that we shared at ACC on one patient with more advanced cardiomyopathy.

While the majority of participants had normal baseline left ventricular ejection fraction and remained stable post therapy, this patient started with significantly impaired cardiac function with a left ventricular ejection fraction of 35%. Following LX2006 treatment, we observed substantial improvements across multiple measures, including an 83% reduction in troponin, a 48% reduction in left ventricular mass index and an increase in left ventricular ejection fraction from 35% to 74% at 18 months. While this is a single patient, it illustrates the potential for LX2006 to meaningfully improve cardiac function even in later-stage disease. Lastly, we also recently shared interim clinical data for LX2006 at ASGCT, where we showed statistically significant improvements in mean mFARS scores for LX2006-treated participants in the Phase I/II studies compared to a propensity-matched control cohort from the UNIFAI natural history study.

Relative to baseline, the majority of LX2006 treated participants demonstrate statistically significant mFARS improvement or stabilization at their most recent visit with an annualized difference in progression of 2.3 points per year. These are compelling findings showing that LX2006 may benefit frataxin deficiency in tissues beyond the heart, supported by nonhuman primate data showing expression in the peripheral nervous system and the dorsal root ganglia.

The separation from natural history, especially a propensity matched natural history control cohort represents clinically meaningful improvement in this measure of neurologic function specific to FA. Treatment benefit was observed in participants regardless of background use of SKYCLARYS. We believe LX2006 provides a benefit with an effect size that is similar to what SKYCLARYS has demonstrated in its registrational study, albeit run differently. And while a 1- to 2-point improvement on the mFARS scale may sound modest, it has the potential to translate into meaningful functional gains, such as greater ease of daily activities like brushing teeth, handling utensils or dressing. We are very encouraged by this data, particularly as they support the potential for broader utility and a more comprehensive label, including possible use as a confirmatory endpoint. Turning to Slide 12, here, you will see the finalized pivotal protocol details. The study design we shared today builds on our discussions to date with the FDA and incorporates refinements to strengthen scientific rigor while maintaining the same overall study size, duration and open-label framework.

Within the SUNRISE-FA 2 pivotal study, each group will have at least 13 participants aged 16 years and older. Participants in the LX2006 treatment group will receive a single intravenous administration of high-dose LX2006 of 1.2E12 vectors per kilogram. The untreated control group will not receive LX2006 or any placebo or sham procedure, and both groups will be followed for 6 months.

Participants that are eligible and enroll for CLARITY-FA into SUNRISE-FA 2 will be randomly allocated to LX2006 treatment or the untreated control arm. Random allocation is an important element of this pivotal study design. It is intended to minimize physician selection bias, such as providers selecting patients with certain criteria for LX2006 intervention. It ensures baseline characteristics are balanced and strengthens statistical rigor. We have incorporated specific measures within the statistical analysis plan to ensure the treated and untreated control groups are appropriately balanced, in particular, stratifying the 2 groups so that average baseline LVMI is comparable. The top-line efficacy and safety readout is expected after the last patient has completed the 6-month follow-up. After that, participants in the untreated control will have the option to cross over and receive LX2006 and will then be followed as part of the long-term follow-up for over 4 years.

So, we will ultimately generate safety and durability data for a sample of over 25 patients with moderate to severe FA cardiomyopathy. Turning to the next slide. The primary endpoint for SUNRISE-FA 2 is LVMI assessed by cardiac MRI. LVMI is a well-established objective endpoint in FA cardiomyopathy and is clearly linked to cardiac outcomes. Published literature demonstrates a strong link between increased LVMI and an increased risk of mortality in FA, with every 10-unit increase in LVMI associated with a 20% higher risk of death.

Importantly, LVMI has also not been shown to have a placebo effect or vary significantly over a 12-month period in FA cardiomyopathy. This study will include participants with abnormal LVMI at baseline, defined as at least 2 standard deviations above the normal mean and is powered to detect an LVMI effect size of 15% or greater. As a reminder, across the 2 Phase I/II studies for LX2006, -- we saw an 18% mean LVMI reduction at 6 months in patients with an abnormal LVMI treated with LX2006 and a 28% mean LVMI reduction at the same time point in participants with abnormal baseline LVMI treated with higher doses of LX2006, which is what we plan to advance into the pivotal study.

This reinforces confidence in our ability to meet the endpoint. The FDA also recommended removing cardiac frataxin protein expression as a co-primary endpoint. While frataxin expression played an important role historically and prior data clearly demonstrated a plausible mechanism for LX2006, LVMI remains the most relevant and clinically meaningful cardiac endpoint in this disease.

Importantly, removal of this endpoint reduces burden for study participants by eliminating the need for invasive cardiac biopsies, which we believe will meaningfully support enrollment and interest in the study. Although pediatric cohorts will not be included in the top line efficacy analysis, there is significant unmet need among adolescents and younger patients with FA cardiomyopathy. As such, we plan to evaluate the potential of LX2006 in individuals aged 6 to 16 following the establishment of safety in adults. Turning to our final slides. We're pleased with the finalized open-label study design and statistical analysis plan for SUNRISE-FA 2 evaluating LVMI at 6 months. We believe we have landed on a study design that positions us well in generating clinical evidence for accelerated approval. From a manufacturing standpoint, we're in a strong position. The FDA has confirmed that no additional nonclinical murine bridging studies are required and that we are able to use our optimized high-yield SF9-baculovirus manufacturing process to initiate dosing in the SUNRISE-FA 2 pivotal study.

Importantly, clinical drug products have already been manufactured at commercial scale and is immediately available for patient dosing, supporting a timely and efficient study start. Looking ahead, we also anticipate some flexibility in PPQ as previously shared, which will support faster timelines for us to reach a BLA filing. I will now turn it back to Nolan.

Thank you, Nani. We believe LX2006 has a clear and compelling path forward with multiple value inflection points in the near, mid and long term. We remain on track to initiate the pivotal study by the end of the month, an important milestone as we advance the program forward. We are proactively and thoughtfully building the commercial foundation needed to support a successful launch. This includes targeted and disciplined investments in launch planning and core commercial capabilities that we believe are critical to long-term success. From an execution standpoint, we are confident in our ability to advance this program. We bring together a leading cardiac genetic medicines platform with proven clinical and commercial experience and a differentiated approach to development and manufacturing.

Importantly, these capabilities are built to translate our scientific progress into meaningful outcomes for patients while creating long-term value for shareholders. Thank you for joining today. Those impacted by FA are central to our mission, and we are committed to advancing the development of LX2006 given the urgent need for new treatment options. I will turn it over to the operator to help facilitate the Q&A portion of today's call.

[Operator Instructions]

Our first question comes from Mani Foroohar with Leerink Partners.

That looks better if I unmute the line. Congratulations on a great update. Can you walk us through nuances of how a potential label could be influenced by characteristics of the patients enrolled? Is there any possibility that the label could be confined specifically to patients based upon baseline characteristics of severity, et cetera? And I have a quick follow-up.

Yes. Thanks, Mani, for joining this morning, and thank you for the question. I would first say, in general, the improvement in left ventricular mass index corresponded to other important biomarkers that we observed in the Phase I study, including reductions in troponin, improvements in lateral wall thickness. The reductions in troponin and lateral wall thickness are in some ways, independent of the left ventricular mass index starting status. So, we'll have this data from the Phase I/II study to support a future label discussion, which we think will not restrict the label to only these patients that have more than 2 standard deviations of left ventricular mass index at baseline. I don't know, Nani, if you have any other thoughts, you'd like to share related to that.

No, I think you've covered everything, Nolan. I think the fact that we've seen that elevated troponin level in those patients even who had relatively just mildly LVMI in our Phase I, Phase II data suggests that that data is going to contribute to show that these patients benefit regardless.

Yes. And remember, troponin is an important secondary endpoint, lateral wall thickness is an important secondary endpoint. mFARS is an important secondary endpoint. All of these are independent of the left ventricular mass index level at baseline.

You guys anticipated my next question by ending on that mFARS comment. When we think about metrics that apply outside of just cardiac benefit, how do we think about the commercial relevance of mFARS benefit, et cetera? And broadly, how should we interpret that? Obviously, the study is not powered for some specific mFARS benefit. But how should we think about the commercial relevance of that potential incremental benefit above and beyond the direct cardiac implications for survival and cardiomyopathy?

I'll say a few words. I mean I think we're focused primarily on patients that have some form of cardiac involvement. But obviously, given this has obviously a clear neurologic component to the disease, it's important to show benefit there, especially if we want to engage neurologists. But I don't know, Nani, if you have any other thoughts, you'd like to share related to that.

No. I think the fact that when we've seen in our studies, when they were -- when we had SKYCLARYS on board, for example, there was really no particular effect from that where they were on it or not. So, it seems that we are showing a similar benefit that we've seen that's out in the market currently. So -- and the fact that we play well with SKYCLARYS from what we've seen in our Phase I/II data, we feel that commercially, if you're having a drug that shows that similar benefit and also gets you cardiac improvement, that should be a favorable profile overall.

I would go further and just say this would be the best-in-class treatment. So, to see this degree of cardiovascular improvement, we have all of the abnormal patients in the normal range from an LVMI perspective. We have the late -- the patient with the 35% ejection fraction improving, and we're seeing a similar mFARS benefit to the commercially approved therapy. I think these things together would make this from a commercial perspective at the moment, the best-in-class treatment out there. But we look forward to advancing this study and being able to demonstrate that degree of treatment effect across a broader number of patients.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

This is Ian on the line for Kristen. Just following up on the last question. I just wanted to clarify. So, based on the secondary endpoints, have you had discussions about the possibility of this to fully encompass FA and not just cardiomyopathy?

Yes. In short, the secondary endpoint includes mFARS, which is the neurologic scale for the disease, if that was the question. So, it does include aspects of the disease beyond just cardiac and the secondary endpoint. Hopefully, I answered the question.

Yes. Yes, it did. And then just if I could sneak in a second question. What percent of the patients do you expect will have the abnormal LVMI at baseline that you will -- that will meet the criteria that you're looking for to enroll?

100% of them. All will have 2 standard deviations above normal from a baseline characteristic standpoint for left ventricular mass index.

Our next question comes from Brian Skorney with Baird.

Congratulations on finalizing the design. I guess 2 questions. Just on the LVMI change, I just wanted to talk through what your expectations would be around what the concurrent control arm would look like? Would the expectation just be that it would be unchanged in the control arm? Or is there an expectation for worsening? And just how did you arrive at that 15% powering? I think in the past, you talked about 10% change as the endpoint.

Just trying to think is this just to do -- because now you're including the concurrent control, that threshold moves up a little bit. And just maybe clarifying on the last question on the mFARS secondary question, would the understanding be that the initial label would look like an accelerated approval in cardiac in FA cardiomyopathy. And then if you hit on mFARS as a secondary, that label would expand to be a full approval that would just be in FA, not -- without sort of the cardiomyopathy specification?

Okay. Thanks, Brian, for the question. It's a multipart. So, let me just kind of break it down into pieces here. So, the first question you asked was about the concurrent control, the untreated control and our expectations for that. Maybe, Nani, you could say a few words in what we would expect to see in 6 months from that group.

Yes. Thanks for that question. So, we do not expect to see any dramatic change at all, actually, barely any change in that 6-month period in that control group. So, your comment that we don't -- that you just said, hey, we don't expect to see much change and that you will really just see the change in the treatment group, that's correct. That's what the expectation is given the published data that we have out there right now in looking at these patients with that level of LVMI abnormality.

The next question was about the 15%. As we've discussed previously, a 10% reduction in LVMI is linked to a 20% reduction in the risk of mortality. That concept remains the same here. 15% was a powering assumption to give us some cushion relative to that 10%. And as you're also aware, at our higher doses in our Phase I/II study, we've gotten a 28% reduction in left ventricular mass at the same time point. So, we believe we have sufficient cushion above the 10% from a powering assumption perspective, but we believe the 28% effect size that we've seen in LVMI in the Phase I would obviously have us clearing that 15% pretty credibly.

So, I think we landed in a good place with respect to the combination of size, length and so on of the study against that 15% powering assumption. And then the last question you had was about the label, the initial label, or our assumptions of that. I would agree, I think the -- while we've not had detailed label discussions at the moment, obviously, so all of this would be some form of speculation, but I think our view would be that the initial label would include patients with some form of cardiac involvement. Exactly what profile of patients that is would be subject to a discussion.

But I would note that troponin is an important endpoint here. The existence of troponin, we saw this across a number of patients in our Phase I/II -- sorry, elevated troponin. We saw this in our Phase I/II study for a number of patients that did not yet have elevated LVMI. So, to the extent we continue to see that degree of treatment benefit across patients with troponin, and we can see that those results also correspond to our Phase I/II study, I think troponin may be a good biomarker to look at to consider for a patient that has some cardiac involvement.

And so that's the direction of travel from our perspective that maybe troponin would be a good biomarker to consider for a future label and identification of patients that would ultimately benefit from a therapy like LX2006. Over the long term, obviously, we'd love to have a possibility to treat patients even earlier in the disease. But I think we need to also consider what effect we're having on mFARS and at what stage of the disease. And so, I think that's a future discussion and probably one that's relevant for the full approval of FDA dialogue.

Our next question comes from Paul Matteis with Stifel.

This is Matthew on for Paul. And congrats on all the progress so far. I guess I wanted to follow up a bit more on the powering that you mentioned before. Maybe I heard incorrectly, but I think, Nolan, you said that the 15% was a cushion on top of the 10% bar originally. Could you clarify that? And then also, the power is only for the 15%. We wanted to double check if the FDA is -- the bar for the FDA approval, is that still 10%?

And then separately, another quick question. Maybe on the 6-month endpoint versus a 12-month endpoint. I guess from the phase -- from the earlier data, the curves continue to kind of -- or the benefit continues to deepen over time. Maybe how would you be able to show that if the untreated arm crosses over at the 6-month endpoint? Do you have other ways to show that?

So, the first question on powering. So, the bar has not changed. The 10% reduction remains the clinically meaningful threshold. So, that -- nothing has changed with respect to that. The 15% is the powering assumption. Obviously, the effect size combined with the variability of effect is what leads to the size of the study. So, we chose 15%, which we believe to be a conservative number, especially relative to the 28% that we've achieved at the same dose. In the same time frame, and yet it also credibly clears the 10% threshold from a powering assumption standpoint.

So, that's what we designed the study around a 15% observed effect. And that was -- that's the -- what led to the size of the study that you're -- that we're discussing today. In terms of 6 months versus 12 months, while the effect does deepen between 6 and 12, it's not a substantial deepening. So, we're at 28% at 6 months, and I think we're -- we're at 33% at 12 months. All of those clear 10% very significantly by almost double. So, the idea of waiting for 12 months, there's a trade-off of getting the file into the FDA sooner so we can get to an accelerated approval sooner. And we look at 12 months across a range of endpoints as possibility for a discussion around full approval. But that's sort of our thinking around 6 versus 12 that we're seeing a very significant effect size at 6 months. So, why wait for 12 in order to move forward for the top line readout and submit the BLA.

Our next question comes from Christopher Raymond with Raymond James.

Just want to dig in a little bit more to the mechanism, I guess, to cross over from CLARITY to SUNRISE. I think I heard you say that you've got double-digit patients enrolled or identified now for CLARITY. What is the bar? Like, how long do patients need to be followed? I'm sorry if you already answered this in CLARITY and then to be able to cross over into SUNRISE?

I'll ask Nani, our CMO, to take this one.

Yes. Thanks. [indiscernible] Chris. So basically, the patients who are in CLARITY can come into FA at any point. Right now, as Nolan said, we've identified double-digit patients that are being enrolled into CLARITY-FA. And once we get the trial up and going on the SUNRISE-FA 2 and get that first patient in later this month, we will then start to just transition folks as they arrive into CLARITY-FA into the trial. And some of this will just depend on where the sites are, how long it's taking for the sites to get activated and then also whether the sites in the U.S. or Europe.

So, all of that is going to impact the transition time from CLARITY-FA into SUNRISE. So -- but there's going to be -- once the trials are up and running, there's not going to be a particular amount of time that you have to spend in CLARITY-FA to get into SUNRISE. But nonetheless, whatever time you do spend in CLARITY-FA will contribute towards the total evidence that we use because that will still serve as a somewhat of a natural history for these patients before they come into the study.

So, it's still an important data set to mine from that perspective. And then regarding -- and then it just depends on whether they -- whether they consent to get in, neutralizing antibody titers are met, those criteria, but those are the only things that we would be considering at that point.

Yes. It's a very good feeder for SUNRISE-FA 2, the identical inclusion criteria. The only thing that would potentially prevent a patient from crossing over would be the existence of neutralizing antibodies that emerge. And we have to go through and do those tests for neutralizing antibodies and then those patients are eligible to cross over into SUNRISE-FA. So, it's a pretty nice bolus of patients that we're starting with here.

Our next question comes from Tessa Romero with JPMorgan.

This is Caroline Pocher on for Tessa Romero at JPMorgan.

Just 2 from us. So, how much safety data did the FDA express they would like to see included in the BLA filing, both in terms of number of patients and duration? And then what are the other relevant enrollment criteria outside of abnormal LVMI? What changes, if any, did you make from the Phase I/II to the pivotal trial? And are you permitting patients to be on SKYCLARYS in the pivotal?

Okay. So, just to break -- how much safety data -- the second question was.

Change from any new criteria in the LVMI, any additional.

Okay. For enrollment and then -- okay. So just on safety, I mean, the study design reflects the safety database that would be relevant for the accelerated approval. So, the safety data that would come out of this study combined with the Phase I/II is viewed to be sufficient to support the accelerated approval path. So, the study fully reflects a combination of the sort of efficacy bar that we've discussed with the FDA, combined with the requirements on safety data. That's fully reflected in the numbers that you see here. On the next one, enrollment criteria beyond LVMI.

Yes. So there's -- the primary criteria still remain the LVMI, more greater than 2 standard deviations from the mean. So, there's no real change other than that. And then the neutralizing antibodies exclusion inclusion still remains. So, there's really no other major change from Phase I, Phase II other than that LVMI cutoff. And the secondary endpoints that we're looking at are pretty much the same. We were measuring them in Phase I, Phase II and measuring them as we go forward. So, really no major difference.

Well, the one -- we have an ejection fraction cutoff, which we had in the Phase I.

Well, we had one in the Phase I as well, Phase I, Phase II as well. They were just different from what Lexeo had versus Weill. There was a 5% difference there. But basically, we have a cutoff of 35%, which has now been put into the criteria because it was 35% at Weill, 40% at Lexeo. We've just aligned at 35%.

Okay. Great. And then just really quick, are you permitting patients to be on SKYCLARYS in the pivotal?

Yes. They are -- they can be on SKYCLARYS. We're going to have certain criteria for SKYCLARYS. They can be on SKYCLARYS on a stable dose prior to coming in, but we will -- they will not be able to start SKYCLARYS once they are in the study, but they will need to be on a stable dose coming in.

Our next question comes from Leland Gershell with Oppenheimer.

Looks like a strong update here. I just wanted to ask in terms of the pediatric approval plan. So, it looks like with the SUNRISE-FA will be enrolling adults, but you mentioned that there'll be 6 patients evaluated for safety in the pediatric cohort. So, should we expect, the accelerated approval will be adults only and then full approval would contain an expansion down to younger ages? How should we think about the younger age [indiscernible]?

Well, so the pediatric patients are being evaluated for safety. Maybe you want to say a few words about that.

Yes. So, you're correct. The initial trial is patients 16 and over, and then there will be 6 patients between ages 12 and 16 that will be recruited afterwards for just a safety evaluation. And so, the pediatric filing will include those patients, but it will come after the adult database will be submitted first. And then as we start to align on the pediatric plan with the agency along with some of the other discussions we're having with them.

And the same thing outside the U.S. So those are -- but for now, the plan is to come in with the adult indication first. But -- and then come in very soon thereafter because we'll have that data coming in very quickly right after we have the adult population. So, there won't be a huge time difference between coming in with the pediatric side.

Not that the duration is substantial to wait. And just to clarify, it's between 6 and 16, so it's 3, 16 and 12 and then 3 at 12 and 16.

Okay. So, we could see allowance for the younger patients even under the accelerated approval just sometime after the initial approval.

Correct. Yes. A label expansion at that point.

Our next question comes from Moritz Reiterer with Guggenheim.

This is on for Debjit. Congrats on the progress. Most of my questions have actually already been answered. So, just a quick one for me. Just to clarify, the primary endpoint is measured after 6 months with the n of 13 or after all 26 patients have completed the 6-month treatment post crossover?

The former. So, 6 months with an n of 13 relative to the untreated concurrent control.

Thank you. I'm showing no further questions at this time. This does conclude today's question-and-answer session. You may now disconnect. Thank you for your participation. Good day.

Good afternoon, and thank you for joining Guggenheim's 2026 Emerging Outlook Biotech Summit. I'm Debjit, one of the therapeutic analysts and my privilege to welcome my next presenting company, Lexeo Therapeutics. And from Lexeo, I have Nolan Townsend, the CEO; and Louis Tamayo, the CFO. Thank you, gentlemen.

Thank you. It's great to be here. Thanks for having us at the conference.

If I could ask you just do a quick intro before we get into the Q&A.

Yes, sure. So Lexeo is a cardiac genetic medicines company. Our most advanced programs, utilizing AAV gene therapy to correct genetic cardiovascular diseases of high unmet need. Our most advanced program is treating Friedreich's ataxia. Our gene therapy is having a meaningful impact on both the cardiac pathology of the disease and it's showing signals of improvement in the neurologic disease. We'll spend some time talking about the data. But on the cardiac side, for all of the patients are presented with abnormal heart mass, they've all returned into the normal range. We've also seen an effect size on the neurologic scales Friedreich's ataxia that are similar to the commercially approved therapy.

So we think this treatment has the potential to change the standard of care in that disease, and we're moving this program into a registrational study this year, which I think we'll spend some time talking more about. But there's obviously a disease of high unmet need. For most of the patients, the cause of death is cardiovascular disease. So to see this type of treatment effect across the totality of the disease, we're very excited about.

Our next most advanced program is treating arrhythmogenic cardiomyopathy. Here, we're focused on the most common genetic mutation causing arrhythmogenic cardiomyopathy, which is the plakophilin-2 or PKP2. This is a 60,000 patient rare disease in the U.S. So it's more than twice the size of a disease like Duchenne muscular dystrophy, making this one of the largest commercial opportunities in systemically administered gene therapy. We completed the enrollment of a Phase I/II study last year. We have 10 patients total enrolled, 7 patients at our high dose. We had a data readout earlier this year with data at early time points for a high-dose cohort. This showed a meaningful improvement on endpoints like ventricular tachycardia, both relative to the patient's baseline, but also relative to a natural issue study that we have running alongside it.

We'll have conversations with the FDA and then a future data readout at more mature time points associated with that program. But I think it's showing some very interesting early signals of clinical benefit against some very important end points in the disease. And we have a preclinical pipeline also focused on genetic cardiomyopathy. So we're making a lot of progress in this new and evolving field within the broader cardiovascular treatment landscape, where you've seen very few precision medicines approved in cardiovascular disease. And we think the AAV vector has unique properties that allows it to treat genetically mediated cardiac disease, and we're really at the tip of the spear and some of that work with our clinical stage programs.

Well, thanks for that. And let's start on the regulatory side in terms of interactions with the FDA. The FDA was open to pooling Phase I/II data and also using an earlier time point. When should we expect that -- expect a definitive update on that?

Yes. So we're -- so maybe I'll just take a step back and kind of walk through where we are. So as you mentioned, our prior meeting with the FDA, they were open to pooling patients from our Phase I/II study with a yet to be conducted a registrational study. It was left to us to come back with the statistical plan that could allow for pooling in that picture. It's not -- it's a relatively complicated exercise, but that's part of the alignment that we're working to reach.

We are expecting to give an update on the final statistical plan and study design in early 2026. I think from a guidance perspective, in terms of study size, study length, we remain in line with the prior guidance. The work that we're doing with the FDA now is really on a couple of fronts from a statistical perspective. I think one is trying to minimize sources of bias in the forthcoming study relative to the control. And the second is trying to give -- have some visibility into the future confirmatory end points. We do not have to design the confirmatory study in order to reach alignment on the accelerated approval study. But we -- I think the CBER would like to have a lens into where we're headed from a confirmatory perspective, and we're likely to have important cardiac endpoints as confirmatory study endpoints here.

So those are a few of the things we're working on, and we expect to give an update in the time frames that we previously guided in terms of final study size, study length and other attributes of the statistical plant.

And given that LVMI is not necessarily subject to biomarker, it's a hard clinical end point, you should be fairly confident that there should be no walk back from the FDA. Highlight some of the recent CRLs we have seen, which are more sort of biomarkers.

Yes. I think LVMI is clearly -- cardiac hypertrophy is the hallmark of this disease. LVMI is the most -- and cardiac MRI is the most sensitive measure for it. Left ventricular mass is a commonly used biomarker by cardiologists that evaluate hypertrophic cardiomyopathy. So it is really the best and most efficient and most sensitive way to evaluate disease progression in Friedreich's ataxia cardiopathy. We've agreed on a 10% improvement in left ventricular mass as a clinically meaningful threshold. There's literature that links this to a 20% risk of mortality. So it's very much a surrogate that's linked to the disease and has a clear link to mortality. So no guidance change with respect to LVMI.

And where do you think the duration of follow-up could land up? Would you prefer a 6-month study or a 9-month study?

Look, there's trade-offs. The FDA is open to a time point shorter than 12 months. We have, at the higher dose, a 28% reduction in left ventricular mass at 6 months. We have a 30% reduction in left ventricular mass at 12 months. So there is some difference in effect between the 2. So there are obviously trade-offs in looking at an earlier time point with potentially less deep treatment effect.

So we're working through all of that in terms of the alignment on the statistical plan, and we'll be able to give a final conclusion on that at -- when we provide the update. I mean our goal is to have the fastest, most derisked path to an accelerated approval. So the design that we land on will take all of this into account to get us there in the most efficient way possible.

Got it. Now the company has 2 late-breakers at the ACC. Are we expecting substantial new data from the 2 programs? Or I mean, given that it's a late-breaker, people are expecting something different?

Yes. So I think for FA, the last data update, we had all of the abnormal LVMI patients were at 12 months. We had most of the other patients with normal left ventricular mass at 12 months. We saw a consistent improvement in left ventricular mass. We saw consistent improvement in troponin. I wouldn't expect a materially incremental picture to that. I mean, there may be some additional data there. But I think the story for FA in terms of the treatment effect, the relevance of the endpoint, I think that's all clear from prior data updates.

I think it's important that this therapy, this LX2006 has not been presented at an academic conference. So this will be the first one. We'd like to ensure that this therapy has been introduced to cardiologists that they understand the treatment effect. They understand the relevance of gene therapy for this type of disease. So I think the focus is more the audience and ensuring cardiologists have awareness of what this therapy is achieving in this very serious disease.

So in your discussions with KOLs, the LVMI greater than 2 standard deviations, is that the threshold for treating? Or if your data look anything like your earlier data set, there's going to be an urgency to treat them out of what?

Yes. So I think the -- obviously, the patients with 2 standard deviations and above will likely be the early adopters for this therapy. Those are the ones that are closer to the latest stages of heart disease. But also looking at the Phase I data, we had 11 patients that did not have abnormal LVMI at baseline. Many of these had elevated troponin, many of these had elevated wall thickness. We saw improvements in lateral wall thickness. We saw meaningful improvement in troponin. So there is a case to be made to treat patients that do not yet have the 2 standard deviations or greater of left ventricular mass disease burden potentially on the basis of troponin.

I would agree that probably the more urgent treatment, those seeking treatment would be for that abnormal LVMI population. But we do not expect the label to be limited to that population. I think we can look across a number of rare diseases including within Friedreich's ataxia where the label of the commercially available treatment does not match the inclusion criteria of their pivotal study to say that we're likely to have a label that's broader than just abnormal LVMI population and then looking at biomarkers like troponin that may be the right trigger point to consider a therapy like this could be the pathway to treat patients earlier in the disease.

And what we've not talked much about is the benefit on the neurologic size. So we're getting about a 2-point improvement in the modified Friedreich's ataxia rating scale, which is the neurologic function scale that evaluates disease progression of Friedreich's ataxia. It was also the clinical endpoint used for the approval of the existing commercial treatment. That treatment was seeing roughly a 2-point improvement in the mFARS scale. So for patients that even have earlier stages of cardiac disease or do not yet have cardiac disease the potential benefit of a 2-point improvement in the modified Friedreich's ataxia rating scale is also clinically meaningful. If you remember, at the outset of the approval of SKYCLARYS, there were, I don't know, up to 4,000 patients on treatment, seeking exactly that treatment effect of this 2-point improvement in mFARS.

So there's a case to be made here for patients that are even much earlier in the cardiac disease and the potential neurologic benefit that they could experience from LX2006. So I think we'll -- the story will play out over time here, but I think we have a strong case to be made for a range of patients across the disease and treatment of this profile.

This is a complicated disease. You've got neurologist on one side, cardiologists on the other side. Who is your primary target? And where does the intervention need to occur?

Yes. So I think the early adopters are likely to be cardiologists. There are a range of patients that are under the care of a cardiologist. They're there under the care of a cardiologist for a reason. They will probably have some form of discernible cardiac disease. Some of the sites we're working with are already doing cardiac MRIs on the patients. So they're tracking the progression of the disease in a pretty robust way. So I think the early adopters for treatment are likely to be cardiologists.

But I think for the points that I just made about the benefits on the neurologic side, we're likely to see neurologists that also engage in therapy in our sites from our Phase I, actually, all of our PIs were neurologists. So a lot of the patients that have been treated to date have been under the care of neurologists and have considered LX2006 for their patients.

So maybe talk about the ease of administration, corticosteroids, et cetera, which adds to the commercial appeal?

Yes. So our immune suppression, we're using a 1E12 vector genomes per kilogram dose, and that's a dose we'll take forward into our pivotal study and into our -- into the commercial setting. Associated with that, we're using a relatively low dose of prednisone as the immune suppression. So as you're pointing out, I think it's not very onerous treatment course. We've had a very compelling safety profile associated with this therapy. I think that's to be expected at this dose. So the expectation would be that this would be a gene therapy that is amenable to the range of patients across the disease.

We also have adolescent and pediatric cohorts that we're expecting to have in the study. So from an age group perspective, we would expect to potentially be able to treat the range of the disease as well.

And from a CMC perspective, do you have end-to-end control of the product? And in terms of PRT, empty-to-full capsids are you versus...

Yes. So we have completed production of the clinical batch for the pivotal study using our final commercial process. This is a high-yielding process, and we have information on our website. But in effect, you can back into when we're looking at cost of goods in some cases that are close to biologics. And this process, we transitioned from a HEK293 adherent process to Sf9 suspension for our clinical and commercial material. This required a comparability study for us to complete. That study is complete. The FDA has approved the comparability protocol. So we're cleared to move forward with dosing in our pivotal study from a comparability and FDA perspective.

We also received CDRP designation, which is a designation designed to advance innovation in what's required from a PPQ process validation perspective for BLA. That conversation is running alongside our conversation about finalization of the clinical trial. We hope to align with the FDA on a PPQ process validation requirements that could allow for a rapid path to a BLA following the completion of the pivotal study and then that top line readout.

What role do you think natural history is going to play in your BLA submission for accelerated approval?

Yes. So that's -- it's a good question. We have the natural history study, the prospective natural history study already running. So that natural history study has an identical inclusion criteria to the treatment study. So we already have sites up and running that are looking for patients that are the identical profiles to what we need for the treatment study. So that study will be a feeder of patients into the ultimate treatment study, allows us to get the sites up and running earlier, allows us to look for the patients that will ultimately be part of the treatment study as well. So I think it will play an important role. And as we align with the FDA, it allows us to advance from a site operations and enrollment screening perspective as well.

Got it. You guys are clearly well ahead, but the competitive landscape is changing. So are you thinking about the dual approach or the dual AAV approach going after CNS and cardiac?

Yes. So I think there's obviously, there's different approaches here. What we're seeing from our systemically administered therapy is it's having an impact across a pretty broad swath of this disease. So I mentioned the improvement on the mFARS scale. We're seeing very definitive and very important improvements in the cardiovascular component of the disease. It's not likely that a substantial amount of our therapy is actually getting into the brain itself. And in the brain, there's aspects of Friedreich's ataxia that are mediated by the deep cerebellum, the dentate nucleus. And there is, as you're pointing out a therapy that's evaluating intraparenchymal injection of frataxin gene therapy combined with a systemic injection.

So -- however, it's not exactly clear to us that these therapies are -- will be direct competitors over the long term. And what I mean by that is there's a possibility that a patient who receives a systemically administered dose of gene therapy may still be eligible for an intraparenchymally administered dose or CNS administered dose of gene therapy. So there's not been definitive preclinical or nonclinical work completed to really flush that concept out. We'd like to understand that a lot better. But in a world where a patient can be sequentially dosed first systemically and then later in a direct CNS administration, it would mean that these therapies are not necessarily direct competitors that there's an aspect of that therapy that may be amenable to patients that have been treated with LX2006.

So I think more to come on the competitive landscape. I think if I look at all the therapies out there today, whether it's protein therapies and others, there may be -- maybe a world where these all coexist as they do in some of the other disease areas that are out there.

So let's talk about the PKP2 program. I mean, in general, people were expecting variability in the PVC side. But you had -- you have some variability on the NSVT endpoint as well. How do we address this going forward?

Yes. So I think going into this, what we understood is that the endpoints are likely to improve at different rates that you won't see at the same exact time point in the same patient improvement in non-sustained VT, PVCs and ejection fraction that likely the remodeling that's occurred -- the modeling that we would expect to occur will cause those endpoints to improve at different rates. So that was expected.

We did see a 22% reduction in non-sustained ventricular tachycardia. If you look at our natural history study running alongside the treatment study, patients saw a 20% worsening of non-sustained VT. So there's a 42% delta between the treated patients and untreated cohort. And that's what several of the patients at the earliest time point where we can evaluate efficacy. If we look at the 9-month time point, there's a 65% reduction in non-sustained VT again versus this 22% worsening. So you're looking at an 85% delta. So I think we're seeing the early signals of a treatment effect in non-sustained VT. And I would draw a comparison to the existing, let's say, commercially available treatments, amiodarone, for example, this is a mid-20s treatment effect in reducing VT about 24%. So already at the earliest time point for many of the patients, we're already seeing a treatment effect that's similar to what's available today for patients.

And what's also corresponding to this is that the patient has the longest duration of treatment follow-up is showing a 30% improvement in their ejection fraction. And one could say a 3% to 5% improvement in ejection fraction could be noise, but I think any cardiologist would say a 30% improvement in ejection fraction is likely to be clinically meaningful. So with that improvement in non-sustained VT, we're showing signals of an improvement in an important structural endpoint like ejection fraction. There is no therapy today that is improving arrhythmia burden at that effect size and also showing any signal of improvement in structural elements of the disease. So with this early data readout, we're already seeing that.

You're pointing out, we had 1 patient who saw an increase in their non-sustained VT burden. This patient was at an early time point at 6 months. It's not clear to us, is this a nonresponder or is this a patient that is yet to respond. But if you look at the overall picture of this early data, we're actually very encouraged by it. The question from here is what's the right pathway to a registrational study? What are the right registrational endpoints? Ventricular tachycardia is frankly the hallmark of this disease. It's not even a surrogate. It is a clinical endpoint. So we think that will play an important role in our the future alignment with the FDA.

And I think the only question is sort of the one that you're asking, which is what is sort of the final treatment effect that we can expect to see at longer time points? Is it something more similar to the 9-month patient? Is it something more similar to the average of what we're seeing today? And then how much variability is there? And the endpoint over time, I think we'll have that answer as we look at the data later in the year and see more of the patients at these longer time points, such as 12 months.

And how do you -- when you think about the PKP2 expression versus mRNA or the protein, I mean there wasn't a direct correlation there or even versus VCN. Why do you think that is? And is there a way to sort of address that?

Yes. So just taking a step back, what we did see. So we saw a dose-dependent response in every one of our biopsy endpoint. So we saw greater vector copy in our high dose than our low dose. We saw greater mRNA in our high dose versus our low dose. And the same with protein. We saw more protein in our high dose versus our low dose. And we got, in some cases, between 3 and 5 vector copies per cell, which we think is a great outcome to achieve that kind of result and do so with no classic gene therapy-related SAEs, so no SAEs related to complement activation, no SAEs related to liver injury. So we defined a very clear therapeutic window. We're getting a great payload. In fact, this validates the use of AAVrh10 for the heart in that I have not seen another capsid demonstrate that type of distribution into the heart, but do so with the safety profile. So that's, I think, a very positive picture that we're happy with.

In terms of the direct correlation on the patient-to-patient basis between VCN, mRNA to protein, you remember these all come from different tissue samples. So you would like to see the high dose with more protein than the low dose across all these measures, which we did see. But you wouldn't expect an exact correlation patient to patient because you're looking at a different tissue sample for each one of those end points. So for us, the usefulness of this data is sort of, as I was describing, I think we know we're at the right dose to get between 3 and 5 VCN implies we don't need more than 5 copies of the gene per cell. We're seeing protein expression. We're seeing protein expression actually localized to the right place in the desmosome. So we know functionally from validating the biology, it's going to the right place. I think this is what this data is helpful for us to understand all of that.

I think it's unlikely to be a pivotal study endpoint both because of tissue quality issues with the disease itself results in fatty fibrotic tissue to accumulate in the heart. So if you end up with tissue samples that are primarily fibrosis, you will see kind of variable picture. The other challenge with using plakophilin-2 as an endpoint or biopsies in a future study is the patients are presenting with a pretty wide range of pretreatment baseline, so anywhere from, let's say, 20% to 50%. So it will be a lot harder to understand how much more PKP2 do you need to add to have a clinically meaningful benefit. So I think the usefulness of the biopsies is as we described, I think we know we're at the right dose. I think we know it's getting the right place in the desmosome. This validates all the biology that we saw preclinically. And now I think we're more focused on the clinical endpoints like non-sustained VT for the future of the program.

And in terms of the 3 SAEs of sustained ventricular arrhythmias that you had, how do you go about addressing that? Do you need any changes to...

Just to correct. There's 1 SAE. Yes, 1 SAE. We had 1 SAE of a sustained ventricular tachycardia. This is actually an endpoint that we're measuring in the disease. This patient had a prior treatment -- prior history of sustained VT prior to entering the study. So while it was assessed it's possibly treatment-related, it looks very much like arrhythmogenic cardiomyopathy, I would note that over the course of this treatment, none of the patients in the trial have had their ICDs fire. So not only are we seeing improvement in non-sustained VT, we're also seeing no ICDs fire. And so that endpoint looks like the disease.

And I would point out, we've not had any SAEs related to complement or any SAEs related to liver injury, which is what you would typically see in some of the higher dose gene therapies. So I think we're in a very positive place from a safety perspective, in particular, for a disease like this one where many of the patients will experience sudden death arrhythmias, many of the patients will go on to require transplant. So from a benefit risk perspective, we think this is a very attractive picture that's developing for this therapy.

Well, awesome. Unfortunately, we have run the clock and looking forward to the data update, especially on the regulatory side and wish you guys the very best for this year.

All right. Thank you. Thanks for having us.

Thank you.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. 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, 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.

[Presentation]

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 platform. 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 -- 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 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 1.5x to 2x 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 AAVrh10 capsid is a tool which we utilized 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's 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's ataxia cardiomyopathy program in the second half of the year. We received a breakthrough designation for our Friedreich's 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 I/II study. We've shared interim data from this Phase I/II 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's ataxia to 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 nonviral 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 I/II 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 '26. And we would expect to initiate SUNRISE-FA 2, 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 I/II 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've mentioned earlier, the safety and 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 a 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's ataxia cardiomyopathy. This is really, for us, a beachhead in cardiac disease. It's a disease that many would know is a neurologic disease, but 80% of the patients in Friedreich's ataxia, the cause of mortality is cardiac disease. You heard earlier from patients, they struggle with this disease. You can 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's 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 I/II 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-FA 2, our pivotal trial in the first half of 2026. So we're moving quickly from Phase I/II 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 the way that we measure cardiac hypertrophy or thickening of the heart walls. And you could 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're achieving a 28% reduction in LVMI at the 6-month time point. So 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. But 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's ataxia rating scale relative to natural history. You can see a 2- to 3-point improvement in the mFARS scale. This is roughly similar to what the commercially available treatment is achieving. And you can see a deepening effect over time and improvement in mFARS. So not only are we reversing the cardiac disease pathology, we're also showing improvement on the neurologic scale simultaneously. So this therapy has the potential to change the standard of care in treatment in Friedreich's ataxia disease. And 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. So 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. And patients with the disease in 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 is absent, we get fatty -- fibro-fatty infiltrates that entered 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 a very compelling cardiac tropism profile that we'll discuss more in future slides.

There are 3 ways that the patient -- that patients typically present with this disease or 3 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 non-sustained 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 2 studies. One is an interventional study, one is a natural history study, a study running in this disease. Heroic PKP2 is the Phase I/II study. We have 2 doses we've studied in this program, a 2E13 dose and a 6E13 dose, they had 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 I/II study, a 15-patient natural history study, evaluating patients -- 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 4 of 5 patients are reporting that they are feeling better after being treated with our PKP2 arrhythmogenic cardiomyopathy.

We've achieved a mean change of 14% and 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 non-sustained 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 6 months, and we're seeing a deepening effect over time.

So at 9 months, we're achieving over 50% reduction in nonsustained ventricular tachycardia. So 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 3 treatment-related SAE of sustained ventricular tachycardia. This is consistent with the treatment history of this disease and of this patient. And we had no other SAEs associated -- no other Grade 3 SAEs associated with the program.

We're also advancing 2 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. And 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 6 years, has become a leader in cardiac genetic medicines, addressing high unmet diseases -- high unmet need diseases with no existing treatments ahead of them. We have a catalyst-rich 2026 across both our Friedreich's ataxia and 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's 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 life cycle. 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, Lou Tamayo, to the stage to discuss the questions that Tessa has.

Wonderful. 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 were building? And how do you see the portfolio evolving over the next several years?

Yes. So when we went public in 2023, the company had -- it was focused on 2 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. 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.

So 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 2 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 nonviral, 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 2 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.

Yes. And can you talk a little bit about how the J&J collaboration came about?

Yes. So 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. So 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 for -- 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 don't know, Eric, if you want to say a few words about that as well.

Sure. I think that -- 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. So by doing local delivery, you can deliver that amount, but do it in a way that you're not -- you're diminishing the risk of toxicity by diminishing your total dose.

Okay. So I thought next, we might just dig into this latest cut of Phase I/II 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?

Yes. Thanks for the question, Tess. May be I'll...

But I think this is a little loaded, sorry.

No, no, no, that's fine.

It has 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 is the important measurement, the clinically relevant measurement that we can make in these patients is VT. And that -- and when we talk about VT, we include non-sustained VT when you have 3 or more PVCs or sustained VT when you have 30 seconds or more VT. And one of the things -- 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 6 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 6 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 2 patients that are in 9 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 history of shocks. So I encourage this as a very clinically meaningful early -- we said it from the very early signal, but really excited about what we've seen.

Okay. And maybe we can just briefly touch on the safety. And just a clarifying question for me actually from the slide. Can you speak to a little bit more detail about these LFT elevations that you saw in 5 patients at the high dose? What level of elevations did you see? And how did you interpret these events?

Sure. 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 associated with high LFT and mortality. None of these were Grade 3 SAEs, again.

So for me, before we started this -- 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. So 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 3 SAEs.

Yes. 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 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 3 to 5 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 and gene therapy. It actually makes us ideal for treating the heart. And I'll note that for patients 9 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. Okay. And I'm assuming you've shown these data to your investigators and our physician colleagues like at this point, like what has been their early feedback on the data?

Maybe, Eric, do you want to take that?

Yes. 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 are excited about that. Clearly, everyone saw the safety profile very excited about a safe -- clean safety profile in gene therapy.

So the combination of treating the most important clinically relevant endpoint and 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 3 SAEs and then having a significant impact on these clinically relevant endpoints. Obviously, they want to see the data mature, but everyone's been really excited.

Okay. And big picture here, like 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?

So 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. But 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. So 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 like, I don't know, the ecosystem of a couple of other gene therapy-based approaches for PKP2. Like where do you see the landscape kind of evolving over time?

Yes. 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 3 therapies in this market, these are all multibillion-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 in clinically meaningful endpoints, but able to do so with a 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 non-sustained 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 to kicking off your study. And from our perspective, this -- your trial design seems very derisked. 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?

Yes. So I think we've communicated quite a bit about the structure, size and sort of time lines 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 is open to considering time points less than 12 months. We're looking at a relatively modest sized 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 are finding patients with the exact profile that we would have in the treatment study.

Okay. And 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?

Yes. 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 a profile of patients 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 will be another important endpoint. We're also evaluating lateral wall thickness, which is a 2-dimensional measure of hypertrophy. And we're also going to be continuing to evaluate the modified Friedreich's ataxia rating scale, or mFARS, which is a neurologic scale.

So 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's 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 like how do you think about the patient funnel in terms of the patients you think that would be most likely to adopt?

Yes. I think we -- 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 the 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 who can benefit from some of the neurologic benefits that we're showing would be sort of the third tier of 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 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.

Good morning, and welcome to Lexeo Therapeutics webcast presentation on LX2020 for the treatment of PKP2-associated arrhythmogenic cardiomyopathy. As a reminder, this call is being recorded today, January 12.

I would now like to turn the conference call over to Louis Tamayo, Chief Financial Officer of Lexeo Therapeutics. Louis, please go ahead.

Earlier today, we released interim data from the Lexeo HEROIC-PKP2 Phase I/II clinical trial of LX2020 for the treatment of PKP2-associated arrhythmogenic cardiomyopathy or ACM. The press release outlining the interim data update is available on our website at lexeotx.com as well as the slides related to today's call. Joining us on today's call will be Nolan Townsend, Chief Executive Officer; and Dr. Eric Adler, Head of Research.

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.

Thanks, Lou, and thank you all for joining us. Today, we are pleased to share preliminary data on the safety and efficacy of LX2020 across a meaningful sample of 10 participants dosed to date, 8 of whom have at least 6 months of follow-up.

Looking first at transduction and protein expression, we have observed mean increases in PKP2 protein expression as well as robust vector copy number and exogenous mRNA at 3 months post dosing with dose-dependent increases between the low and high-dose cohorts. We are also seeing appropriate co-localization of the PKP2 protein within the desmosome using immunofluorescence. In terms of clinical measures, we are seeing early benefit in 2 key measures of arrhythmia burden associated with increased risk of poor outcomes, including sustained ventricular tachycardia, ICD shock and sudden cardiac death. Premature ventricular contractions or PVCs have been stabilized or reduced in the majority of participants at latest visit, and we've observed a 14% mean improvement across participants in the high-dose cohort. Non-sustained ventricular tachycardia has also been stabilized or reduced in the majority of participants at latest visit with a 22% mean improvement in the high-dose cohort.

Finally, treatment with LX2020 has been well tolerated across all 10 participants dosed with no clinically significant complement activation and no new serious adverse events to report. We are encouraged by these collective data on the therapeutic potential of LX2020, including those from relatively early time points in the high-dose cohorts, and we are eager to advance development of this therapeutic candidate as the data continue to mature.

I will now turn the call over to Dr. Eric Adler to provide an overview of PKP2-ACM and to review these data in more detail. Eric?

Thank you, Nolan. Arrhythmogenic cardiomyopathy is most commonly caused by mutations in the plakophilin-2 or PKP2 gene, affecting approximately 60,000 people in the United States. PKP2 deficiency in ACM is a disorder of the cardiac desmosome, a protein structure which allows cells to adhere to each other and is strongly associated with the fibro-fatty infiltration of cardiac tissue. Patients with PKP mutations are at high risk for cardiac rhythm abnormalities, heart failure and sudden cardiac death. Tragically, over 20% of patients experienced sudden cardiac death as their first presenting symptom, which is why familial history and genetic testing is so critical in timely diagnosis of this disease.

Following diagnosis, most patients with PKP2-ACM receive an ICD or implantable cardioverter defibrillator. While this device can mitigate the risk of sudden cardiac death, it does not address underlying disease progression with patients continuing to experience ongoing arrhythmia and associated anxiety. Additional medications such as beta blockers and anti-arrhythmia drugs have shown some benefit in managing arrhythmia symptoms but do not address the underlying genetic cause of disease or progression. When looking at arrhythmia burden, we often focus on 3 measures in order of severity.

First, individuals with PKP2-ACM may experience frequent premature ventricular contractions or PVCs. In fact, one of the minor diagnostic criteria for ACM is greater than 500 PVCs per day. A PVC is an extra or early heartbeat that originates in the ventricle, disrupting the heart's normal rhythm. These early beats may be caused in part by calcium ion instability. And as we will discuss, PVCs can go on to trigger more severe sustained arrhythmia. Non-sustained ventricular tachycardia, or NSVT is another key measure in this disease, closely associated with poor outcomes such as increased risk of sustained VT, ICD shock and sudden cardiac death.

Non-sustained is defined by episodes that are self-terminating and last fewer than 30 seconds. Although brief, people with PKP2-ACM are more likely to feel episodes of NSVT compared to PVCs, which can contribute to significant physical discomfort as well as heightened anxiety regarding the underlying disease. PVCs can trigger NSVT events when the extra heartbeat continues for 3 or more consecutive beats, consistently overriding the normal heart rhythm. In some cases, ventricular tachycardia fails to self-terminate, which is life-threatening and can result in a third measure of sudden cardiac death. In individuals with an ICD, sustained VT can trigger an ICD shock to restore normal heart rhythm. People with PKP2-ACM are at particularly high risk for sustained VT and may undergo surgical ablation to manage this risk, although recurrence after ablation is very common.

As mentioned on the previous slide, PVCs may trigger VT, so the 2 measures are related but driven by potentially different mechanisms. Think of PVCs as a spark and VT is a fire. One PVC may not be hugely clinically significant alone, but patients with a high PVC burden are at high risk for development of both ventricular tachycardia and heart failure. PVCs may initially arise due to calcium ion leak, disrupting the heart's refractory period and depolarization. Calcium instability due to PKP2 deficiency is likely due to downstream proteins, not PKP2's direct function in the desmosome. So we hypothesize it may take more time to observe significant reduction in PVCs to normal levels in this disease. When a PVC meets another underlying vulnerability, this is when a fire or when VT can occur.

In PKP2-ACM, one key vulnerability is slowed electrical conduction caused by the destabilization of the desmosomal complex due to PKP2 deficiency, which is essentially a scaffold protein. Another example is the development of scar tissue or fatty fibrotic tissue, which can disrupt the normal flow of electrical signals throughout the heart. When a PVC meets a vulnerable area of the heart like this, a reentry loop can also occur so that the premature beat propagates and contributes to re-excite the heart consistently. This combination is what leads to VT. Given the different mechanisms of these endpoints, we hypothesize that VT could be reduced if vulnerable areas of the heart are improved even if high PVC burden persists.

Looking briefly at the natural history of disease, you can see on the left that individuals with PKP2 ACM can experience high and persistent PVC burden, though there is significant variability both between individuals and within the same patient over time. It's important to note that activity and exercise significantly influence measures like PVCs and NSVT, so it can be hard to separate lifestyle factors from underlying disease progression. What you can see in the chart on the left is a reduction in PVCs immediately following diagnosis, usually because health care providers recommend a cessation of exercise and some patients may begin other therapies, including beta blockers or antiarrhythmic drugs.

However, following this initial intervention, PVC burden persists and even appears to increase after 4 to 5 years. The middle graph illustrates risk for severe VT, which is higher with a high PVC burden plotted on the X-axis. PVC burden alone does not fully explain arrhythmic risk. As you can see in the orange and dark gray lines, patients who experience NSVT are significantly more likely to develop VT than those without NSVT, even if their daily PVC burden remains the same. Finally, on the right, we are sharing some preliminary data from the Lexeo-sponsored snapshot prospective natural history study. 15 patients is a relatively small sample, but what's interesting about this data set is that it includes individuals further along in their disease progression, 8 years from diagnosis on average, and it also quantifies NSVT burden rather than reporting as a binary outcome, which is how it is most often presented in the literature.

Here, you can see that PVCs and NSVT both increase over a 12-month period and each are associated with greater VT risk. Importantly, arrhythmia burden persists or progresses in some patients despite consistent use of beta blockers or other antiarrhythmic drugs, highlighting the need for disease-modifying therapies. LX2020 is designed to treat the root cause of PKP2-ACM by delivering a full-length PKP2 gene to cardiomyocytes. We package the full-length PKP2 gene in an AAVrh10 vector, which has an increased affinity for cardiomyocyte cells in the heart, allowing us to use relatively low doses compared to commercially approved gene therapy treatments. LX2020 also includes a cardiac-specific promoter to further localize expression in the heart, which we believe could support a more favorable safety profile while still delivering efficacy in treating this cardiac disease.

LX2020 is currently being evaluated in the HEROIC-PKP2 Phase I/II clinical trial, an open-label single-arm multicenter trial designed to assess the safety, tolerability and preliminary efficacy of this therapeutic candidate with 2 dose cohorts. This study is focused on adults with a documented PKP2 mutation, an existing ICD and no pre-existing immunity to the AAVrh10 vector. 10 participants have been dosed, including 3 participants in Cohort 1 at the low dose of 2E13 vg per kg and 7 participants in Cohort 2 and 3 at the high dose of 6E13 vg per kg.

On this slide, you can see the baseline characteristics summarized across participants in the low and high-dose cohorts. These characteristics are consistent with the clinical manifestations of PKP2-ACM and you can see that these participants are pretty advanced in their disease progression on average, especially at the high dose with a mean of 9 years since diagnosis and significantly elevated arrhythmia burden. Importantly, I will note, 9 of the 10 participants had no limitation from heart failure symptoms yet as measured by the New York Heart Association class, which is consistent with arrhythmogenic cardiomyopathy, where arrhythmia burden presents earlier in the disease and end-stage heart failure may not develop in all participants or within the decade following initial diagnosis.

Here, you can see the baseline characteristics for each individual participant who is dosed as well as some relevant medical history related to arrhythmia burden, sustained VT, ICD shock and ablation. You can get a sense of the advanced disease progression in these individuals. For today's presentation, safety data is summarized for all 10 participants who were dosed, while efficacy data is inclusive of those participants with at least 6 months of follow-up as of the data cutoff date of January 7, 2026. At the bottom of the table, you can see the latest visit for each participant.

I will now share safety data. LX2020 continues to be generally well tolerated across all 10 participants at both dose levels, and we have not observed any clinically significant complement activations or instances of TMA. We did observe elevations in liver function tests or LFTs in 5 participants treated at the high dose, consistent with what we would expect with gene therapy treatment at this dose. All 5 were treated successfully with modified immunosuppression per the trial protocol. For 3 participants, the elevations occurred following steroid taper and resolved after the reintroduction of low-dose prednisone treatment for a few weeks.

In 2 participants, elevations occurred prior to steroid tapering and resolved with increased prednisone and sirolimus treatment. All of the elevations have since resolved without other complications or hospitalizations and no other medications were required for resolution nor were any serious adverse events observed following the LFT elevations.

Finally, one previously disclosed Grade 3 serious adverse event of sustained ventricular tachycardia was observed 3 months after dosing in a single participant in the high-dose cohort and assessed as possibly treatment-related, though the event is consistent with the natural course of PKP2-ACM and its known clinical manifestation. The participant was successfully treated with anti-arrhythmic medication and discharged with no additional intervention required and no new serious adverse events have been observed. So we're confident in the favorable safety profile of LX2020 to date.

Turning now to the evidence we've collected with cardiac biopsies. On this slide, you can see the robust transduction and transcription observed in all participants. I'll remind everyone that participant 3 in the low-dose cohort declined the post-treatment biopsy, so we do not have any bioanalytical data for this participant. Unfortunately, we did not have sufficient tissue to perform VCN analysis for Participant 1 in the low-dose cohort either. But looking at the available data on the slide, you can see meaningful increases in both vector copy number and exogenous mRNA consistent with PKP2 transduction and transcription. Looking at the mean values, you can also see clear evidence of a dose response.

Looking at PKP2 protein expression. Again, we are seeing mean expression increases across participants with a greater response at the high dose. As I mentioned previously, PKP2-ACM leads to the replacement of healthy cardiac tissue with fatty fibrotic tissue, which can contribute to sampling variability and sample quality issues with cardiac biopsy tissue. We believe that it's what's driving the results for participants 4 and 5 because the reduction in PKP2 expression is not logical and both of these participants do demonstrate LX2020 transduction and transcription with the VCN and mRNA results. In these 2 instances, it is likely that we happen to analyze a sample with a greater percentage of fat or fibrotic tissue, which is confounding the western blot results. But looking across all samples, we are encouraged by the evidence of increased PKP2 expression and dose dependence.

Finally, looking at immunofluorescence staining, you can see appropriate colocalization of PKP2 protein at the cardiac intercalated disc after treatment. Essentially, these images show us that PK/PT protein is going to the right place after treatment with LX2020 and it's traveling alongside other important structural proteins in the desmosome and gap junction such as connexin 43 and N-cadherin where you see clear lines, particularly in the merged images, you can see the intercalated disc where cardiomyocytes connect both mechanically and electrically, allowing the heart to beat in synchronized fashion. We've chosen participants 4 and 5 here for illustrative purposes, but appropriate co-localization of PKP2 protein is consistently demonstrated across our patient population.

Turning now to the clinical data. We have observed a reduction or stabilization in arrhythmia burden across participants with a greater mean effect in the high-dose cohort. PVCs are reduced or stable in 7 of 8 participants with a mean improvement of 14% at the high dose despite a relatively earlier follow-up. Even more important is NSVT, which is a major risk factor for sustained VT and where we see reduction or stabilization in 6 of the 8 participants, including a mean improvement of 22% at the high dose. The most significant reduction in VT in participant 4 also appears to be associated with modest gains in cardiac function as assessed by right ventricular ejection fraction, although the majority of patients remain stable with respect to RVEF.

Looking at these data over time, you can see improvements in arrhythmia burden on average and evidence of a clear dose response. On the left are PVCs measured at baseline, 6 months, 9 months and 12 months, including participants who have reached at each time point to date. You'll see the mean across all patients as well as the mean for each of the 2 dose cohorts. The right-hand side presents the same view for NSVT events over time. Looking at the high dose in red, there is clear clinical benefit and a dose response in terms of reducing arrhythmia burden and potential evidence of greater improvement over time. We look forward to seeing these data mature and also adding participants 9 and 10 to this emerging picture. Even with some measurement variability, the directionally consistent improvements observed across measures of arrhythmia burden and cardiac function give us early confidence in the potential treatment effect of LX2020.

Finally, looking at EKG data and other clinical measures, participants appear stable over time. You can see the mean per dose cohort and the dots represented individual participants at baseline and latest visits. The left-hand side shows QRS duration. The majority of participants start and stay within the normal range as of latest visit. We have previously reported an improvement for participant 1, which you can see in the purple dot. But looking across the sample, we are largely seeing stabilization on this measure of electrical function.

On the left, T-wave inversion is also largely stable across participants with minimal change from baseline. No participants experienced any change in New York Heart Association class. And in fact, 7 of the 8 participants started at Class I, so they continue to report no signs or symptoms of limitations from heart failure. While these measures remain stable overall, we are most encouraged by the observed reductions in arrhythmia burden, including reductions in more severe NSVT events, which are both clinically relevant and highly meaningful for patients.

I'll now turn the call back to Nolan to close.

Thank you, Eric. I believe these interim data demonstrate an exciting emerging profile for LX2020 with favorable safety, robust transduction, increased PKP2 expression and clinically meaningful reductions in arrhythmia burden. In terms of next steps, we recently completed enrollment of the HEROIC study in Q4 2025 with the final 2 participants, participants 9 and 10 dosed using drug supply produced with our final manufacturing process. This process demonstrates higher potency and higher yield relative to earlier lots. So we look forward to reviewing data for these participants in 2026, including cardiac biopsy data in the near term.

Looking ahead, we expect to receive 12-month follow-up data for all high-dose participants by Q4 2026, at which point we plan to provide a subsequent data update. I'd like to close by thanking the study participants, caregivers, investigators and other members of the ACM community who have helped us to reach this exciting milestone. Those impacted by PKP2-ACM are central to our mission, and we are committed to advancing the development of LX2020 given the urgent need for treatment options.

I will turn it over to the operator to help facilitate the Q&A portion of today's call.

[Operator Instructions] And our first question comes from Paul Matteis with Stifel.

This is Matthew on for Paul. Congrats on all the progress. So 2 questions from me. The first is, what gives you confidence that we might see further benefits on PVC and NSVT in the high dose cohort at 12 months given the protein expression already seen in the earlier biopsy? And then the second is staying on the biopsy, the PKP2 expression, how does that compare to wild type in terms of percent of normal? And at what degree of PKP2 expression do you think you start to see benefits?

Thanks for the question. So first, on time course, I don't think there was a predetermined time frame in which we would expect to see resolution of this underlying biology of the disease. I mean the best indicator we have for the time course would have been from murine models where we saw improvement at 3 months, but obviously, that does not translate directly to the human context. The best indicator we have at that current is what we're seeing in NSVT. So we're seeing a time course of improvement. So at 9 months, for example, at the high dose, we're seeing greater reduction in NSVT than we're seeing, for example, at 6 months and versus baseline. So that's a trend that we would expect to continue as we go out to 12 months and longer time points.

With respect to the biopsies, I guess you're asking on average, what percent of normal are we achieving or -- but irrespective of that, I don't have that number at my fingertips here. I actually think it could be calculated from the slides. But in general, it's not clear to us that this is a disease where it's completely resolved at a specific value of PKP2 expression, in particular, because we're taking biopsies from the septum, but this is a disease mediated by the right ventricle. So while this is a good surrogate for expression in the right ventricle in the septum, we may not be accurately capturing the amount of protein that we're seeing in the septum, but -- in the right ventricle, sorry. But as you can see, we're getting robust PKP2 expression, we're getting robust mRNA and also we're seeing a dose-dependent response across the biopsies and then across the endpoints that we're evaluating from a clinical perspective.

So I think the question here is more about time. These are early time points, 6 months is the earliest time point where we can begin to evaluate efficacy. And so we are seeing an increased response over time, in particular with NSVT. So I think we'll keep our eyes on this data and keep our eyes focused on the 12-month time point where we'd expect to see an even greater response.

Our next question comes from Brian Skorney with Baird.

Congrats on the data. Can you just review how frequently you have NSVT and PVC data measured in the study? Is it every 3 months? And how are the PVC and NSVT measurements being done? Is the PVC at 12 months, for instance, measured for 24 hours going into the visit and NSVT the 7 days before the visit? Or is it over a longer time frame and then being sort of adjusted for the 24-hour, 7-day average?

And then just going back to the time course of NSVTs over time, it does definitely look like longer follow-up shows greater reduction, but there's also the shrinking in and at 6 months, there's that 1 outlier with an 80 NSVT increase at 6 months, bringing up the mean. So I was just wondering, is that true if you look at NSVTs on a patient-by-patient basis, particularly in the high dose, it's very clear that you're seeing a decline on an individual basis?

So Brian, first on the NSVTs, yes, we're measuring them every 3 months. So maybe, Eric, you could speak to the time?

It's a 7-day Holter on an average. So they're measured for 7 days and then we come up for a 24-hour per day number for NSVT and VT.

Does that answer the question, Brian?

That answered it on that. What about the -- on a patient-by-patient basis? Are you -- is it clear that there's a decline over time in measurements?

Yes, absolutely. You can see, as you can see, we have the error bars on the slide that shows that with the temporal changes. And you can see on a patient-by-patient average, it does decline over time.

Yes. So we are seeing a deeper response at 9 months versus 6. So that is a trend that we're observing in the data.

Our next question comes from Kristen Kluska with Cantor Fitzgerald.

Congrats on these data. I was hoping we could talk a little bit more about the relationship between NSVTs and SVTs, particularly how to think about the reductions here and ultimately down the line, how that may reduce the probabilities of SVTs occurring? I know there's really no approved drugs that have looked at this, but I'm curious if there's any research that can really contextualize some of the benefits you are seeing.

Yes. So the definition of non-sustained ventricular tachycardia is more than 3 beats and like basically 3 consecutive PVCs. And the definitions of sustain VT, it's a little murkier, but generally around 30 seconds is what most people will say is sustained VT. So you can see that they're just essentially the same process. It's just temporal. One is lasting longer than the other. So there's a clear relationship between NSVT and sustained VT, it's just the amount of time that they last. So having non-sustained VT is a harbinger that most clinicians would say that would predict sustained VT.

I mean I might add -- just to add to that, the sustained VT you would -- obviously is more concerning regarding the patients receiving shocks. And one of the things we've mentioned that none of our patients in this trial have received any shocks from their defibrillators. So suggesting that there's no sustained VT in this cohort of 10 patients thus far.

Our next question comes from Chris Raymond with Raymond James.

Congrats from us on the data as well. Just maybe looking ahead a little bit, this might be early to sort of to ask this question. But any plans maybe or are you thinking a little bit about how your next trial might look in terms of patients with more severe disease? And can you maybe talk about the enrollment sort of what you have to solve for there, just given that patients with more severe disease obviously have more events and just kind of how that might work? And then maybe a question on how you and the FDA might be thinking about PKP2 protein expression? Is it the totality of VCN mRNA and PKP2 protein? Or is there some other measure that we should be thinking about going forward?

Thanks, Chris, for the question. So I think it's our perspective that the patients we've enrolled, in particular in the high dose are pretty severe in terms of their disease burden. Typically, they have very high PVCs at baseline, 500 is a threshold for patients to be diagnosed with arrhythmogenic cardiomyopathy along with several other criteria. Some of these patients are starting with PVCs in the thousands, one patient as high as 6,000 PVCs.

Most of the patients have meaningful non-sustained VT burden. The -- some of the patients have reduced ejection fraction, which is a structural measure. So they're presenting with pretty meaningful signs of arrhythmogenic cardiomyopathy. We would say that they are severe, probably not in the latest stages of the disease, but they're pretty severe. So I think we're trying to understand the effect size across the range of patients presenting with this disease. We have some patients that are a bit earlier. We have a number of patients that are later. And so that picture right -- I think can go forward into a discussion with the FDA.

On your second question for the next trial, I do think it's early to come to any formal conclusions on this. I think we believe non-sustained VT would be a good endpoint to build a future study around, but there are possibly others here that could be important such as RVEF and maybe some of the patient-reported outcomes as well. With respect to protein expression, I know that our FA study, and I believe another study are using protein expression as a co-primary endpoint. I think there are some questions that we would need to discuss with the FDA about the use of protein expression as an endpoint in a pivotal trial.

As you can see, there's a different pathology here in arrhythmogenic cardiomyopathy. The fibro fatty deposits are one factor. The fact that the patients start with highly variable pretreatment baselines is another factor. So the question of what's this target level you need to reach in PKP2 expression relative to these variable pretreatment baselines is definitely another question here.

So I believe that this one as well would be potentially a bit larger study than, for example, what we are undertaking for Friedreich's ataxia. So obviously, adding biopsies to a large study increases the study execution -- some of the study execution challenges as well. So I think those are all the factors we'll be considering as we talk to the FDA this year about next steps in the program. But I would just note that we believe NSVT is an important endpoint in this disease and showing an improvement in NSVT, as Eric was just describing, can potentially be a good surrogate for sustained VT and obviously then for ICD shocks. We've not seen any patients with ICD shocks in our study to date across 10 patients treated, and we have patients that are out to 12 months of treatment follow-up.

Our next question comes from Moritz Reiterer with Guggenheim Securities.

This is Moritz on for Debjit. I've got 2 questions. First, in your natural history study, what does the intrapatient variability NSVTs over time look like? And sort of related to that, what's your threshold for defining a patient as stable when it comes to NSVT versus improving or getting worse? And then the second one, I believe you've already mentioned this during the Q&A, but just to confirm, you did not see any ICDs fire in any of the patients throughout the trial period, correct?

Sorry. So there are a few questions there. You may have to -- we may have to ask you to repeat some of them. But the first -- on the last one with ICD fires, correct, we did not see any patients with ICDs that fired in the trial. In terms of variability in the natural history, we don't have that information.

It's still emerging.

It's still emerging. We don't have that information available yet. But you could see in both NSVT and PVCs, there was an increase over a 12-month time period in the 15 natural history patients. Could you repeat the other questions that you mentioned?

Yes. It's sort of -- it's related to the intrapatient variability in an NSVT over time. I was just wondering, you referred to some of the patients earlier on as stable when it comes to NSVT. So I was just wondering how do you define a patient as being stable? At what point is the effect size of the delta still defined as stable versus what do you see as an improvement or getting worse?

We haven't set strict criteria around stable, worse or better. But you can imagine, certainly, 10% to 20% -- 10% differences is -- wouldn't be considered meaningful.

Or we have a patient with 2 NSVTs going to 4 in terms of the materiality of that change in 2 is a question from a threshold perspective. We're encouraged by the fact that for some of the patients with the highest NSVT burdens like patient 4, patient 7 and so on, we're seeing reductions in NSVT there in a double-digit percentage range.

Yes. And I think it's really important to look at absolute change in NSVT in particular. So if these numbers are low to begin with, like you have 1 patient that goes from 2 to 4, is that really meaningful? Or is that -- the percentage is high, but the reality is that that's not particularly clinically relevant and it seems more like noise, where as opposed to you see patients going from like 169 to 44, like it's unequivocally a large reduction.

Our next question comes from Geulah Livshits with Chardan.

Can you expand a little bit more on your hypothesis of why the kinetics of PVC count improvement could be later than NSVT. And what are your expectations for the kinetics for things like T-wave inversion, restoration and right ventricular function?

Yes. Great question. I think you have to remember that there are fundamentally different biological processes here. So PVC is really an intracellular process in which trafficking proteins that go along with the desmosome regulate and -- regulate depolarization and lead to early after depolarizations, which cause PVCs or delayed after depolarization. So that process is quite different than when you have entrapment of an arrhythmia leading to non-sustained or sustained VT. So we think it's quite possible that though you might not be able to suppress the initial PVC, the spark that you can still suppress whether those are -- that spark becomes a fire and is sustained.

Got it. And then how does that relate to the potential kinetics for the -- to those other metrics?

Yes. I think those other metrics, you can imagine those are -- a surface EKG is capturing the entire ventricle, and you can imagine that it would just take longer to change in, for example, a T-wave, which is reflective of the entire myocardium. So it's logical to me that those type -- that type of remodeling could just take -- you're talking about overall large structural changes to impact that, which may take time.

[Operator Instructions] Our next question comes from Michael Obodai with H.C. Wainwright.

Mike on for Mitchell Kapoor. Can you please share the baseline PVC burden and NSVT frequency for each of the 5 high-dose patients or at least give us the range and the median because kind of without baseline levels, it's hard to judge how meaningful the 14% and 22% mean changes are? And also what the PVC, NSVT measured by Holter versus ICD interrogation and where METs or ablation stable level of follow-up? And basically, I'm pretty much asking because Holter versus ICD can capture arrhythmias differently based on the monitoring window and which kind of affects how comparable the real -- how comparable the percent changes are?

So just to clarify, PVCs are on the slides. So if you look at Slide 16, the number on the left side of the arrow is the baseline PVC value. So we're simply calculating the percent change from that value on the left relative to the value on the other side of the arrow, the latest visit, which is the latest visit.

And can you repeat the second question, sorry?

I was just asking if the PVC, NSVT were measured by Holter versus ICD interrogation and if there were any METs or ablations or either METs and ablations were stable over follow-up?

Yes. So in regards to your first question, they were measured by a 7-day Holter and an average to give you a 24 hour, which I think is the right way to do it. So it gives you an average for this with -- as opposed to just one random 24-hour measurement. In terms of the second question, I think it is all disclosed on the slide. Again, there's minimal use of anti-arrhythmic with 2 patients or anti-arrhythmics of the entire cohort.

Our next question comes from Rohan Mathur with Oppenheimer.

This is Rohan on for Leland. Just on mRNA expression in PKP2, based on the current levels of PKP2 expression you've shown in the VCN numbers there, do you expect those numbers to stabilize over time? And if so, would there be -- would you still expect to see a greater degree of cardiac remodeling with the extended time of exposure?

Yes. I think it's a great question. This is obviously an early time point. Most of the patients are -- especially in the high-dose cohort where you only have 2 patients at 9 months. And we do expect that you can see this deepening and improvement, especially as we get out -- as we look at non-sustained VT that we do expect over time that this indeed should get better. Obviously, the data will be the data and that will tell us, but we think it's quite promising that over time, you see these reductions. So do expect -- we're hopeful that that's going to occur.

And we're seeing it, I mean, already in our opinion, if you look at the high dose mean NSVT change, we've seen a greater effect in 9 months versus 6 on average. So more to come. It's a small end, but one would expect that as this fibro fatty deposits are cleared as we've seen in the animal models, you begin to see even a greater response. And so I think it's a function of time. Again, as we've mentioned, this is the earliest time point where we can begin to evaluate efficacy. So to see these early signals that patients that are primarily at 6 months is encouraging with a clean safety profile and good protein expression. So yes, we're -- I think all these things are aligning for us.

[Operator Instructions] I'm showing no further questions at this time. I'd like to turn the call back over to Nolan Townsend for any closing remarks.

Okay. Well, thank you, everyone, for joining this morning. We appreciate the interest in the program, and we're excited about this program going forward. I mean I'd say we're looking at a set of patients here in this disease. And if you look at their baseline characteristics and some of their past treatment history, a lot of them have ICD shocks, sustained VT in their treatment history. They have high both PVC and non-sustained VT burden. And here, we're seeing in this early data that we are reducing premature ventricular contractions. We're reducing non-sustained VT. We've had no ICD shocks through the duration of the study. So we think we're seeing a positively emerging clinical picture here and obviously, alongside a very compelling safety picture for gene therapy at this dose. And so we're excited about the next steps in the program.

As we mentioned, we have patients 9 and 10 that have been dosed with a final commercial process for final manufacturing commercial process, which is yielding higher potency. So we'll have that data forthcoming in 2 patients. And then we have the 12-month data across the entire study that would be coming in the second half of the year. So a lot of exciting future moments for this program, including a conversation with the FDA about the registrational study. So thank you for your interest and for the interest in the program and the company. Thank you very much.

Thank you for your participation. You may now disconnect. Everyone, have a great day.

Good afternoon, and welcome to the fireside chat titled: A Clinician's Perspective: Holistic Approach to Managing PKP2-Associated Arrhythmogenic Cardiomyopathy, hosted by Lexeo Therapeutics. As a reminder, this call is being recorded today, Tuesday, December 9.

I would now like to turn the call over to Louis Tamayo, Chief Financial Officer of Lexeo Therapeutics. Louis, please go ahead.

Thank you. Welcome to this fireside chat session. Joining us today on the call from DC where they are both participating in the Cardiovascular Clinical Trialists Forum are Dr. Eric Adler of Lexeo Therapeutics; and Dr. Victoria Parikh, Clinician, Scientist and Director of the Stanford Center for Inherited Cardiovascular Disease at Stanford School of Medicine.

Before we begin, I would like to remind you that this call may 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.

Additionally, both Dr. Adler and Dr. Parikh's disclosures are listed on the slide.

With that, I would like to turn the call over to Dr. Eric Adler.

Thanks, Lou. I'm really happy to be here today at this session. As you know, at Lexeo, our mission is to change how genetically mediated cardiovascular diseases are treated by research and applying pioneering science. Currently, we have a cardiovascular gene therapy candidate LX2020 that's been evaluated in clinical trials for the treatment of plakophilin-2 arrhythmogenic cardiomyopathy, otherwise known as PKP2-ACM.

While a lot is known about ACM, as the treatment landscape evolves, perspectives on how ACM is viewed and managed is also evolving. There's growing evidence both in the literature and from clinical experience that supports approaching complex diseases like arrhythmogenic cardiomyopathy from really a holistic perspective, something we'll discuss more today. And to do that, I'm really excited to have Victoria Parikh with us. Vicki is the Director of one of the largest inherited cardiovascular disease center in the country, the Stanford Center for Inherited Cardiovascular Disease. She's an associate professor at Stanford and just a wonderful clinician and scientist. We're really lucky to have her today. Her center specializes in the care of patients with genetic cardiovascular conditions, including ACM and her clinical experience provides valuable insights into expert level and world-class patient care, and I'm sure we're going to learn a lot today and have a great conversation.

So let's dive right in, Vicki. Thanks for joining us today.

Thanks so much for having me, Eric.

Yes. So to start off, give us a little bit of background on your experience in managing patients with arrhythmogenic cardiomyopathy.

As you said, our center is one of the largest in the country in the world. And so we see thousands of patients with inherited cardiomyopathies, families with inherited cardiomyopathies. And one of those, of course, is arrhythmogenic cardiomyopathy. One of the things that we're really focused on and traditionally have been focused on at our center is implementing precision medicine. And as you all know, that is something that is uniquely suited to genetic cardiomyopathy. So not only do we see and diagnose sort of the clinical phenotype of patients with arrhythmogenic cardiomyopathy, but we also are really focused on deploying genetic testing and genetic diagnosis to be able to get to the root cause of those diseases in the clinic.

Great. So with all that being said, let's dive in a little bit to discuss ACM. Can you give us a little bit of background on the disease and its etiology?

Absolutely. So arrhythmogenic cardiomyopathy or ACM, is first and foremost, as it is named, a cardiomyopathy. But clinically, what we see in these cardiomyopathies is that progression toward heart failure is coupled with a particularly arrhythmogenic substrate, meaning that there's a structural change in the heart muscle that is also conferring very high risk of early and life-threatening arrhythmias like ventricular tachycardia. So it turns out that this particular disease is slightly more rare than other inherited cardiomyopathies, but is still present in about 125,000 individuals in the U.S.

Of these individuals that have been diagnosed, about 20% on clinical presentation actually come to our attention because they've had a sudden cardiac arrest. So it is a very severe disease. And that sudden cardiac arrest is often caused by ventricular tachycardia or fibrillation. Most of these patients when we do genetic testing, especially those who have their right ventricle involved, have a genetic diagnosis of plakophilin-2, which explains more than 50% of those ARVC ACM subset patients.

Great. Let's dig in a little bit more. How does the mutation of PKP2 gene actually contribute to the development of ACM? What do we know about the kind of the pathobiology?

That is such an important question. The way that PKP2 or plakophilin-2 works is it's a part of the glue that holds heart cells or cardiomyocytes together. And it turns out that just like humans, cardiomyocytes need to talk to each other in order to stay in rhythm and work together. So when you lose PKP2, which is part of that glue, also called the desmosome, you lose those connections. This leads not only to abnormalities in rhythm because those cells can't talk to each other very well, but also to the death of those cells because they are over working and therefore, leading to more arrhythmias and then when they die, to replacement of that section of the heart by scarring or fibrosis.

So it's a complex situation with PKP2 ACM, but the bottom line is that mutations or variants in PKP2 and other desmosomal genes lead to significant electrical and structural abnormalities.

Yes. Such an interesting disease with especially this unique infiltration of fibro-fatty tissue. So it's just fascinating. So with that background, talk to me a little bit about your approach to assessing and managing ACM patients.

Yes, it's tough. We don't have a lot of options for them. I think as a clinician, I tend to sort of separate simply each disease into how I diagnose it and then how I follow it and manage it going forward.

With respect to actually diagnosing ACM patients, as I mentioned, many of these folks, their first clinical manifestation is a significant ventricular arrhythmia, like ventricular tachycardia. But when that happens, there are a lot of reasons why patients might get ventricular tachycardia. So what we're doing is we're making a systematic evaluation of that patient from the structural disease in their heart, all the way through to electrical changes that might actually tell us a little bit more about the underlying etiology of that VT.

So for patients with ACM, we generally, especially in the right-sided ACM, right ventricular ACM, use what we call the Task Force Criteria, which came out a long time ago, but are still really tried and true for defining this disease. Those are complicated because this disease spans both structural and electrical abnormalities. Some salient examples of that are that we're going to take really, really detailed pictures with MRI, imaging and echo of both ventricles to try to understand whether that fibro-fatty replacement that you mentioned is actually disrupting the function of those ventricles and in particular, in certain spots of the ventricle.

And then we also do a really thorough electrical evaluation. So that includes an ECG, where we try to understand if the heart is depolarizing, so that means activating, right, normally, but also if it's returning back or repolarizing correctly as well. And then we look for arrhythmia. So the first thing that we look for is this patient having something called nonsustained ventricular tachycardia, is a really, really good sign that, especially we can localize it, that they are developing worsening ARVC or ACM. And then, of course, we also look for PBC count. These can show up a little bit earlier than nonsustained VT. But when those PVC or premature ventricular contraction counts are quite high, that can give us a clue as to whether this is an ACM patient.

So importantly, though, you can't base the diagnosis on just one of those. There's a very sort of complicated point system where you have to show that within those structural and electrical categories, multiple of them are actually disrupted in order to make the diagnosis of ACM. So that's the diagnostic criteria, which are quite complicated. But moving forward, right, you look at the management buckets in terms of what's going on with their arrhythmias or their electrical complications and what's going on with their structural disease.

So when I'm monitoring these patients, I'm very frequently monitoring their rhythm. The first decision we have to make is whether they are at high enough risk of a sustained ventricular tachycardia or major ventricular life-threatening arrhythmia in order to warrant implantation of a defibrillator, right? And there's a complicated calculus that goes into that. And then, of course, I'm looking for the development of heart failure, which tends to appear a little bit later in this disease, but it's certainly a huge and currently really unmodifiable progression that we see.

Great. Curious, how often do you see cascade patients as well, so family members that just might have a family member with ARVC?

To your point, we, of course, are using genetic testing as part of that diagnostic criteria. As we mentioned, having a known causative variant in, for example, plakophilin-2 is going to get us closer to a diagnosis. And so when we can make those genetic diagnoses, that helps us to screen family members because if they then don't carry that causative genetic variant, we can often release them from screening, which can be lifelong. So we do see those patients.

We see folks with very early stages of disease where they carry a PKP2-truncating variant, maybe they're having a run of nonsustained VT, maybe their right ventricle is a little bit big. And so in that diagnostic criteria, we do heavily weight the presence of that genetic diagnosis, that PKP2 truncating variant, for example, because that can really help to tell us how closely we need to monitor those patients in order to catch disease before it becomes a sudden cardiac arrest.

Got it. That's great. Okay. Well, let's transition a little bit to this area around nonsustained ventricular tachycardia, NSVT, and PVCs. There's this clear consensus to look at the components of the diagnostic criteria, but these various parameters need to be looked, as we said, holistically when assessing a patient's cardiac status as well. Do you want to talk about how you look at these 2 parameters in arrhythmias in general?

Absolutely. So I mean, diagnostically, they're actually differentially weighted. So it turns out that nonsustained VT, which is basically a run of rapid extra beats that are coming from the wrong place in the heart, from the ventricle. It should be coming from the atrium and normal beats. So nonsustained VT is something that is heavily weighted in the diagnostic criteria if it seems to be coming especially from the right ventricle. And so it's a major criterion for diagnosis, which gives it more weight in that sort of summative formula that we were talking about, the Task Force Criteria. And then PVCs, if that patient is having more than 500 PVCs or single extra beats from the bottom of the ventricle per day, then that counts actually as a minor criteria, which is sort of 0.5 point. So diagnostically, they're weighted differently, certainly.

When we're thinking about following patients going forward, I think of PVCs really as a diagnostic sign of disease. When I start to see nonsustained VT or NSVT, then I'm thinking more about disease progression. Certainly, we see increasing PVC numbers associated with disease progression as well, but it's a little bit of a chicken and an egg there in terms of whether that's actually going to worsen the patient status or whether that is just a diagnostic sign. With nonsustained VT, if that becomes more frequent, longer, faster, those are things that make us worry about the patient then having a sudden cardiac arrest.

In fact, when we have developed risk calculators as a community in this ACM population to try to determine who's going to benefit most from a defibrillator, it turns out that nonsustained VT has a really, really big effect on that percentage likelihood of sudden cardiac arrest or sustained VT than the number of PVCs.

So in sum, we have to think about both of these things. They're both important. But when I'm following patients in the clinic, I am very, very concerned when I see nonsustained VT. And I think reversing that gets us sort of closer to reversing the risk of sudden cardiac arrest.

Do you think about them differently in terms of kind of the pathology disease like PVCs being a spark and then you have to actually have reentry for an SVT or something like that?

Yes. That's a good point. I think that's probably the underlying reason for my gestalt about NSVT being sort of a heavier sign when I weigh disease progression. So as you're pointing out, nonsustained VT because it's many rapid beats in a row, often it's happening around scar or fatty fibro infiltration in the ventricle that you've described. And so that can sort of tell us that there is a worsening structural disease in addition to those electrical abnormalities. PVCs by themselves can often be a very small number of cells that are not necessarily causing multiple beats around a fibro-fatty scar, but instead are sort of beating out of turn more frequently.

So you could, I think, put that together to say, look, nonsustained VT because it's reentrant has the ability to turn in to a longer, sustained, symptomatic, potentially life-threatening VT, whereas a PVC is terminating, right? It's one beat at a time. And so theoretically, it's not going to turn into VT by itself. But there are a lot of complexity that goes into that pathophysiology that makes it an imperfect model.

Got it. Okay. That's great insights. Let's switch gears a little bit and talk about management for these patients. So can you walk through how your -- your current management approach?

Yes, absolutely. Well, I mean I think the first thing to say is that our management approaches are largely trained on the electrical arrhythmias that we see, and that's because we've had some amazing leaders in the field who are, in fact, electrophysiologists and because, as I mentioned, this is the more common presentation of symptomatic diseases to have a sustained ventricular tachycardia or symptomatic nonsustained VT. So for those arrhythmias, the first thing that we try is a beta blocker. It turns out that they are somewhat sensitive to blocking adrenaline, which is what beta blockers do. But in general, for patients that are having those nonsustained VTs, they are going to progress at some point to having a sustained ventricular tachycardia.

And so, like I said, we do those risk calculators to make sure that we are understanding the risk-benefit ratio for each patient in terms of giving them a defibrillator, which is, of course, implanted and carry some risk with it. But that's, of course, to prevent sudden cardiac arrest. So that is the second sort of mainstay of therapy is to prevent sudden cardiac arrest with ICDs.

And then additionally, as that disease progresses, as their VTs become longer, as they become more symptomatic, there are other antiarrhythmics that can be used. Most recently, flecainide paired with beta blockers has been shown to be relatively safe. There was some concern about that in terms of very old trials with ischemic cardiomyopathy. And then sotalol is another one that can be used, although there's some data to suggest that, that's not as effective.

I think in summary, what we're trying to do in ARVC patients is tamp down their arrhythmias and cross our fingers that they're not going to really progress to heart failure because when they progress to heart failure, we do not have good disease-modifying agents. This is a disease with a huge area of need to be able to actually reverse disease and stop -- medically stop the risk of arrhythmia and heart failure.

Sure. And are some of these patients getting ablation like surgical procedures or interventional procedures?

Yes. Thanks for bringing that up. Of course, if the medical intervention of flecainide, for example, fails to control their ventricular tachycardia, these patients absolutely can go for VT or ventricular tachycardia ablation. There are some amazingly skilled electrophysiologists around the U.S. who can provide that service to patients, both from inside of the myocardium and outside, we called that an epicardial ablation. The problem is that in many of these patients, the entire myocardium is affected because the entire myocardium doesn't have enough PKP2, right? So you ablate one VT and then you wait for the next one to happen, and it can turn into a game of whack-a-mole, right? So even ablation is not a cure. So it's a hard disease to take care of in many patients.

And even that doesn't really change the underlying progression to heart figure, right?

Exactly. Exactly.

Yes. All right. Well, that naturally opens up the opportunity and need for novel therapies like gene therapy. So this is obviously a big topic on many people's minds. No gene therapies are currently approved specifically for cardiovascular disease, but there are several investigational gene therapies in clinical trials, and they're getting a lot of attention from clinicians. I noticed this topic all over the agenda, both you and I have been spending some time at CVCT discussing it, highlighting the fact that it's of interest to physicians and investigators, regulators, et cetera, and patients. So where do you think gene therapy could fit in for cardiovascular disease? And how do we move gene therapy forward? Who could be the right candidate, et cetera?

Yes. These are the most critical questions that the clinical community is asking right now. I think in terms of what is the right disease for gene therapy, the first question that we ask as clinicians is who is undertreated, right? What is the disease that we don't have any other answer for? And then also, what is the complexity of that disease? So arrhythmogenic cardiomyopathy is a great example of a disease that, number one, we don't have great options for treatment, especially in terms of progression to heart failure, as you and I just talked about. We have really bad outcomes in this disease that include things like sudden cardiac arrest. And even for patients that we identify early by family screening, we can't always prevent that, right? We have to use a defibrillator to prevent it, which itself is a really -- it carries risk, especially when you're putting a defibrillator in a 35-year-old who's got to have wires in their body until they're 80, right?

And then I think once you've talked about area of needs that ACM is -- has huge need as we're discussing, you need to think about sort of which patients with that disease are the right patients to treat. And I think because we've developed so many risk scores and because we have a knowledge of how this disease progresses once it shows up, we're able actually with ACM to find the right patients and tell that patient, I think that you could benefit from a potentially disease-reversing therapy. And that's a powerful thing. So this is, I think, the right disease for this type of precision medicine.

And how about within ACM, is there a sensor you're getting in your mind about which patients might be the right patients?

Yes, I think so. I think that as we talked about, patients present mostly with these pretty severe arrhythmias. And I can tell you from the patients that I've talked to the first time they've had an arrest, the first time they've had a really, really symptomatic fast ventricular VT even if they didn't lose consciousness or the first time they've been shocked, they're telling me, sign me up because I know that this is going to happen again, right? I know I don't want it to happen again. And I also know that there's nothing that you, my physician, can do to stop the progression of heart failure when it comes. So give me something to repair the underlying defect, which is that my body is not making enough plakophilin-2. So I think that as soon as we start to see those first signs of VT, especially symptomatic, especially requiring shocks, that those are the right patients to try to jump in and reverse disease in.

Great. I don't think we got to capture this at all thus far. But can you talk a little bit about what you might be looking for to measure the benefit of gene therapy then signs or signals?

Yes, absolutely. So I think the holy grail here is as somebody who sees a lot of cardiomyopathy to be able to prevent or reverse even progression of that fibro-fatty infiltration, which we can see as an increasing size of the right ventricle as weakness in the right ventricle. But we know that, that will probably take quite a bit of time, especially if we expect to reverse disease, which we all know that replacement of cardiomyocytes is really hard to overcome just based on sort of the biology of the way they don't necessarily divide once they're differentiated, et cetera. I think that really what would be extremely meaningful to my patients would be to see that their heart is less electrically active over time. And so we're thinking about those things like nonsustained VT, which we know is a huge risk factor for having more VT or sudden cardiac arrest.

And certainly, looking at how PVC's change can be helpful, too, although as we mentioned, that's a minor criterion and not as predictive of events in the future. So that would be my hope that we would definitely see fewer of those nonsustained and sustained arrhythmias over time. And that in the long term, we would hope to see at least less progression to heart failure, if not repair of existing weakness in the right ventricle.

Great. Well, that's -- thanks so much, Vicki. I think that last point really drives on the key takeaways that we have to look at this holistically. And I think hopefully, by focusing on totality of disease, we can better understand patient needs and the true impact of emerging therapies like gene therapy.

So thank you so much for spending some time with us this morning at CVCT. And let me hand this back over to Lou, so we can take some questions from folks.

Thank you, Dr. Parikh and Eric. We'd like to open the call for Q&A. Please note that while we welcome general questions about ACM and today's discussions, we cannot address any inquiries specific to our LX2020 program at this time. We look forward to sharing clinical data related to LX2020 early next year and addressing those questions at that time.

[Operator Instructions] Our first question comes from the line of Geulah Livshits from Chardan.

Good afternoon. Thanks for that really helpful overview. I guess just to better understand the NSVT and PVC component, are there thresholds with respect to levels of NSVTs and PVC that might significantly change management that you would be looking for in terms of degrees of benefit? And just in general, with respect to the efficacy that you see with the antiarrhythmic drugs and the ablation. Is there additional color that you can provide on the kind of degree of benefit that those provide versus what you'd be looking for with a gene therapy approach?

Yes. Of course. So I think the first point to make is that mainly what we want to do is reduce patient symptoms. So that's always the first thing that matters to us in terms of especially PVCs. The threshold of NSVT that we're looking for, it depends on how fast it is and how long it is, and then also on sort of the number of times we see it. Meaningful reductions in NSVT have not been modeled very well in terms of risk of meeting an ICD shock or of having a sudden cardiac arrest. Usually, it's a binary variable is there NSVT or not. That's not to say that clinically, when we see a small reduction in NSVT, we're not happy. It's just that I can't give anybody meaningful changes in outcomes with like a specific threshold change in those two factors.

Our next question comes from the line of Paul Matteis with Stifel.

This is Matthew on for Paul. Our question is for Dr. Parikh. Can you help us understand the natural rate of disease progression in these PKP2 patients? Do you expect electrical measures like PVC or QRS or heart function markers like LVEF to worsen within 1 year, within 2 years? And is there any specific marker that progresses faster than others in patients?

Yes, thanks. So a couple of things there. So in terms of what we see change first in a patient population that is genotype positive, meaning that we know that they carry a PKP2 variant, but they have not yet presented with disease. These are people that are being family screened basically. What we know is that the first change we see is in the ECG and then we tend to see arrhythmias come up after that. But once the diagnosis has been made, in particular, someone who has positive findings on a cardiac MRI that would lead to diagnosis as well as NSVT and the other things that we have been mentioning, I think that the progression is generally relatively rapid for us.

So I would say that of my patients who I've seen present with a symptomatic arrhythmia, we move from medication treatment to ablation therapy relatively quickly. So likely within 1 to 2 years of seeing their first significant VT, we're going to be sending them for an ablation if not sooner, depending on how fast that VT was. And then we tend to see the cardiomyopathy or the heart failure aspect of this disease start to show up later than those ablations. So generally, in these patients, those that I'm sending for transplant, for example, are patients that have ended up with really, really bad heart failure after having 5 or 6 different ablations who have been on medical therapy for 5 to 10 years. So those are the type of time horizons that we see. But in general, I think it's obviously different for every patient. There are certainly patients who present with heart failure earlier, et cetera.

Our next question comes from the line of Brian Skorney with Baird.

Thank you so much for doing this call, Dr. Parikh. So I guess we're going to see a bunch of different measures in future studies of gene therapies and PKP2, both electrical and structural. And I guess my question would be, if you could just kind of discuss the inherent variability of each of these measures that you might see within a PKP2 patient, especially when you introduce a level of care that would be associated with a clinical trial. And what I'm really getting at is what sort of changes could absolutely not be a placebo effect of a clinical study, right? In oncology, we generally don't think a tumor can show a 30% decrease on a scan. There's this regulatory view that a greater than 10% improvement in left ventricular mass within a year would not be seen in the absence of intervention. Is there any way to kind of think about what you can exclude as just normal variability when we see initial data from some of these therapies?

Yes. I wish that I could give you exact percentages, and it's really hard because we don't have a tumor that's going back, right? We have a sort of stochastic arrhythmia that's going to kind of come and go as at once. What I can comment on, I think, is sort of the relative variability of those outcomes. So in terms of PVC count that we talked about with diagnosis, that can fluctuate rapidly like whether you're talking about ARVC or whether you're talking about a relatively healthy patient who just gets PVCs with their mental cycle, for example. So it's really hard to say what the sort of error bars would be around those variations.

The same, of course, can be true for nonsustained VT. But again, we're really looking at a -- for many of our predictors at a binary variable there. But in general, I think we're happy with any reduction that we can see as providers who are trying to treat these patients. And then when it comes to the function of the myocardium, I think that any improvement is great. I think that that's probably going to be something when you have serial measurements where the trend over time will be less variable than the arrhythmias?

I might jump in, Brian. It's Eric. One of the things that you can think about is can you reduce the variability in and of itself. So in other words, patients with ARVC will have these spikes in PVCs. So the reduction in spikes or the -- in and of itself is something interesting in that, that could be quantifiable and measurable. Obviously, over a longer period, but we often see these patients have this variability, have these spikes. And if you -- the absence of that would be something to keep an eye on for sure because the accumulation of spices is prognostic in and of itself and there's some recent data to support that.

Our next question is going to come from the line of Mitchell Kapoor with H.C. Wright.

This is [ Jay ] on for Mitchell. So could you approximate how many patients are coming to you from that family diagnosis versus a referral from a community cardiologists upon presentation of symptoms? And how severe are those symptomatic patients generally coming in by the time they've been referred to you?

Yes, great question. So it's a mixed bag, right? So I would say that, in general, the majority of new referrals to us from the community are going to be those that already have disease. They usually present with a really bad arrhythmia. So like a sustained VT that was so symptomatic that they went to the ER, right? And they come to us like with a life vest and on amiodarone or some medication that it's going to be really hard to get them off of. But because it is a really scary presentation is my point.

The patients that we see with family screening are generally going to be those patients that we have recommended be screened based on one of their family members being diagnosed with disease or be referred to us by another physician who cares for ARVC or ACM patients in particular.

It is, I think, important challenge that many people in the genetic cardiomyopathy community are trying to address in terms of how to help these families understand that they need to be screened. And we've made significant progress there. I think there are specific centers where there are folks who basically live near their families, right? So I live in California, my families have like pretty broad diaspora, right? So I'm trying to find them a place to be screened that's in Ohio or something like that. But there are other places like in Boston or like in Spain, where family units tend to stick together, and then you're going to see a much higher sort of percentage of family members there. So it's really going to vary by geographic location, but those are sort of the sources of referrals if that makes sense.

But -- so what's your particular percentage? Is it like 80% patients with symptoms when they come to you, 20% family members or -- and would you consider that the proportion of your patients who are coming to you symptomatic, do you think that they could be eligible for a gene therapy? Or are they too far gone by the time they're seeing you?

I would say that the proportion of patients who come to me who would be eligible for a gene therapy is actually quite high. So the majority of those folks who come and they've had their first sort of major arrhythmic event like that VT that I described, those are patients who would like time for gene therapy, right? We should try because it's not like we're at a point of disease where they're so far progressed and the right ventricle has blown out that we're not going to be able to make a difference for them simply by releasing the gene that they've lost.

And then in terms of our clinic, I have to be honest with you, I don't have the exact numbers, but I would estimate that it's something like folks who have been diagnosed with disease already. And then within the PKP2 truncating variant population, it's probably, frankly, even higher just because it's very specific for ARVC as an entity.

Our next question is going to come from the line of Tessa Romero with JPMorgan.

This is Mariam on for Tess. We are curious on -- can you just quantify how many patients with PKP2-ACM do you think would be eligible for gene therapy approach? And how are you thinking about the patient funnel who would most likely adopt a gene therapy?

Yes, that's a great question. Again, the patients that come to my clinic who would be eligible or I think early enough in their disease for a gene therapy approach, I will say that it's pretty high. I think it's going to be something like 70% of them. Very few patients, PKP2-truncating variants present to me at the time when like they're ready for a heart transplant in which case it would be too late, I think, for gene therapy. And then there is, as I mentioned, a small population that's slightly too early, which would be just genotype positive at this point and phenotype negative.

And then I'm sorry, the second part of your question was?

And how are you just thinking about the funnel of the patients who would most likely adopt a gene therapy?

Yes. So I think that this is a really specific type of disease where the first time that a patient presents with symptoms is often very, very, very scary and life-threatening. And so of those patients, the ones that I would recommend for gene therapy, I think the uptake in readiness among them would be very high, like 80%, 90%.

Our next question will come from the line of Leland Gershell with Oppenheimer.

Thank you very much, Dr. Parikh for this educational session. Just a question for me, which may overlap a little bit with what's been asked before. But I just wanted to understand, obviously, you're at a tertiary referral center, there's many patients out there in the community who maybe kind of a longer journey to getting properly diagnosed and treated. What extent do you think that would change with the hopeful introduction of a gene therapy for PKP2-ACM. And as you yourself begin to adopt what could be an approved product down the road, you say that you'd expect most of your patients to be eligible. But would you expect an initial uptake as all physicians kind of maybe take some time to become used to using a new product? Would that -- would it be used primarily in patients who are younger? Would you look to try to kind of seek the maximum amount of benefit from patients who have not progressed as far? Just wanted to sort of ask kind of on the cadence of your adoption as based on what we know now and then I have a follow-up for the management team.

Of course. I think that I can speak from our recent experience, both with cardiac myosin inhibitors for hypertrophic cardiomyopathy and then, of course, various therapies for cardiac amyloid, which have come out in the last few years. So number one, our referral volumes went up massively. So I think what this meant was that those community providers heard, "Hey, there's actually a therapy for this patient now. Let me get this patient to someone who knows how to do it." And then I think the next step in that process is for us and for the folks who make these drugs to get out there and educate those community physicians on how to use those drugs safely.

But I can tell you that for cardiomyopathies like those, which are very common, of course, they can overwhelm the system. I think with ARVC, you are kind of in a sweet spot where you can likely handle, at expert centers, gene therapies for all the patients that are going to be sent to you or set up expert centers pretty easily at other academic institutions. So I think that there most likely will be an uptick in what's referred to us when we start to see precision therapies for these other cardiomyopathies. And I think that there are absolutely enough resources in our system to be able to get them the therapy that they need.

Great. And then just a question for the company. You've indicated we'll have a data update, I believe, next month. Just wondering if you could remind us the scope of what you plan to present on.

Sure. So we'll have updates on -- as we said, this is a trial with 10 patients. We'll have updates on 8 of them and clinical and some of the -- clinical endpoints as well as readouts from the pathologic studies done.

Our next question will come from the line of Hannah Wei with Guggenheim.

And my question is for evaluating the efficacy of PKP2 gene therapy. Which is more important, the patient has disease manifestation primarily in the right ventricle or [indiscernible] disease.

Thanks. So I think that the most important thing that we know about PKP2 truncating variants is that they cause RV disease predominantly. There are certainly patients who have a disease that affects both ventricles. I think that classically, because this was first sort of reported in autopsy series, it was thought that having both ventricles involved necessarily meant worse disease. I think that what we've seen as a community is that, that's certainly not evidence that this patient is going to not be repairable, right? Like not everybody that has biventricular involvement goes to transplant, for example. So what I would say is that there -- the majority of these patients will present only with RV disease and that there is a significant proportion of patients with biventricular dysfunction who would also be able to still benefit from gene therapy.

Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

I wanted to drill down an understanding whether there's anything different we should be thinking about the profile of those patients that have already had sudden cardiac arrest, especially as it may not necessarily have been correlated with their disease progression, but rather activity that led to it?

That's a great point. There has been a lot of data, especially early on in studying this disease that potentially, certainly, long-term high-intensity endurance athleticism, so we're talking about marathon runners, Iron Man, like really real high-intensity and endurance athleticism could increase the progression of disease. However, if a patient had a sudden cardiac arrest or a prolonged and symptomatic fast VT, that patient still requires medical and potentially also ablative therapy. So even if the patient has a history of being a really serious endurance athlete, if they carry a PKP2-truncating variant and they've had an arrest, then we still treat them the same as if they hadn't been an endurance athlete prior.

Okay. And on that point, though, thinking about their future progression on some of these endpoints and measurements we talked about, would you expect them to progress perhaps at a different rate versus somebody that has not had a cardiac arrest yet? Or would you expect them to follow a pretty similar path?

I understand. So for just looking at sudden cardiac arrest, I think that is a tipping point for these patients. And so if they've had a sudden cardiac arrest, then that tells me that pretty quickly within a short number of years, we're going to be looking at somebody who's getting multiple ablations. I think that if they're an athlete, they're an endurance athlete, I should say, and they continue to exercise at that high level despite recommendations and there is evidence to suggest that, that will increase their disease progression, but it's not clear how something like a gene therapy would affect that trajectory. The idea would be that you replace the PKP2 and that you end up now being able to be an endurance athlete without having a risk of progression, and it's just something that needs to be proven.

And I would now like to hand the conference back over to Louis Tamayo for closing remarks.

Thank you, Michelle. Thanks again, Dr. Parikh, and thank you, Eric, for facilitating such a great discussion. To those that listen and ask thoughtful questions, we hope this was informative and helps to shed light on this complex disease through the eyes of expert clinicians that care for and manage these patients. As we said, we look forward to sharing more data on our LX2020 program with you soon, and we'll share that new data from our Phase I/II trial at the JPMorgan conference in January. So for everyone, thank you for joining us today, and we hope you have a great day.

Michelle, I think you can close the call there. Thank you.

This concludes today's conference call. Thank you for participating, and you may now disconnect.

Good morning, and welcome to the Lexeo Therapeutics webcast presentation on LX2006 for the treatment of Friedreich's ataxia cardiomyopathy. As a reminder, this call is being recorded today, October 7, 2025.

I would now like to turn the conference over to Louis Tamayo, Chief Financial Officer of Lexeo Therapeutics. Louis, please go ahead.

Earlier today, we released the regulatory update on our discussions to date with the FDA regarding a potential accelerated approval pathway for LX2006 for the treatment of Friedreich's ataxia cardiomyopathy alongside new interim clinical data from 2 ongoing Phase I/II clinical studies. The press release outlining these updates is available on our website 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; and Dr. Sandi See Tai, Chief Development Officer of Lexeo Therapeutics; Dr. Eric Adler, Chief Medical Officer and Head of Research; and Dr. Manny Otero, Chief Technical Officer, will also be available for Q&A following the call.

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.

Thanks, Lou, and thank you all for joining us. Today, we are pleased to share regulatory feedback on LX2006 and as well as the latest safety and efficacy data from ongoing studies in FA cardiomyopathy. As we shared this morning, the FDA is open to a BLA submission that polls clinical data from the ongoing Phase I/II studies of LX2006 with data generated in the upcoming pivotal study and we are planning to submit enhanced comparability data to support this approach. The FDA has also agreed to evaluate the co-primary endpoint of LVMI at a time point earlier than 12 months which we believe has the potential to shorten the length of the pivotal study. We will share more details on our progress with FDA on this call and we expect to continue discussions with the agency into 2026 on the pivotal trial protocol and comparability requirements.

Looking at the interim clinical data since our last update, we are pleased to see sustained or deepening improvements over time in both cardiac and neurologic measures of FA. All participants with abnormal LVMI at baseline have now reached at least 12 months of follow-up and we've observed a 23% mean improvement in LVMI at this time point. We've also seen 18% mean improvement at 6 months after dosing, well above the FDA line threshold for the pivotal study of 10%. We have also observed what we believe is clinically meaningful improvement in the modified Friedreich's ataxia rating scale, or mFARS which we will detail this morning.

From a safety perspective, LX2006 remains generally well tolerated across all dose cohorts, utilizing relatively low doses for a systemic gene therapy program. These data collectively give us great confidence in the therapeutic potential of LX2006. Lexeo is proud to collaborate closely with the FA community, and we've highlighted 3 stories this morning from Ali, David and Ann Marie and Ron and Rachel. We deeply appreciate them sharing their experiences with FA, and I know these stories are highly motivating to myself and all Lexeo colleagues as we continue our work to progress the development of LX2006.

Friedreich's ataxia is a devastating condition and cardiac complications are the most common cause of death in FA, leading to an average life expectancy of just 35 to 40 years. Treatment options are urgently needed for those impacted by FA cardiomyopathy, and we are hopeful that our research can bring this one step closer. I will now share a brief background about this condition and ongoing LX2006 research before jumping into more details of the regulatory update. Friedreich's ataxia is a rare progressive devastating multisystem disorder that impacts approximately 5,000 people in the United States and 15,000 globally. Almost all people with FA will develop some cardiac complications during their lifetime and up to 40% have left ventricular hypertrophy as defined by abnormal LVMI which is a key inclusion criteria for the LX2006 pivotal study.

Importantly, as I previously noted, cardiac complications are the leading cause of death in FA and currently, there are no approved treatments for FA cardiomyopathy. Individuals with FA have very little for frataxin protein expression which leads to impaired mitochondrial function in the heart and throughout the body. LX2006 is designed to treat the root cause of this disease by restoring frataxin. We package the full-length frataxin gene in AAVrh10 vector, which has an increased affinity for the cardiomyocyte cells in the heart, allowing us to use relatively low doses in this program which we believe could support a more favorable safety profile while still offering efficacy in treating cardiac disease.

LX2006 also includes a CAG promoter, a strong clinically validated, ubiquitously expressed promoter that could enable expression in other tissues with frataxin deficiency beyond the heart, such as in skeletal muscle. As a reminder, LX2006 is being evaluated in 2 parallel trials, 1 multicenter study sponsored by Lexeo and another investigator-initiated study run by Dr. Ron Crystal at Weill Cornell. These 2 trials are very similar, both enrolling adult patients with FA cardiomyopathy. Although cardiac biopsies were only performed in Lexeo's SUNRISE-FA trial, so frataxin expression has only been evaluated in participants in this study. The SUNRISE-FA trial completed enrollment at the end of last year.

Based on FDA's feedback to date, we believe we now have the potential to reduce the size and length of the LX2006 pivotal study, possibly accelerating our overall time line to BLA submission. First, the FDA is open to a BLA submission in which we pull the Phase I/II LVMI data with data from the upcoming pivotal study as long as enhanced comparability data are provided. The Phase I/II studies, both use an inherent HEK293 process that is not commercially scalable and Lexeo since migrated to an optimized Sf9-baculovirus manufacturing platform which produces high-yield, high-quality vector with a low empty capsid ratio.

We intend to use this process for future clinical and commercial supply and we will be submitting enhanced comparability data to FDA to support this change, including analytical comparability and data from a nonclinical murine bridging study using pre- and post change drug product. By pooling this data, we believe that we have a potential pathway to a smaller pivotal study with sample size determined primarily by the LVMI treatment effect. The FDA has also agreed to assess LVMI at an earlier time point, which could reduce the length of the pivotal study as we previously guided to assessing LVMI at 12 months. We continue to discuss the final pivotal protocol design with FDA, including the precise time point for this assessment, and we expect to provide further regulatory guidance in early 2026.

But I should note that in discussions to date, there have been no changes to the previously disclosed alignment with the FDA on key parameters related to the LX2006 planned registrational study including the aligned co-primary endpoints for this pivotal study, which remained LVMI and frataxin expression and the threshold for clinical benefit which remain 10% reduction and any change from baseline expression respectively.

Finally, the other co-primary endpoint frataxin expression will need to be assessed with a validated assay in the pivotal study. The biopsies in the SUNRISE-FA study were analyzed with the frataxin LCMS assay appropriate for a Phase I/II study, but not a validated assay intended for BLA submission. So this data will be supportive evidence for BLA. We remain highly encouraged by the Phase I/II data, and we appreciate the FDA's willingness to collaborate on an expedited development strategy for LX2006 especially given the urgent unmet need for treatments in FA cardiomyopathy. We plan to initiate the pivotal study as quickly as possible in the first half of 2026, pending finalization of the pivotal protocol.

I will now turn the call over to our Chief Development Officer, Dr. Sandi See Tai, to review the latest interim data for LX2006.

Thanks, Nolan. I will now review interim clinical data as of July 2025, which were also shared with FDA as part of our most recent interaction. On this slide, we are sharing baseline characteristics of the 17 participants treated to date across the SUNRISE-FA and Weill Cornell Medicine trials. The dark pink shading represents an abnormal cardiac measure for a value that is at least 2 standard deviations above the mean from healthy volunteers. The lighter pink shading represents a measure within the normal range but greater than 1 standard deviation above the mean, which we are labeling high normal. At baseline, all participants had some evidence of cardiac abnormalities and 6 participants had abnormal LVMI, which is often seen in this population as the heart thicken.

We will focus much of our discussion today on this subset of 6 participants with abnormal LVMI given they closely match the population we intend to enroll in the pivotal study, representative of those in most urgent need as higher LVMI is associated with increased risk of death. At the bottom of the table, we are sharing for the first time baseline data relevant to mFARS the neurological, functional scale specifically developed to measure FA disease severity and progression. You can see each participant's mFARS score at baseline with a score of 0 representing no impairment and a score of 93, representing maximum impairment on the scale.

The mean baseline score across the 2 studies is 63 which reflects a meaningful level of neurologic impairment at baseline, and is consistent with our adult study population, most of whom were also nonambulatory. You can also see which study participants use SKYCLARIS, or omaveloxolone at any point during the LX2006 study period. Concomitant use is permitted in the protocol as long as participants were either stable on omaveloxolone prior to dosing or they can begin treatment later following dosing. Omaveloxolone was approved based on its impact on mFARS and those with green checkmarks took omaveloxolone for some period of time during the ongoing studies, though not every participant is continuing on therapy today. These baseline characteristics will be important when we review neurologic functional measures later in the presentation.

I will start by sharing the safety data. LX2006 continues to be generally well tolerated to date. We've not observed any clinically significant complement activation or instances of TMA. We have observed minimal elevations in liver function tests or LFTs with no participant exceeding 3x the upper limit of normal. Notably, even the highest dose of LX2006 at [ 18, 12 ] vector genomes per kilogram is significantly below the doses used in other programs in which LFT elevations or liver injury have been observed. This dose is 100x lower than the recommended dose of Zolgensma, for example, and 133x lower than the recommended commercial dose of ELEVIDYS, and we believe the low dose is an important consideration for safety.

As we've previously shared, there was one participant who was diagnosed with myocarditis 1 year after dosing. This individual had multiple comorbidities at enrollment and their early treatment course was complicated by multiple pneumonias with required modifications to their immunosuppression. At their 12-month visit, this individual presented with elevated troponin and cardiac MRI suggested a focal myocarditis, although the participant was otherwise asymptomatic and a biopsy performed at that time could not definitively confirm myocarditis.

This individual has since been treated with corticosteroids and other immunosuppressants to manage the myocarditis and their biomarkers are improving but remain elevated. Expert opinion on this case has suggested this may be intermittent episodes of myocarditis on top of disease progression for the underlying FA cardiomyopathy. Additional biopsy samples have been collected, which will be assessed to better understand the underlying frataxin expression and potential disease progression. Of course, we continue to monitor this participant closely, and we are pleased to see the recent cardiac measures begin to come down.

Looking now at the efficacy data. Here, you can see cardiac biomarker data for the 6 participants with abnormal LVMI at baseline, which, as noted, matches the inclusion criteria for the planned 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 2 standard deviations or more above the mean and 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. All of these participants have now reached at least 12 months of follow-up. And on average, they achieved an 18% reduction in LVMI at 6 months and a 23% reduction in LVMI at 12 months.

Looking at patients in Cohorts 2 and 3, the mid- and high-dose cohorts, the mean reduction in LVMI was 28% at 6 months and 33% at 12 months. So we are seeing evidence of a dose-dependent treatment response. These reductions well exceed the target mean improvement of 10% in LVMI previously aligned with FDA for the planned pivotal study. We are also very encouraged to see the directional consistency between LVMI improvement and improvements in other biomarkers, including lateral wall thickness and troponin and in subsequent slides, you can see the durability of the improvement over time now that participants have reached at least 12 months.

This chart visually demonstrates the sustained and deepening treatment effect over time. All of these 6 participants have reached the normal range for LVMI at latest follow-up which is a highly encouraging signal for the potential of LX2006 to stabilize or even reverse cardiac disease due to FA. We are pleased to see durable improvements over 2 years in cohort 1 suggesting persistent transgene expression with an underlying disease-modifying impact, and we are beginning to see similar trends in Cohorts 2 and 3 now that these participants have reached 12 months of follow-up.

Looking at the other cardiac measures for those with abnormal baseline LVMI, we have continued to observe a pattern of sustained or deepening improvement over time with a potential dose response. Lateral wall thickness is on the left and high-sensitivity troponin Is on the right. We're particularly encouraged by the troponin results as elevated troponins are a marker of myocardial injury and this is a simple blood-based biomarker that is easy to evaluate in clinical practice.

You can see that participants achieved reductions in troponin from 25% to over 85% from baseline. Lateral wall thickness is also a relevant measure in FA cardiomyopathy, but it's important to note that it represents a 2-dimensional measurements compared to LVMI, which is a 3-dimensional assessment of the heart's entire mass. Compared to LVMI lateral wall thickness measurements may have greater variability, even with some measurement variability, the directionally consistent improvements observed across cardiac measures, from LVMI to lateral wall thickness and troponin give us great confidence in the treatment effect and therapeutic potential of LX2006. We've reviewed the results for participants with abnormal baseline LVMI.

Now I would like to share data for the other 10 participants who began the study with baseline LVMI measures within the normal range. Those with a baseline more than 1 standard deviation above the mean for healthy volunteers are noted in pink, which we are labeling high normal. In this group, 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 and myocardial edema 12 months after dosing and is a potential nonresponder. Participants 7, 8 and 15 with higher baseline LVMI values showed greater improvements in LVMI, and almost all participants demonstrated stabilization of lateral wall thickness and meaningful reductions in high-sensitivity troponin I. Taken holistically, we believe these data demonstrate the potential of LX2006 to positively impact cardiac status at earlier stages of disease even before severe hypertrophy has emerged.

Now looking at the complete picture for LVMI. On this slide, you can see the absolute change in LVMI across all 16 participants with 6 months or more of follow-up. The normal LVMI ranges for men and women differ. So we are showing men on the left and women on the right. As you can see, 15 of the 16 participants reached or remained within the normal range for LVMI at their latest visit with evidence of sustained or deepening response over time, again, powerful evidence of the therapeutic potential of LX2006.

Looking at the supportive endpoints again, now for all 16 participants, we continue to see consistent trends of improvement or stabilization of cardiac disease across most of the group. As noted previously, 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.

On the right, almost all participants experienced large reductions in troponin anywhere from 25% to almost 100% from baseline. Participant 14 in green appears to be an outlier, but I will note their absolute change in troponin was relatively small here, from 11 at baseline 16 at latest follow-up and both values are within the normal range. Finally, I'd like to share the exciting evidence of functional improvement observed to date. We have assessed functional status using the modified Friedreich's ataxia rating scale or mFARS, where reduction is favorable and reflects less physical or neurologic impairment.

This scale measures function in people with FA across 4 subscales: Bulbar function, upper limb coordination, lower limb coordination and upright stability. A change of 1 to 2 points is generally considered clinically meaningful. And without treatment, individuals generally progress by approximately 1 to 2 points per year on average. Here, we see evidence that LX2006 improved functional outcomes specific to FA. While some of this improvement may be due to the observed cardiac changes, for example, making some physical movements easier by reducing heart failure burden, we hypothesized the improvements may also be explained by extra cardiac changes.

In preclinical murine and nonhuman primate studies of LX2006, we did observe some transduction of LX2006 beyond the heart for example, in the dorsal root ganglia and in skeletal muscles. While the AAVrh10 capsid is cardiotropic, the systemic delivery of LX2006 combined with the ubiquitous promoter means that there could be beneficial off-target effects of this therapy impacting neurologic disease. Skeletal muscle biopsies are being performed in a subset of participants from the SUNRISE-FA study as part of an investigator-initiated study and we look forward to further evaluating this hypothesis and sharing those data in early 2026.

Looking now at the chart, you can see the mean improvement over time relative to natural history on the left. Since this is an interim update, we have participants at different stages of follow-up and we've noted the sample size for each time point. We are seeing clinically meaningful improvement of 1 to 2 points on average with a sustained response over time. To give you some perspective on this improvement, it represents greater ease with daily activities such as brushing teeth, handling food and utensils or dressing. Although study participants had very different baselines, 11 of the 16 participants showed improvement or stabilization relative to baseline at their latest visit.

Also included on the chart is natural history data from the FA-COMS database. This graph is based on published data, which is not propensity matched to the LX2006 study population, but it gives a directional sense of disease progression without treatment in an FA population of similar age. Finally, we'd like to share individual patient data to demonstrate the improvement in mFARS scores relative to natural history in red. There is some measurement variability, both inter and intra-patient with this type of assessment. But in general, we are seeing functional improvement with 11 of 16 participants improving or stabilizing relative to baseline.

On the left, you can see evidence of the potential dose-dependent impact with each participant highlighted by their dose cohort. On the right, we are addressing the concomitant use of omaveloxolone. Participants were not excluded from taking this in the Phase I/II studies. Ultimately, we did have 8 participants who received this drug for some amount of time during the study period, including 3 who are on therapy at the time of dosing and 5 who began therapy at least 7 months or more after dosing.

It's natural to ask how much of the mFARS benefit observed in these studies may be due to underlying omaveloxolone treatment? To help answer this question, we have isolated data for the 8 participants that have never tried omaveloxolone in yellow. And as you can see, we're still observing positive trends in the subset of participants, which suggests that LX2006 alone can improve neurologic functional measures of FA. In light purple, you can also see those participants that did not begin omaveloxolone treatment until later in their follow-up, and many of these participants still saw neurological improvement in early time points.

Finally, these data have been previously reported, but I'd like to remind everyone that all participants in the SUNRISE-FA study did show an increase in frataxin expression at 3 months post treatment with evidence of dose-dependent increases across cohorts. Cardiac frataxin expression remains the co-primary endpoint in the pivotal study, along with LVMI and the FDA aligned threshold is any increase in frataxin expression over baseline using a validated assay for assessment. I've covered a lot of data this morning.

So to summarize, FA is caused by deficiency of frataxin and following dosing with LX2006, we have shown an increase of frataxin in the target organ of interest, the heart. And coupled with this increased expression, we have observed improvement in cardiac structure and in biomarkers of cardiac cellular injury as well as directionally favorable changes in neurologic functional scores. Taken together, these data illustrate the therapeutic potential of LX2006 and its potential to treat the underlying cause of FA.

I will now turn the call back over to Nolan to close the call.

Thank you, Sandi. I believe these interim data continue to demonstrate the potential of LX2006 to be a first and best-in-class treatment for FA cardiomyopathy. We've observed improvements in cardiac and neurologic measures of FA across a majority of participants alongside a generally favorable safety profile and we are meeting or exceeding FDA aligned thresholds for target improvement. We are collaborating with the FDA to fully understand the necessary conditions to leverage the Phase I/II data for BLA -- for accelerated approval, and we are working to design a pivotal study that is potentially more efficient while advancing the necessary work on manufacturing comparability.

I want to thank the study participants, caregivers and investigators who have helped us reach this exciting milestone, and we will now take questions.

[Operator Instructions] And our first question will come from Paul Matteis with Stifel.

This is Matthew on for Paul. Congrats on all the progress. So my question is on the pooling, and I understand that the stat plan hasn't been finalized yet. But in terms of the threshold for LVMI of 10, what sort of scenarios do you envision that might apply to the pool data? Do you think it's the overall pool data that needs to meet that threshold? Or does the Phase I/II and the pivotal study need to hit that threshold separately? And then as a quick follow-up, on the natural history study, how do you envision that playing a role in the analysis -- for the pivotal analysis?

Thank you for the question. So just if I can repeat the first question. You're asking if the data from the Phase I/II study and the effect size required on LVMI would be measured separately from the data for the upcoming pivotal study and the effect size required there. Is that correct?

Yes. Or is it just one, just the pooled LVMI between both the Phase I/II and the pivotal that will be compared against the threshold?

Yes. I'll pass it to our Chief Development Officer, Sandi, to say a few words about that.

Yes. So when we talk about pooling data, we envision it being a combined single endpoint that would meet that threshold that we've discussed in terms of LVMI not as 2 separate. Not as 2 separate analyses but this will be finalized, as you noted, when we work to finalize the SAP with the alignment of FDA.

And then can you repeat the second question?

Yes. So for the natural history study, how do you anticipate the data from that supporting your pivotal analysis for which end points?

Yes. So we would anticipate that study being supportive in terms of utilizing LVMI data from the natural history study. In addition, we are collecting other biomarkers that include troponin as well as mFARS data. So we envision that this can be supportive data, how exactly it would be analyzed remains to be further discussed and finalized.

And to note that natural history study has already begun earlier this year. So we're in a place where we've begun to identify patients that match the inclusion criteria of the registrational study. So to the extent we are getting to the place where we have smaller, shorter study, I think this just helps us to derisk the enrollment even further from where we are today with respect to the enrollment of that natural history study.

And the next question will come from Tessa Romero with JPMorgan.

So what are the bookends for when you think you will be able to submit the BLA to the FDA and what is the additional nonclinical requirement exactly? And how long roughly will it take for you to complete? And final question is what is the nature of the dialogue that you have had specifically around comparability?

Okay. A few here, which we'll take. So the first on BLA timing, we won't be able to guide today to updated BLA timing. I think we'll be able to provide clarity in this guidance once we have finalized the protocol and the SAP with the FDA. So I would say that's early 2026 update for BLA timing. But I would just note that given some of the parameters we're working with here in terms of study size and length, it's likely to be timing that's pulled in from our prior guidance.

Your next question was about the nonclinical requirements. So we need to complete a murine study with head-to-head of the pre-change product and adherent HEK293 relative to the post-change Sf9 suspension baculovirus material. We have a lot of experience with this Sf9 suspension process. It's the same process we're using for our PKP2 program. So we have multiple GMP batches we produced for that program. As well here, we've done quite a bit of comparability work. So we're confident in our ability to achieve the comparability requirements that the FDA has outlined. I'd say if we weren't confident in it, we would not be pursuing the strategy that we've outlined today. So I think we have a lot of familiarity, both with the process and also with the murine model for which we'll be introducing this comparability. So we have confidence in our ability to get there.

Lastly, on comparability, the detail we described around the FDA interactions came from a meeting with the FDA. This included both CMC and clinical discussion as part of it. The comparability discussion came up in the context of that meeting, and there's minutes that have come out of it. So that's the structure and scope of the discussion that's occurred around the clinical path and the CMC requirements.

And our next question will come from Brian Skorney with Baird.

Congrats on the regulatory update and the continued good clinical data. I guess my question is for the pivotal design, are you planning on using the Kawel-Boehm criteria for enrollment criteria as what the threshold for normal is on LVMI. I ask because it does seem like there's a pretty consistent effect of higher baseline LVMI resulting in a larger numerical 1% improvement. And I'm just wondering if you would consider an easier target to enroll a patient with like 100 or 110 grams per meter squared versus an 86 because I think the 10% improvement may be easier to achieve in the clinical relevance of getting like 110 to an 84 when you consider that more obvious than getting an 86 to a 74 -- just would love to hear your thoughts on maybe raising the criteria threshold for baseline LVMI.

Yes. Thanks, Brian, for the question. So just if I can read it back, you're asking if we would further enrich for elevated LVMI even beyond the 2 standard deviations that we have assumed in the inclusion criteria.

Exactly, right? Like I'm questioning like is an 86 to an 84 like participant 6, were there -- if you got all patients like that, would that have less meaning than like patient 13, where you're taking 110 to a 54 and therefore, like you'll be raising that criteria would benefit the study. That's all.

Yes, I'm following. So I think, one, this abnormal LVMI to the patients with 2 standard deviations above normal represents 40% of the FA population as per our adult population as per the natural history data that we have access to and actually represents roughly the same percentage in our Phase I/II studies. So I think that, that's a very appropriate pool from which to draw patients for enrollment. So I think we'll continue to focus there and keep the inclusion criteria identical to what we described. I mean, even with the 2 standard deviations cutoff, we're achieving an over 20% improvement in LVMI at 12 months. We're achieving an 18% improvement at 6 months. If you look only at the higher doses, we're achieving even greater improvement.

So I think with the inclusion criteria matching that of the elevated LVMI that we have in the Phase I, we should be pretty easily clearing the threshold that the FDA has set for us. And I'd note even for the patient to start at lower baselines and look at the high-dose patient that starts at a lower baseline amount. We're still getting to, I believe, about 12% improvement. So we're clearing the bar even for patients that are just above that 2 standard deviations change of -- in respect to hypertrophy. So I think we're pretty comfortable with the inclusion criteria because it's supported this result we're seeing in the Phase I, and we think it should support a similar result in the registrational study.

And the next question will come from Mani Foroohar with Leerink.

This is Lili Nsongo on for Mani. Just a quick question regarding the mFARS data acknowledging that this is relatively exploratory at this point. So it appears that most of the benefit is seen as the earlier time point with some potential challenges at 18 to 24 months. Based on your understanding of the underlying mechanism of action for this result do you have any incentive as to whether this should be expected to be a transient benefit? Or is this just something that will have to weigh against natural progression?

Good question. Maybe I'll ask our Chief Development Officer, Sandi to say a few words and maybe also, Eric, after this to also comment as well.

Yes. The changes that we see early on, it may be impacted by the fact that patients are aware they have received treatment. But once you move beyond that early 10 point, we are seeing that sustained reduction in terms of the score on mFARS. So there seems to be an improvement even relative to baseline that is sustained well beyond the period where you might expect to see sort of a placebo effect for these patients. We are seeing it as a durable improvement relative to baseline and even more so relative to natural history data, and we're seeing that at the 12- and 18-month time points. So there's definitely persistence that we're seeing in the scores so that it's very pronounced in terms of looking at these changes, in terms of what it means for functional benefit for these patients, whether it is improving activities such as brushing their teeth, being able to get dressed that it really may be meaningful from the standpoint of -- from the patient perspective.

Eric, is there anything you'd like to add to that?

Just that I agree that you would expect the placebo effect to be strongest in the beginning and decline over time. And here, you see the sustained and deepening effect. So I think that's very suggestive of an impact.

And I'd also note, just if you were to take a look at other studies that have looked at the similar endpoint, you would see a similar trend of some deepening effect at 6 months that could be placebo. But then once you look at the longer time points, I think you see the true treatment effect. And I think that's likely what we're observing here. So I would think the time point at 12 months and beyond are very relevant of the -- for the treatment effect of this particular therapy.

And our next question comes from Leland Gershell with Oppenheimer.

Just 2 from us. First, I just wanted to ask with the FDA indicating a shorter time frame for the LVMI than 12 months. Just wondering if you have any thoughts in mind in terms of what you may propose 6 months, 9 months if you could share thoughts there? And then I also wanted to ask if you continue to look forward to the update from the PKP2 ACM study later this year.

Okay. So on proposal of time points, I think it's early for us to comment on that. But I think we've shown data here that is showing a meaningful treatment effect as early as 6 months. But I think it's early for us to guide to what time point we may land at. But you can see that the treatment effect is meaningful and relatively rapid in particular, at the higher doses. So more to come on that as we get through this conversation to finalize the protocol with the FDA. We, today, are not focused on PKP2-ACM. That's a discussion to come a bit later in the year. So I would defer questions to that later time point for -- in respect to PKP2 ACM.

And our next question will come from Luca Issi with RBC Capital Markets.

This is [ Cathy ] on for Luca Issi, and congrats on getting potentially closer to our product here for FA. This question is a follow-up on your comparability study/cell line. How should we think about the full to empty capsid ratio here between the HEK cells and Sf9. Assuming here that Sf9 has actually a higher ratio, does that mean that you could potentially use an incrementally lower dose for the pivotal versus your Phase I/II? Any color there much appreciated and congrats again team.

Thank you for the question. I'll pass it to our CTO, Manny, to say a few words about this.

Yes. Thank you for that question. So as we noted in the presentation, the Sf9 material to date has been showing a lower empty capsid ratio. I'll point to you that -- and it's included in the press release, we presented manufacturing CMC data at ASGCT this year. There's 2 posters on that. And those posters also described in detail our quality attributes around the product, including the empty low capsid ratio. I'll also highlight that we have been manufacturing using Sf9 as a platform across our clinical stage programs. and we've been manufacturing at a relevant commercial scale that includes for FA. So we believe that we've got data that's highly representative of our go-to commercial process moving forward.

And the next question will come from Mitchell Kapoor with H.C. Wainright.

I wanted to ask if the FDA mentioned anything about post-approval commitments. For example, are they looking for some type of mFARS follow-up or could you just comment on what they might expect if you do receive some type of accelerated approval? And then separately, on the comparability package, is this something the FDA requested? Or was it a proactive step by Lexeo to derisk the manufacturing? And does the FDA need to sign off on that comparability package before pivotal dosing?

So I'll take the first question on post-approval commitments. We've not reached any final agreement on post-approval commitments, obviously, as with any accelerated approval. We need to reach alignment on that post-approval confirmatory study before we file the BLA. So I think we still have some time for that one. But our assumption -- working assumption from the data that we've observed to date is that mFARS would likely be the confirmatory endpoint, the size, structure of that mFARS study to confirm -- and length to confirm that as a confirmatory endpoint, as I mentioned yet to be discussed.

In terms of the comparability, I think this was, let's say, back and forth dialogue with the FDA. We asked the question of finding ways to accelerate or expedite the pathway to a BLA from our base case plans. This resulted in a conversation where they showed an openness to that expedited pathway in respect to the clinical benefit we're observing and the use of the Phase I/II data, but they needed to -- they wanted to ensure that, that product was as close to identical as they deemed for the purposes of pooling. So that was our focus in that conversation. And we've already filed some analytical comparability data with the FDA. So they have a sense of the comparability profile here. So it's a matter of checking a few boxes on these requirements in order to reach the point of pooling, which we believe will ultimately result in this expedited pathway that we've been discussing with the FDA.

So I think in general, this was certainly a positive step, the openness to this type of approach. I think the requirements we've been asked for here are relatively modest in exchange for the acceleration that this could likely produce. So we're happy with the outcome here and it matched what we were looking for.

Is comparability a gating factor to starting the pivotal dosing?

It's not in particular. We have certain requirements that are certain, that are not. I think we will have to work through that, but I think we're in a place where we've begun to submit this data already. So we can guide to the start of the study in the first half of 2026, and we think we can confidently get there with the data we've already begun to submit to the FDA to support that.

I am showing no further questions in the queue at this time. I would now like to turn the call back over to Nolan Townsend for closing remarks.

So thank you for joining today. We appreciate the interest in the program. I think we're excited about this update. I think in one sense, it shows a continued interest and engagement with the FDA in getting rare disease gene therapy treatments to patients faster in particular with diseases that have high unmet need and no existing therapies out there. At the same time, I think we're showing increasingly promising clinical data. I think the improvements in left ventricular mass are sustained and they're significant, and we're seeing these improvements as early as 6 months. All that meet the prealigned thresholds with the FDA. And then the mFARS benefit is something that we think is very important both for patients but also ultimately for the confirmatory path for this therapy and ultimately, being able to show benefit for all FA patients, those that are earlier in the disease, that are struggling with the neurologic disease, but also patients that are later in the disease that have both cardiac and neurologic manifestations of FA.

So we think this update and the product profile that's developing here has the potential to be a step change in the standard of care for FA treatment. We're excited to see this continued progress, both on the regulatory and clinical front. And thank you for taking the time to speak today.

This does conclude today's conference call. Thank you for participating. You may now disconnect.