Good morning, and welcome to Lexeo Therapeutics webcast presentation. At this time, all participants are in listen only mode. A brief question- and- answer session will follow the formal presentation. As a reminder, this call is being recorded. I would 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 three 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, Narinder 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 a leading cause of mortality in FA.
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 multi-system 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 three 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 Narinder 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 seven, the Mantle portfolio includes four programs, which I will highlight in more detail on the next two 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 four 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 three 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 eight weeks later. Despite pre-existing 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.
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, Narinder. 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 to 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 standalone, 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.
Thank you. If you'd like to ask a question, please press star one one. If your question has been answered and you'd like to remove yourself from the queue, please press star one one again. Our first question comes from Roanna Ruiz with Leerink Partners. Your line is open.
Hi, everyone. Morning. 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 c?
Sure. Thank you for the question. I think we intend to and have been prioritizing the programs against predefined patient impact, regulatory probability of success, and overall return profile characteristics. 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.
I think what's interesting here is this portfolio allows us to evaluate multiple biologic theses 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. 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.
Yeah, that makes sense. 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 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. We're achieving a 2- 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, the 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.
Sounds good. Thanks.
Thank you. Our next question comes from Kristen Kluska with Cantor Fitzgerald. Your line is open.
Hi. Good morning. This is Ayan on the line for Kristen. Congratulations on the announcement here, and thank you for taking our questions. First, what are some of the best ways to truly understand the potential of the neurological benefit from these CNS-directed programs? Is anything beyond mFARS, given that you've already seen some benefit here from LX2006?
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. There's a certainly commercial market opportunity associated with that.
But I think what LX2006 is probably not addressing as well is patients that do not yet have cardiovascular involvement in the disease. 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. 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. Thank you for that. Makes a lot of sense. I guess you 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. From the answer, it sounds like there's some rationale here for sequencing these treatments.
Yeah, absolutely. If you're talking about gene therapy for the brain, we had a poster at ASGCT demonstrating the potential of sequential dosing. Non-human 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.
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. Whether you look at non-gene therapy approaches that come through the Mantle portfolio or 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.
Great. Thank you so much, and come back again.
Thanks.
Thank you. Our next question comes from Tessa Romero with JPMorgan. Your line is open.
Good morning, team. This is Caroline Pocher on for Tessa Romero with JPMorgan. Thanks for taking our questions. Just a few from us. 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? Which asset do you think has the largest potential reward?
Well, it's 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 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. We'll communicate in early 2027 which one we've prioritized and sort of the rationale behind that prioritization.
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. That's something we will be able to guide to early next year.
Okay, great. If I could just squeeze one last one in here. Of the 22 participants that you noted are enrolled or imminently enrolling 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 in that many are undergoing neutralizing antibody screens. I think we'll give an enrollment update at a major milestone when it comes to SUNRISE-FA. 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.
Okay, great. Thank you so much.
Thank you. Our next question comes from Leland Gershell with Oppenheimer. Your line is open.
Hey, good morning. Thanks. It looks like some interesting opportunities for Lexeo here. Nolan, just wondering, with two of the more advanced Mantle programs focused on HDAC, just wondering if you could share with us what we know about HDAC inhibition and its potential in FA and what the consistency and breadth of maybe HDAC inhibition across various patients with FA might be? Thank you.
I would ask Narinder, our Chief Medical Officer, to say a few words just about the broader strategy.
Yes. So certainly, there is data on HDAC inhibition looking at frataxin and looking at the mechanisms of action that we described. 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 is where the fusion and the binding with the Fab and everything becomes really important as we think through the approaches that we have. I think from a HDAC inhibition perspective, from a mechanism perspective, there is clinical data on the HDAC component of the combo that we talked about, the LX3010 in the clinic, and we are leveraging that.
There is earlier data from other companies on HDAC as well in addition. When we look at all those data sets, we are encouraged by what we see. This is also a third-generation, the one that is in clinical development right now, a third-generation benzamide HDAC inhibitor. That is designed to be a little bit more potent, have more preferential blood-brain barrier crossing. Those are all the things that we feel are complementary to the backbone of LX2006 for the cardiomyopathy side of things.
You will 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 clinically safer treatment than what you may see out there. 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. Obviously the increase in frataxin and muscle is something that is notable.
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? These are a lot of the decisions we will 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 are 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. Thanks.
Thank you. Our next question comes from Brian Skorney with Baird. Your line is open.
Hey, good morning, guys. Congrats on the deal. Really nice to see the company really leveraging into FA, a really horrible disease without a lot out there to meaningfully move the needle. I am kind of curious, in broad strokes about the sequential dosing strategy and 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 intracerebral administration, at least in terms of some specific timeline 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 crack the immunological egg that limits dosing or redosing, and in particular, Sarepta, who I believe still has an ownership stake in Lexeo. I would be interested to know how much dialogue there is there because they, I believe, also had a license for a different imlifidase through Hansa that they terminated.
I do not know how much insight you have into what happened there. Just sort of how do you think about a target for antibody titers for systemic administration versus intracerebral and sort of the stepwise process of increasing the ability to target higher and higher titers and eventually redosing in a sequential basis in patients or even redosing systemically in patients? Thanks.
Yeah. Thanks, Brian. Thanks for the question. I think the first thing I would say is I think we are really charting new ground here. I think when most companies talk about, quote, "redosing," they are 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 us say, compartment, let us call 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. I think that that is what we understood, and that is the conclusion we reached from the non-human primate studies that were part of our ASGCT presentation where we demonstrated that despite a primate being treated systemically, they were sequentially dosed with intracerebrally administered vector, and that vector reached its target in the cerebellum. So we know therapeutically that sequential dosing is very much feasible.
The question as you are raising is then the subsequent antibody response from the systemic leak of the vector, and I think that is where the IgG approaches would really come in to manage that safety risk. So that is 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 do not think we have a cutoff predefined.
In looking at the capsid from Apertura, we are also evaluating even the cross-reactivity between AAVrh10 and that capsid, and it may be that they are sufficiently different from one another that there is not even a systemic immunity question that emerges there. I think that is 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 intracerebral approach has already demonstrated in primates that it can reach its target at a reasonable dose. We will 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 we've 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.
Great. Thanks, Nolan.
Thank you. Our next question comes from Chris Raymond with Raymond James. Your line is open.
Hey, thanks. Yeah, this is Sam Lee 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 have 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 combining the mechanisms. Maybe I will ask our Chief Medical Officer to speak to this.
Yeah. There is obviously preclinical data in the combination from what Mantle used. Previous to that, the data is mostly on the isolated components. It is on the HDAC component of this combo and on the, as you said, the NRf2 to the Keap1 pathway. Those data exist. I think it is hard to know whether we would expect a synergistic or additional type of interaction.
That is why as we look at this early data and what we have seen in it, as I said, as Nolan said, it is encouraging, but we want to make sure that there is durability to this data and long-term efficiency to this data. We will continue to follow that and see where that leads. Most of the data that exists is actually on the individual components on the clinic side of things.
Great. Thanks and congrats.
Thank you. Our next question comes from Paul Matteis with Stifel. Your line is open.
Hey, thanks a lot for taking my questions. I appreciate it. I have two questions on the HDAC program and then just one on the FA pivotal for LX2006. On the HDAC program, can you talk a little bit more about safety? HDAC inhibitors, I know not all are the same, but there's been some historical safety tolerability issues with this class in oncology and just how comfortable are you with the therapeutic index?
On the frataxin biopsy data, what did you find in these patients for baseline frataxin levels? With a ninefold increase, how high are you getting them? Lastly, on SUNRISE-FA, maybe just talk about the 22 patients that are in this natural history study and could be enrolled soon. What are you seeing in terms of LVMI and maybe the proportion of patients that are greater than three standard deviations? Thanks a lot.
Okay. Maybe we'll take those in reverse order in respect to the last question on the pivotal study. As we mentioned, there's 22 patients in CLARITY-FA. I won't go into specifics on the baselines, 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, and that's probably all I can say about the patients' baselines 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 with respect to the muscle biopsies. 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 about that.
Yeah, sure. Your point's well taken. Certainly there's been a lot of data on the HDAC side, which has talked about some of the safety stuff. 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. That's part of the work that we will be doing as we go forward on the early development side. Yes, we're very cognizant of that. 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.
Thank you. Our next question comes from Luca Issi with RBC Capital Markets. Your line is open.
Okay, thanks so much. It's Cassie for Luca. Good morning, team, and congratulations on the announcement. We would like to ask a question about the landscape of the neurological aspect of FA. We already have an LRRK2 activator, may have a frataxin protein replacement therapy as soon as next year. Then there's also mitochondrial antioxidants behind. How do you think about the neurological space becoming increasingly competitive here? Does LX2006 cardiac differentiation remain sufficient to anchor the platform's commercial thesis, even if the CNS programs for Mantle will take several years to reach proof of concept? Any comment very much appreciated. Thank you.
The second question we couldn't hear. It 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 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.
This is obviously highly complementary with LX2006, which is transducing the heart, transducing dorsal root ganglia, transducing skeletal muscle, transducing the peripheral nervous system. It's unlikely that we're seeing substantial uptake of LX2006 into the brain. This is where I think the potential of adding a therapy onto 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 could be fast follower programs behind those that could represent a best-in-class profile. I think that actually the landscape evolving in the way that you described could be, in a way, advantageous to de-risk 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 you mind repeating it?
Yeah. Thank you so much, Nolan, and I appreciate the comment 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 two still go hand in hand in terms of a commercial thesis of treating this disease?
Yeah, 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. Not only did we see that, but we also saw patients that were abnormal via LVMI return to the normal range. We saw these meaningful reductions in troponin. 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 timelines that we've communicated. 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 category leadership in this area.
Super clear. Helpful. Thank you, Nolan.
Thank you. This concludes the question- and- answer session. Thank you for your participation. You may now disconnect. Good day.