Thank you, and good morning, everyone. Welcome to our next session here at Oppenheimer's 36th Annual Healthcare Life Sciences Conference. I'm Leland Gershell, one of the biotech analysts with the firm. We're delighted to have with us as our next company, Lexeo Therapeutics. Lexeo is a public company, ticker LXIO. We've been covering Lexeo for a little while now and really like the story as it prosecutes in Friedreich's ataxia cardiomyopathy and some other indications in rare disease. On behalf of the company, we have Nolan Townsend, Chief Executive Officer, as well as several members of his leadership team. We'll be having a chat. Please feel free to post any questions you'd like us to weave in through the portal. Welcome, everyone. Thanks for joining us.
It's great to be here. Thanks for having us.
Terrific. Nolan, I think, you know, I think it would be great, you know, for maybe those who are less familiar is, you know, the company has positioned itself as a leader in cardiac gene therapy. You have a candidate for Friedreich's ataxia cardiomyopathy, as I've mentioned. You're also looking at a different candidate for a rare arrhythmic disorder called PKP2-associated arrhythmogenic cardiomyopathy. Those are kind of your key value drivers. You know, sort of if you could just sort of set the stage. You know, how do you describe the overarching thesis that connects those programs to your platform and maybe differentiates Lexeo's approach in inherited cardiac disease?
Yeah. There are, if you look at the cardiovascular disease landscape, there are very few, fewer than 10, you know, precision medicines approved, and several of these are focused on the same disease. Our thesis is that precision medicine will play an increasingly important role in the cardiovascular treatment landscape. We think the AAV vector will be at the tip of the spear of this effort, because for the moment, lipid nanoparticles, GalNAc, other delivery systems cannot access the cardiomyocytes. The most efficient way to deliver a genetic payload to the heart is with the AAV vector. In that context, we're using a highly cardiotropic vector, AAVrh.10. We've seen one and a half to two times greater biodistribution in the heart when using 10 relative to other, you know, commonly used vectors.
We saw that preclinically across two different large animal models. We saw this in small animals as well, but we've also now validated this cardiotropism profile clinically across a range of doses in our Friedreich's ataxia and PKP2 program. I think the basis of our strategy, in utilizing AAV to correct genetic cardiac diseases is the utilization of AAVrh.10, you know, in order to do that. You've highlighted the two programs. We've been able to show significant clinical benefit in our Friedreich's ataxia program. We have some early, you know, clinical data in our PKP2 program that is showing an improvement in an important endpoint in that disease.
I think we're seeing both trends in biodistribution and also trends on clinical benefit that we think are validating the thesis of AAV gene therapy in cardiac disease. We're doing so with a very favorable, you know, safety profile associated with, you know, with both programs. We're excited to see the field evolve in this direction. I actually think the heart is an ideal organ to study for gene therapy. I mean, you can take tissue samples to look at biodistribution. You have non-invasive biomarkers like cardiac MRI, you know, Holter, and so on, to, you know, look at hypertrophy and arrhythmias. Then you obviously have hard endpoints like mortality, hospitalization, and other symptom-based endpoints.
We have a full suite of tools available to us to design trials around, in addition to just the kind of typical ways you would evaluate a rare disease treatment benefit.
Great. Before we get into, you know, sort of more detail on these development programs, would love to hear, you know, just sort of the framing kind of the market opportunities here, in both, FA cardio and, maybe FA in general, and also PKP2-ACM.
Yeah. So Friedreich's ataxia is globally about a 15,000 patient rare disease. The concentration of patients is in the US, Europe, and some countries in Latin America, primarily. About, you know, 70% of these patients, the cause of death is a cardiac disease. Many would know this as a neurologic disease. However, you know, you can really only address mortality in Friedreich's ataxia by addressing the cardiac component of the disease. Our therapy primarily is focused on the cardiac disease. However, you know, we're seeing benefit across other endpoints, such as the mFARS scale, which is the scale that evaluates the neurologic progression, you know, in the disease.
Taking the two together, the benefit we're seeing in the cardiac disease, combined with the benefit that we're beginning to observe in the neurologic disease, we think this therapy could represent a step change in the standard of care in this disease. While the early adopters are likely to be the more advanced heart disease population, we think there's a case for patients that are, you know, earlier in the cardiac disease course, and potentially those that do not yet have cardiac disease that would like to prevent the progression of those symptoms of hypertrophy, but also benefit from the neurologic component. You know, what I'm describing is a therapy that could theoretically be appropriate for the entire FA population.
We also have adolescent and pediatric cohorts we're intending to include into the pivotal study. By age, we could theoretically treat the entire population. You know, we're looking at a therapy that could be a very compelling treatment option for, you know, for that group of patients.
Excellent. LX2006, this is your IV gene therapy that's designed to give a functional frataxin gene or FXN gene to the heart and restore levels of the protein in these patients. You've shared with us some interim clinical data with clinically meaningful improvements in left ventricular mass index, cardiac biomarkers, functional measures like the mFARS and KCCQ. Also just been increases in cardiac frataxin expression in biopsy patients. Could you maybe review some more details of that data and kind of which of those data points are most striking to you as you continue developing 2006?
Eric, if you want to say a few words about the data and maybe I would invite Nani to comment after. You're on mute or something.
Sorry about that. If we think about the data, I think we know that the leading cause of death in FA is cardiomyopathy. 70% of these patients will die. The best biomarker for death in these patients is LV mass. In fact, across cardiomyopathies, LV mass is consistently seen as a biomarker associated with mortality. I think what you're seeing in our program is a consistent and large reduction in LV mass across our doses in a dose-responsive way. That becomes a primary marker for us. It's been used in other cardiac gene therapy trials as LV mass is being used as well as the primary endpoint. The other endpoint, I think that's particularly meaningful for us is troponin. Troponin is a biomarker that's familiar to all cardiologists.
It's associated with myocyte death, and dysfunction and stress, and it's associated with, you know, heart attack. It's primarily used to diagnose patients with heart attack. Again, we know in cardiomyopathies that troponin is associated with worse outcomes. We see these striking reductions in troponin across, and again, in a, you know, generally a dose-responsive way in our cohorts.
Yeah. Go ahead.
I would just add, you know, the patients that presented with abnormal LVMI at baseline, they all returned into the normal range. We have reversed the hallmark of the disease. As Eric described, this hypertrophy leads to mortality. it's been reversed in these patients, and their hearts, from at least from a perspective of hypertrophy, as measured by LVMI, have become normal. That's a, you know, very significant finding in respect to the treatment benefit that these patients are receiving today and obviously can benefit from as we treat more patients in the next study and as we move towards commercial.
I mean, you know, from a biologic perspective, we've seen meaningful increases in frataxin expression. From the regulatory point of view, you're pretty much at the point of nailing down the requirements for your pivotal, which, if I recall correctly, you have a kind of a dual primary endpoint where you need to show sort of any increase in frataxin together with at least a 10% improvement in LVMI. Could you maybe just frame for us, maybe back to Eric, like kind of how much frataxin increase is needed in these patients? How much do they have relative to the normal population, and how much do they need to go up by for that to make a difference to them?
Sure. One of the things that we found, which was really never described before, because If you think about the largest collection of biopsies in Friedreich's ataxia patients in cardiac biopsies, is that these patients in general with cardiomyopathy have extremely low amounts of frataxin, either, you know, around 2% or less of normal, which was lower than, you know, frankly, people hypothesized. What we know from the animal models is that even 5% of normal frataxin associated with a normal cardiac output, I should say normal cardiac output, normal cardiac function generally. We think very small amounts of improvement can have meaningful impacts.
That makes sense biologically, because frataxin's acting as essentially a catalyst between the, to allow for the binding of iron to sulfur. You don't need a lot for this reaction to occur. Similar to kind of hemophilia, where very small improvements in an enzyme in patients that are essentially devoid of it can make meaningful impacts in physiology. We think greater than, you know, even as greater than 5% is something meaningful, and frankly, any more increases is probably meaningful on a per patient basis. As we see these increases in our patient, we think that's all meaningful and to the patients.
Frankly, the FDA, you know, agreed with us, and that's why the thresholds that they were using for biopsy were any increases in frataxin was sufficient as an endpoint in our discussions, which we've disclosed in previously.
Great. I believe you have your next... I'm sorry, Nolan, you were going to say something.
Yeah, I mean, you know, the frataxin end point is sort of validates , you know, plausible biologic mechanism. The registrational study will be powered on the left ventricular mass endpoint. I'd say between the two, the LVMI endpoint is the important one because it's, you know, it's the hallmark of the disease. You know, while both are in the picture, you know, LVMI is certainly the key endpoint that powers the study, and that will be the treatment benefit that cardiologists will be, you know, looking towards in order to decide whether to kind of underwrite a treatment, you know, in this disease.
Yeah, and, yeah, so you have your next trial, you know, essentially planned at this point. I think you're waiting for one last, kind of a, you know, confirm or interaction with FDA. Can you share with us kind of what you're looking to get comfort on? Maybe just talk a little bit about the overall design of the next trial?
Yeah. You know, we know the endpoints that are relevant for accelerated approval. We talked about two of them now, with left ventricular mass being the most important. We know that the FDA is open to a time point earlier than 12 months from a follow-up perspective with for that LVMI endpoint. You know, we know the effect size that's relevant for LVMI and a greater than 10% improvement. Though there's a lot of principles that, you know, we have around the study that we're, you know, taking forward into this final, you know, alignment process.
As we work currently with the FDA, the work we're doing now is to, you know, better identify the link between the surrogate endpoint that we're utilizing here, which is a cardiovascular surrogate of left ventricular mass, and then how that links to future confirmatory endpoints. We're also working with CBER to think about how to eliminate, you know, sources of bias in that future pivotal study. You know, we're not working on this with blinders on. We see what's happening around us to other, you know, companies that are in, you know, rare disease, with accelerated approval studies and how CBER is thinking about sources of bias in those studies.
We're working to embed a lot of that thinking into the final design and statistical plan that we're working towards to... You know, they're working towards finalizing. From a guidance perspective, we're on track to be able to report those results in early 2026. I think the principles that I described, you know, endpoints, effect size, duration of treatment, and so on, remain, you know, remain the guidance with respect to where we're headed.
You have a natural history study on that's, you know, also running in parallel. That should provide additional color here on how these patients do over time. Are we going to see data from that, kind of, as you get through the next study? How important is that to the FDA?
Yeah. You know, the natural history study has a few purposes. One, you outlined. It has identical inclusion criteria to the treatment study, so it's allowing us to find patients that fit the inclusion criteria of the future treatment study. Those patients will be able to, many of them will be able to cross over into the treatment study. While we work to finalize this alignment with the FDA, we're currently finding patients that will ultimately land in the treatment study. The point I'm making is we're not losing any time as we work to finalize the details of the, you know, of the treatment study.
That's a, that's a major benefit in that it helps us to accelerate enrollment, it helps us to get the sites up and running. That will ultimately be the treatment sites in the future, registrational study as well. Then the benefit that you describe is we get to better understand the untreated disease course. Typically, we would expect to see left ventricular mass increase slightly over time. Obviously, this is something that the work in the natural history study will allow us to observe. Also, it will allow to demonstrate that there is no spontaneous, you know, improvement in left ventricular mass outside of the context of a medical therapy.
That's another, you know, aspect of what we can observe out of the, out of the natural history data.
When you guys got breakthrough designation for 2006, you know, we all saw that that was actually kind of just for FA without any specific cardiomyopathy, subset of FA. We talked a little bit about mFARS, as you've shown some promising mFARS data so far. Any thoughts in terms of, you know, ultimate label and the ability of the next study to allow a label that could, you know, sort of support use apart...
Yeah
from just the cardiomyopathy benefits? Yeah.
The primary endpoints, you know, left ventricular mass, and we, you know, we talked about the secondaries, troponin, mFARS, lateral wall thickness. I mean, all of these endpoints present themselves at different stages of this disease. Not only in the advanced heart disease population, patients earlier in the disease course have elevations in troponin. Patients earlier in the disease course have, you know, abnormal wall thickness. Patients, obviously, throughout the disease course, have a progressive neurologic disease as measured by mFARS. All of that data will support a discussion around the label. You know, it's typical in rare diseases that the inclusion criteria in the pivotal study does not precisely match the, you know, the label of the therapy.
You know, you can look as an example in Friedreich's ataxia itself, the SKYCLARYS label does not match the inclusion criteria of the, of the registrational study. It's our perspective that our label would not be restricted to only the abnormal LVMI population, based on some of the other supportive data that we'll have, you know, in the, in the, in this trial. Then we're, you know, obviously thinking about other ways to help fully, you know, fully demonstrate the impact of the therapy and the neurologic side of the disease, both in this, you know, study, this study and potentially others, you know, others in the future.
Just, you know, lastly on FA. There is an approved product, SKYCLARYS, which is now, you know, being sold by Biogen, and that's, you know, had a successful launch for the neurological manifestations of FA that doesn't target the cardiomyopathy. As you think about kind of a market in which you've got LX2006 coming up to the market with SKYCLARYS, you know, any perspective there on, you know, how those therapies may sort of exist in the marketplace for FA?
You know, first, we have patients in our trial which have been simultaneously treated with SKYCLARYS. There will be data on patients that are SKYCLARYS naive, those have been, you know, treated with SKYCLARYS through the duration of our study. The mFARS benefit we've seen, we've observed across patients that have not been treated with SKYCLARYS and patients that have been treated with SKYCLARYS. We, we think there is a true benefit on the mFARS scale in the, you know, in the absence of SKYCLARYS. And that benefit is in, you know, one to two point improvement on the mFARS scale, which is roughly similar to the benefit that SKYCLARYS showed in their registrational study. What we're also achieving is this regression of the cardiac disease.
You know, I mentioned these patients have presented with abnormal LVMI. They were turned into the normal range. You have a therapeutic option here that both is slowing the rate of decline of the neurologic disease, but also simultaneously improving the cardiovascular disease. To put both together, this could represent a step change in the standard of care in this disease. I think, you know, what this therapy offers is, one, it looks like durable improvement in the mFARS scale, and also improvement in the cardiac disease as measured by several endpoints. LVMI is one, wall thickness is another, troponin is a third. I think we're, you know, potentially credibly treating the range of the entirety of this both cardiovascular and neurologic disease.
This, you know, could be the only therapy that could achieve that result.
Great. Now, let's spend a little bit of time on PKP2-ACM. This is a certain type of, again, arrhythmia, and I guess we'll go back to Eric maybe for this. I think, you know, many of us are familiar with, you know, arrhythmic management, using a variety of drugs as well as, you know, devices. If you could, you know, share with us, you know, what this disorder looks like and why maybe it's not so well addressed by those various drugs and devices.
Sure. There's a little noise on the line from the operator. Okay.
Yeah.
So-
Sure. This is one of the most common inherited cardiomyopathies that we see in practice. It's a disease, as you stated, that causes arrhythmias, often fatal arrhythmias. It's the one that, you know, we should probably associate when we see sudden death that's unexplained, along with hypertrophic cardiomyopathy, so very morbid disease. Recently, I would say in the last 1 or 2 decades, more and more recognized by cardiologists for this reason, for causing such, you know, for being so prevalent as a cause of sudden death. It's also for patients, it is associated with a high level of anxiety because they're constantly worried they're gonna have these arrhythmic events and ultimately with the development of heart failure. These patients, over a decade or so, often progress to requiring heart transplantation.
In terms of the management, we're stuck as practicing cardiologists with essentially, you know, antiarrhythmics, which are, you know, we joke around, we call them poisons with good side effects. They almost all have pretty severe adverse events, including causing arrhythmia, which we're trying to prevent. All kinds, you know, amiodarone, for example, associated with all kinds of toxicities of the liver, eyes, lungs, pretty much every organ. Your skin turns purple. We call it Smurf syndrome. Defibrillators, which are, you know, effective at preventing death from arrhythmia, but not to prevent progression of disease. You know, a shock from a defibrillator is exquisitely painful. Patients describe it as being kicked in the chest.
You know, it's kind of torture for these patients, hence the high degree of anxiety that they have.
You guys, so your gene therapy here, which is LX2020, that's delivering effectively a functional PKP2 gene into cardiac muscle, again, to restore what are the underlying deficits and abnormalities that lead to this arrhythmic risk. I think we've seen some very encouraging preclinical data, and you showed us an initial clinical look earlier this year. If you could maybe just, you know, give us a summary of what you saw, and it was, you know, early, maybe what we might see maturing from that trial as the data, you know, continue to collect down the road.
Sure. I don't know-
Do you want to say a few words, and maybe I'll ask Nani to comment as well after?
Sure. You know, this is, you know, first and foremost, we look, can we reexpress this protein plakophilin-2? That's important because the thesis is based around restoration of plakophilin-2, because we know in this disease, essentially, plakophilin-2 helps to kind of glue cardiomyocytes together, and it's the loss of this glue that allows cells to drift apart and is the genesis for arrhythmia. In this case, we saw a dose-dependent increase in plakophilin-2 across our cohorts. Importantly, so as a first-order therapy, we can restore the, you know, the first-order problem, which is the loss of plakophilin-2. In terms of endpoints, I think the most meaningful endpoint is a reduction in nonsustained VT or ventricular tachycardia. That's these heartbeats that lead to, you know, sudden death. We saw this again across cohorts.
We saw this be meaningful over time, so a time-dependent improvement, so a 22% improvement in 22% reduction in nonsustained VT at our earliest time point. Albeit with a smaller number of patients, we see closer to 60% improvement. The 22% improvement is probably the same, if not better, than the antiarrhythmics that I mentioned. The 60% improvement would be far superior to any of the therapies we have. Keep in mind, in our natural history study, if anything, we saw an increase in the risk of VT. I don't know, Nani, if you have other things to add.
No, that was, I think. Yeah, I think your last point was important as well, that, you know, when you look at just what the natural history of these patients is, it's progressive dysfunction in the heart, progressive fibrosis, and then leading to this increase in arrhythmic burden. The reduction in arrhythmic burden, you know, when you kind of correct for that natural trajectory, is even more remarkable from what we're seeing currently.
Great. Have you indicated what we might see further clinical updates there? Could it be later this year, or?
We've guided to two things this year. One is the regulatory update, where we intend to align with the FDA on the relevant endpoints for the next study, and some of the details around that. We intend to have a clinical update in Q4 of this year. We'll have most, if not all, of the patients at 12 months of treatment follow-up, so we'll begin to understand the durability of the treatment effect. We're seeing a trend towards deepening over time. The two patients at the high dose are at 9 months, are at an average improvement of 65%. We'll see if that deepening trend is consistent across, you know, all of the patients, are we seeing any, you know, benefit across other endpoints.
We have the patient who presented with the lowest, right ventricular ejection fraction at baseline, saw a 30% increase at 9 months. We're also going to be looking at the structural endpoints to see if those are improving as well, and those are likely to improve at slightly later time points in some of the arrhythmia endpoints. That's the picture I think we're gonna be looking forward to, as we present data around this program later in the year.
Great. It's become a little bit of a competitive space. Some other companies are developing therapeutics here. Just wondering if that presents any enrollment challenges, you know, looking into the future for you or-
None. You know, this is a 60,000 patient rare disease. It's more than twice the size of something like Duchenne muscular dystrophy. We have seen the patients to be highly motivated to seek treatment. I mean, even our phase 1, for every dosing slot, we had several different, you know, we had multiple patients interested in being, you know, in being treated. We are, you know, definitely, you know, definitely able to enroll a future study, highly motivated population, large population for, you know, for a rare disease. From that perspective, I don't...
I think this is actually a disease that can support multiple therapies, and I think if you look at, you know, the type of patients we're focused on and the type of patients that some of the other programs are focused on, you're actually seeing a bit of a different phenotype that each company appears to be, you know, working towards. I think that's an interesting, you know, development in this disease, which, you know, has a broad range of patients across both arrhythmia and heart failure.
Great. Then, lastly, I think, you know, when you're in the topic of gene therapy, you know, people are always concerned about the, you know, potential safety issues. You guys have had a quite a clean record there, and your platform is differentiated. I think you've mentioned a little bit about it in the intro, but, perhaps Nolan or others, you know, just share with us kind of what your advantage here is here with your vector and the, you know, the ability to give, you know, much less in the way of dosing and exposure.
Yeah. It's, you know, we have identified a highly cardiotropic vector, which means at relatively low doses, we can deliver sufficient, you know, a sufficient genetic payload to the heart. We see that via the PKP2 program as an example. We're getting between 3 and 5 vector copies per cell, but we're doing so with no classic gene therapy-related assays. No assays related to complement activation, no assays related to liver injury. We're really able to get a meaningful amount of gene product, protein, etc., into the heart, but do so with a modest safety profile.
I think that's what's important to us, is you could think of Lexeo as a company that's, you know, treating these cardiac genetic diseases, but doing so at lower doses because we have chosen the right tool for the job we're trying to accomplish, which is to, you know, to primarily treat the heart. So that's, I think, a core principle behind all of our programs today, and our clinical data is validating, you know, that approach.
Excellent. Okay, good. I think we'll, you know, we'll wrap up just to review upcoming milestones. Final alignment in FA cardio, and then the kickoff of that study, which could, you know, well, take you to a accelerated approval. Of course, PKP2, it sounds like we'll see some more updates, both in the regulatory and data side. Any further things to look out for or closing comments?
No, I think we're, you know, again, we're working to finalize the, you know, accelerated approval study, and we'll be able to report that in the coming period of time, and we're looking to start the registrational study before the end of the first half. We're excited to keep move the program forward.
Yeah. I guess we should give Louis a chance to speak, and the cash is always important for any biotech. You guys have a pretty good runway. If you could just remind us, you know, your cash balance and so forth.
We, you know, we had a very successful financing in October on the back of the meaningful FA data that the team described today. That put us with a number in the mid $200s, and our quarterly burn rate, think about a number in the mid $20s. That gives us runway into 2028. That includes everything that we need to do to get FA through the BLA filing, inclusive of the manufacturing and initial commercial readiness, and also funding of the PKP2 program through the conclusion of the phase 1/2 study.
Excellent. Terrific. Well, thanks. This has been a solid update here. Glad to have all of you participate. Thanks to everybody who zoomed in. Please enjoy the rest of our conference.
Thank you.