Welcome, everyone, to the 43rd Annual JP Morgan Healthcare Conference. My name is Tess Romero, and I'm one of the Senior Biotech Analysts here at JP Morgan. We're pleased to welcome to the stage our next presenting company, Lexeo. And presenting on behalf of the company, we have CEO Nolan Townsend. Nolan, over to you.
Thank you, Tess, and the JP Morgan team for having us at the conference. It's always great to be here, so I'm excited today to talk a little bit about the progress that we're making at Lexeo Therapeutics. We really think we're at a turning point in terms of the treatment of cardiovascular disease with genetic medicines, and I'll tell you a little bit about what we're doing and some of the progress that we're making across our pipeline, so as cardiovascular disease is looking historically, the FDA has required CV outcome studies to support the approval of cardiovascular treatments, and this has typically confounded the development of precision medicines in cardiovascular disease but this has been changing over the last few years, and recently, the FDA has been open to biomarker-based endpoints to support the approval of cardiovascular treatments.
We've been advancing a very compelling pipeline of cardiovascular gene therapies in some very important diseases. The first one is Friedreich's ataxia, which many would know as a neurologic disease. However, the typical cause of death in this disease is cardiovascular, is cardiomyopathy. These are patients that live lives that are very fulfilling. They get married, they go to school, they have children, but they want to live beyond their 30s. We're advancing a treatment that we think can address the mortality in this disease. And I'll talk a little bit more about this. Our initial clinical data in Friedreich's ataxia demonstrated an ability to address the hallmark of the disease, which is hypertrophy. We've also reached alignment with the FDA on an accelerated approval path and endpoints that we're currently meeting in our phase one study. We're expecting to announce high-dose data by mid-2025.
We have a potential to initiate the registrational study by the end of 2025 or beginning of 2026. Our next most advanced cardiovascular treatment is treating arrhythmogenic cardiomyopathy. This is another very challenging disease. Typically, patients will suffer from sudden death, arrhythmic events, or premature ventricular contractions. This therapy is now in the clinic. We've completed enrollment of cohort one. We're expecting to have our first clinical data readout for this program by the end of Q1 or beginning of Q2. These two programs are core to Lexeo's focus going forward. I'm showing a snapshot of our pipeline, the two clinical stage programs which I mentioned. We're also advancing two preclinical cardiovascular programs. We also have a program in the Alzheimer's disease space where we're pursuing business development opportunities to take that program forward.
I'd note that this program will be taken forward through business development opportunities alongside a partner. And no future Lexeo capital will be deployed into the Alzheimer's program. So I'll take some time to talk about FA cardiomyopathy, which we think represents an area of very high need within the Friedreich's ataxia treatment landscape. Many would know that there is a neurologic therapy that's approved, but this therapy does not have an impact on the cardiovascular disease. So take a step back to talk about Friedreich's ataxia. This is a rare and devastating neurologic disease, but also represents a cardiovascular component of the disease, which many are unaware of. These complications are the leading cause of death. And there is no commercially approved treatment that addresses the cardiovascular component of this disease, leaving significant unmet need with cardiovascular functional impairment. This disease is a mitochondrial disease.
Deficiency of frataxin is the cause of the disease. This results in mitochondrial dysfunction, deficiency in energy production. This is really the cause of FA cardiomyopathy, leading to hypertrophy, which is thickening of the heart wall. We're advancing a therapy with AAVrh10 capsid under the control of a ubiquitous promoter, expressing the full length of functional protein that addresses the disease. This has been shown in preclinical studies to improve survival in mice. We've also demonstrated some interesting results in the clinical setting in terms of our ability to impact hypertrophy with this clinical construct. To take a step back and look specifically at the cause of FA cardiomyopathy, these thickening heart walls or hypertrophy is really the hallmark of this disease. You could see this on the figure shown on the left. Left ventricular mass index is the most common way to evaluate cardiac hypertrophy.
And typically, these patients, as they progress through increases in lateral wall thickness and then increases in left ventricular mass index. So this is a key endpoint that we've been focused on in our clinical study, is evaluating left ventricular mass index and the ability of our therapy to impact that endpoint. Now, as I mentioned before, 60% to 80% of patients will die from cardiac dysfunction. They typically result in progressive concentric hypertrophy. And natural history data would suggest that over time, patients progress towards heart failure. And typically, left ventricular mass index is an endpoint that we've been focused on and we think is important in other cardiovascular diseases. And typically, the cardiovascular community would use LVMI as a marker of progression of a disease. But I would say, importantly, spontaneously, left ventricular mass index does not improve on its own.
You would only see improvement in LVMI via some type of therapeutic intervention, so if you look at other HCM studies that evaluate left ventricular mass index, it only changes with therapeutic interventions. The control groups do not see any change in this endpoint. Our study in Friedreich's ataxia cardiomyopathy has been advancing over the last couple of years, and we actually have two ongoing studies that Lexeo owns the data rights to. One's a Lexeo-sponsored study. Another is a study being run by Cornell. It's the same drug product being utilized in both studies. I would note that to date, there are a total of 16 patients dosed across the two studies. There's three different dose cohorts. We've completed enrollment of SUNRISE-FA, which is a Lexeo-sponsored study, including four patients in cohort three for which the data is forthcoming.
The alignment we reached with the FDA was a milestone in the progress of the Friedreich's ataxia program. First, we reached alignment on the inclusion criteria for patients in the pivotal study. This will include patients with abnormal left ventricular mass index at baseline. These patients will have two standard deviations above normal in terms of their LVMI, their left ventricular mass index levels. The target reduction threshold for left ventricular mass is 10%. This is a threshold that corresponds to mortality in this disease. It's also a threshold that's been considered in other studies to be clinically meaningful. Our interim phase one results suggest that in this population of abnormal patients, we're exceeding this 10% threshold across every patient that's reached 12 months. The second endpoint, or the co-primary, is frataxin expression via immunohistochemistry assay.
For this endpoint, we need to reach a 40% of total staining area for frataxin expression via this assay. You could think of this as a proxy for the percent of cells transduced, so the coverage of frataxin. These two co-primary endpoints represent key biomarkers that are important in the treatment of Friedreich's ataxia. We also have two secondary endpoints, that are wall thickness and troponin, which are also important endpoints in evaluating the comprehensive aspects of the disease. The data that we're showing here are the three patients in our cohort one, so our lowest dose, that have reached 12 months. What you're seeing here are the three clinical endpoints that we've measured, first left ventricular mass index, where we're showing between an 18% and 12% improvement in left ventricular mass index for an average of 14%.
As you can see, all three patients that have reached 12 months are exceeding the 10% threshold that we've aligned with the FDA. This is important because I think our goal would be to replicate the results that you're seeing on this slide in a future study. You can also note that we're seeing improvements across lateral wall thickness and improvements across high sensitivity troponin as well, which are the two secondary endpoints. In totality, at our lowest dose, we're seeing a clinical effect that we think would support an approval in a pivotal study. I would also focus on the other co-primary endpoint, which is frataxin expression. Here you could see the immunohistochemistry results across the three patients that we have in the study in cohorts one and two, where we see an average immunohistochemistry staining area of 44%.
As you would note, this is relative to the 40% alignment that we reached with the FDA on this endpoint. So we're exceeding both in left ventricular mass index and in immunohistochemistry the thresholds that we've aligned with the FDA for the co-primary endpoints in the pivotal study. Now, we have four additional biopsies to come out of cohort three. We've dose escalated. We would expect to see a dose response. So we would expect to more comfortably clear this threshold when we look at immunohistochemistry and the 40% bar that we've set. So that's a key aspect of the future of the program. Our readout in 2025, which we're expecting at mid-year, would be focused on the four biopsies that are coming out of the high dose. We would also have additional data at longer time points and additional patients showing left ventricular mass, wall thickness, and troponin.
That's really the focus of the future readout. I would then change gears here to talk about arrhythmogenic cardiomyopathy. This is another very devastating disease, I think unknown to many. It represents very high unmet need. We have a therapy that we think can change the treatment course in this disease. Arrhythmogenic cardiomyopathy is most commonly caused by the PKP2 gene, or Plakophilin-2. Deficiency in this protein results in desmosomal dysfunction and typically results in life-threatening arrhythmias. Typically, 23% of patients present with sudden death in an arrhythmic event, which is very challenging for families to manage. ICDs are commonly utilized, but they do not halt disease progression. Many of these patients progress to requiring heart transplants.
This is a disease where what we know today is about 60,000 patients are impacted by PKP2 arrhythmogenic cardiomyopathy, making this a very large, rare disease and therefore substantial unmet need within this population. And current approaches do not treat the fundamental components of the disease. And we believe that gene therapy is the ideal treatment approach to address this condition. Our gene therapy, from a preclinical perspective, has addressed all aspects of what's known to be arrhythmogenic cardiomyopathy. We've been able to address arrhythmia burden, life-threatening arrhythmia events, and also EKG abnormalities across the disease. So our preclinical body of evidence is very compelling. And I think there are a few questions on the biology of the disease based on the preclinical studies that we've run. So moving on to the clinical trial that we've launched last year, this is a 52-week study. It's called HEROIC-PKP2.
We've completed enrollment of cohort one, and we're working towards a data readout for the cohort one patients at the end of Q1 or beginning of Q2. Now, importantly, we're looking in this readout at Plakophilin-2 expression via cardiac biopsies. We're also evaluating safety. Throughout the study, we're collecting other clinical biomarkers, such as premature ventricular contractions, EKG abnormalities, RVEF. But we were focused on a clinical data readout in the second half of 2025. We anticipate moving into cohort three, and that readout later in the year will also include data from cohort two. So as we think about the totality of the pipeline and the milestones we have upcoming, I hit them across the programs earlier. But I would say first, in the cardiomyopathy program for FA, we're working towards a mid-2025 readout.
This update will include the four cardiac biopsies in FA, longer duration cardiac biomarker data across all cohorts. Our anticipated goal there is to see a dose response in the four biopsies and also have a consistent theme of improvements in left ventricular mass index, wall thickness, and troponin across the patients that we're reporting. In arrhythmogenic cardiomyopathy, the first readout will be focused on safety and biodistribution, primarily the cardiac biopsies, where we'd understand if we're translating the protein expression that we observed in the preclinical studies into the clinical setting. The second readout in 2025 will be a clinical biomarker-focused readout, really focused on efficacy, where we'll see patients at six and 12 months, and we'll see patients across both cohort one and cohort two, and for Alzheimer's disease, we're pursuing partnership opportunities.
This is a program that would be taken forward alongside a partner with outside capital. I'd also mention from a cash and marketable securities perspective, we have $157 million in cash. This gives us a runway into 2027. I think more than sufficient capital to deliver the milestones on this slide and also progress the Friedreich's ataxia program into a pivotal study. I would note from a timelines perspective that program is moving very, very quickly. We would expect after the readout to align with the FDA on the final design for the pivotal study. I think the last element of alignment we need to reach is on the dose for the pivotal study. Once we reach that alignment, we're working towards a launch of a pivotal by the end of 2025 or beginning of 2026. With that, I'll stop here.
And we'll move to questions. I'd invite our CFO, Kyle, and our Chief Medical Officer, Eric, to the stage to join me for questions.
Great. Thank you, Nolan. Welcome, team. So I thought I'd start with a little bit of a bigger picture question on the FA cardiomyopathy program. What learnings do you want us to come away with in 2025 related to the program?
Maybe I'll start and then ask Eric to comment. I think what we've seen in the study thus far is at the cohort one dose, we're seeing an improvement in left ventricular mass index that exceeds the threshold that we've set with the FDA. So I think we simply want to replicate the results of that, the cohort one data in a larger study. So I think what we want to do this year is to give confidence that we can achieve that threshold in a pivotal with additional data, with more patients and longer time points. I don't know, Eric, if you have anything to add there.
Yeah, I think we've already shown that we can achieve what the FDA is asking for. So it's just a question of repeating it at a dose. Now we're excited to be able to share results at a dose that's even shown more efficacy in our preclinical models. So really excited about that.
It sounds like in terms of gating items, Nolan, you basically just said it's just dose. There's nothing else, really.
Yeah. So the alignment we reached covered the population that we would include in the study. It covered the endpoints that are eligible for accelerated approval. It covered the thresholds. The last piece of information we need is the cohort three biopsies, which will allow us to determine the dose. And that alignment we would reach with the FDA in 2025. I think that also will allow us to size the study. Obviously, the dose would link to the size of the study. I think we have some assumptions on what that would look like. But we need the information from the last four biopsies to reach that final alignment.
How does the population that you're enrolling in the registrational trial de-risk the study?
Maybe Eric, do you want to take that question?
That's a good question. I think it's one of the key takeaways from our alignment with the FDA is that we plan to enroll patients that have abnormal LVMI and specifically defined by two standard deviations above the normal. Those are the patients in which we expect to have the most robust response to LV mass reduction when we re-express frataxin. So we think that's the perfect population to establish efficacy.
I would say that's, in our view, the most de-risk path we can take to an accelerated approval. We know we're seeing an effect size in that population that exceeds the threshold we've met with the FDA, discussed with the FDA.
What elements of the registrational trial, in terms of the future results that you'll get, will ultimately matter to physicians in driving a view of the overall profile?
Maybe Eric.
I think among providers that take care of patients with genetic cardiovascular disease, it's actually not a huge number of us, 5,000 or so, that really see these patients day to day, and among those providers, we recognize the importance of reducing hypertrophy. You can see this across the spectrum of diseases that cause cardiac hypertrophy, HCM, amyloid, all these diseases we know that lowering LV mass is associated with better outcomes. That's why this outcome is so important to the FDA, and I think providers already know that when they check their echoes and show that LV mass is reducing, they know it's meaningful. I mean, one other thing I would add just quickly is that we've also already shown some improvements in its early data, but in functional assays like KCCQ. Again, this resonates a lot with cardiologists.
Heart failure doctors specifically are very familiar with these functional scores and know that that has an impact on the quality of life of their patients.
Yeah, I would add to that. And even beyond KCCQ, we've seen some improvements in the mFARS scales. And again, this is early data with a handful of patients. But that's the component of the disease that typically you would think a neurologic therapy would address. Yet there are some domains within mFARS that actually a cardiovascular treatment can address. So from both the neurologic perspective and the cardiac perspective, I think we have a potential to show some improvement in functional scales as well.
Can you talk a little bit about which FA patients you think will go on to LX2006 of the 5,000 in the US? And how should we think about the overall market opportunity here, including what is an appropriate framework to peak sales?
I maybe can start just from the commercial standpoint. So the cardiomyopathy typically manifests itself within adult patients. So this is a pretty significant swath of patients within the FA community. We think patients that are beginning to have early symptoms of cardiovascular disease would be the ones most eligible for treatment. So we're probably looking at 60% to 70% of the total patient population that would be eligible for therapy. And Eric, I don't know if you want to add anything on the population that may be in it.
I think that from a patient perspective and a provider perspective, it's not an if. It's a when patients will develop cardiomyopathy because we know this is going to be the leading cause of death for patients. So if there's an available therapy that can attenuate the progression of disease, patients with genetic disease are going to want to get it.
And I think it's analogous to Duchenne muscular dystrophy, spinal muscular atrophy. Whenever you have these very challenging, rare genetic diseases that have no existing treatment and the patients would otherwise be progressing towards mortality, I think you typically see pretty rapid uptake of these treatments. And we've seen that across diseases like DMD and SMA. I think Friedreich's ataxia is no different. So a gene therapy in this space, you could model in a similar way to what you've seen with SMA and DMD.
I feel like I asked this question last year, but I'm going to ask it again. What have been the key learnings for you from the Skyclarys launch?
I think the first is that patients are really motivated to seek treatment. I think that's the most important aspect of what we can see in that patient population. They're very, very motivated. I think the FDA, the flexibility that the FDA showed in that approval was very important. I think we would expect to benefit from the same flexibility in advancing a cardiovascular therapy. I think importantly, we now know that patients do have a neurologic treatment. It may not be perfect, but it does address some components of the disease. I think many patients are turning to focus on how do they address the cause of death, which is the cardiac disease. I think that urgency to seek care is one of the important themes that's come out of the Skyclarys experience.
Just to clarify, are patients that are on Skyclarys allowed to enroll into your registrational trial?
Yeah, Eric, do you want to take that?
Yes, absolutely.
OK. What are your thoughts on the evolving FA development space here? I don't think there's a lot in the competitive landscape. But just generally, how do you think about something like a dual route of administration drug treating both neurologic and cardiac manifestations versus your approach?
Yeah, I think one of the challenges in Friedreich's ataxia is that it is both a neurologic and a cardiovascular disease, and this has probably confounded the development of FA therapies historically, so I think that that's a component that's challenging for gene therapy, and in particular, the CNS target is a challenging one to address. Ideally, you transduce the dorsal ganglia, the motor cortex, and the deep cerebellum or the dentate nucleus, so a CNS therapy that would attempt to treat the comprehensive components of the disease would need to address all three of those. I would also note that in gene therapy, typically, the capsid or vector that's best for the brain may not be the best for other target organs, so you would want to optimize your therapy for the target that you're seeking to address.
For example, if a dual therapy was using the same capsid across the brain and the heart, the question would be, is it best in class in both target organs? Or is it best in class in one? And so in our view, a patient that is looking to extend their life or improve their symptoms of cardiovascular disease would want to seek the best-in-class treatment for each component of the disease that they're seeking to address. So that, I think, would be one of the challenges with the dual administration treatment. And our therapy, obviously, is optimized exclusively for the heart. We're looking to take that component of the disease off the table for patients that should address mortality in this disease. And I would expect that successively improved CNS therapies would advance into this treatment landscape.
So switching gears now to the LX2020 and PKP2 ACM, with respect to PKP2 protein expression, what magnitude of improvement do you think you can achieve at the low dose and the high dose in your study?
Do you want to take that one, Eric?
I think if you look at our preclinical studies, the low dose provided significant survival benefit in the murine model. So we think we have a dose that could, in fact, be quite efficacious. But we'll need to explore that in the context of the human condition. But at both doses, we saw improvement in key what would be clinical features of the disease, including improvements in premature ventricular contraction, improvements in EKG, improvements in structural structure and function. We saw more improvement at a greater magnitude with the higher dose. But we did see improvements at both doses.
Can you quantify how you're thinking about what you'll see in the clinic?
I don't think that's. We don't plan on doing that because this is a first in human condition that's obviously different from the murine studies. So I think speculating what we're going to see, it's very exciting because this is a tremendous opportunity and advancement in cardiac gene therapy in general. But speculating the magnitude and creating some kind of number, I think it would be misguided.
Yeah. What I'd add is I think it's clear to us that we probably don't need wild-type levels of protein to correct the disease or achieve a treatment effect. These are heterozygous patients. So they probably start anywhere from 30% to 50%. So I think we're looking at somewhere between 30% and 100% is the level that need to be reached. But I think, as Eric said, this is a first in human study, the first clinical data, frankly, potentially in this disease in totality. So that threshold of where you see this flip of clinical improvement is not known today. And I think that's what we're looking to explore with this study.
Can you talk a little bit about the additional cardiac functional measures that you're looking at and any specific benchmarks you can give us? Or is it just also maybe just a little bit too early?
I think you can look at the clinical criteria to define patients with genetic cardiomyopathy is based on 2010 guidelines. That includes premature ventricular contractions, EKG changes, changes in cardiac structure and function as assessed by imaging like MRI. We'll be looking at all of those parameters comprehensively in our study. On top of that, I think understanding how patients feel is going to be important and getting assessment of symptoms from standardized patient-reported outcome testing. These are patients with a really poor quality of life. Finally, they're walking around with defibrillators, these patients. Though that might take longer to play itself out, keeping track of are they having shocks from their defibrillators would be obvious. I just don't know the spectrum of that, how often they have that.
It might not play itself out as an outcome that we could see in a small trial.
What is your initial thinking on the design of a registrational trial here in PKP2 ACM? And what are the key elements of your phase 1/2 trial that will help drive these decisions?
I think it is early to give a definitive perspective on what a registrational study could look like. I think some of the endpoints that Eric described from a clinical perspective, premature ventricular contractions, EKG abnormalities, these will likely be part of the picture. I think we're seeing an evolving framework within CBER that they're open to tissue biopsies and protein expression as an important component of a registrational study for accelerated approval. I would expect that to continue. So I think there's some version of tissue expression combined with a clinical and objective clinical endpoint that are likely to be part of a registrational study. I think premature ventricular contractions are most likely. But there are others that we're looking at as well.
On PKP2, can you just talk to us a little bit about how well identified these patients are, Eric?
Yeah. I mean, I think it depends when you look at it from a U.S. perspective versus the European perspective, and I'll start with Europe, where this has been a well-identified and understood disease for a long time. You can look at countries like Italy, where everyone performs a pre-sports participation cardiovascular exam because they know and want to try to avoid patients first presenting while doing sport. That being said, in the U.S., as there's more and more awareness thanks to patient advocacy organizations and maturity in the electrophysiology field, people recognize this disease. We think this is one of those things as a genetic cardiologist, you see one patient at clinic, so I don't think it's. I think this is a relatively mature space. A lot of the identification of patients comes also from cascade testing.
So once you identify a patient because the first manifestation of disease could be sudden death, it's on us to then aggressively genetically test first-degree relatives. And so then a lot of these patients, I'll follow 12 or 15 patients that are all interconnected, cousins of each other, et cetera. So I think that's well understood.
Zooming ahead, I mean, what are the commercial similarities and differences between these two patient populations?
Yeah, I think there's some differences. Primarily, the FA population, first, they suffer from neurologic disease. So the two therapeutic approaches will need to coexist with one another. I think the therapeutic approach that exists today within PKP2 is simply to have an ICD, which is a different construct. I also think PKP2 patients, a lot of them will go on to require heart transplants. So you have an existing cost benchmark that exists for treating the disease from a transplant perspective. So this validates the potential price of a gene therapy. Whereas in Friedreich's ataxia, we would be establishing a new price point and a new value for the treatment of the cardiovascular disease. It's effectively untreated today. The PKP2 population is larger. This is a 60,000-patient disease. Whereas in FA, it's a 5,000-patient disease. So obviously, that size of population can support multiple treatments.
So we're likely to have a landscape where there are other therapies out there. Whereas in FA, I think given the progress we've made and where we are with the therapy, this is likely to be the first-in-class treatment. And if it addresses the cause of death in the disease, we'll see a lot of patients that probably opt to seek treatment. And so we could see a rapid uptake there. So I think those are some of the commercial factors I would point to. I would also say both are global diseases. So there's patients outside of the U.S. with both that would require treatment. So I would expect to see both products commercialized both in the U.S. and outside of the U.S.
I'd love to talk a little bit about the perception of the most recent data you presented at CTAD for the LX1001 program in APOE4 homozygous Alzheimer's disease. Can you talk a little bit about that? And then also, how have the conversations been going? What are you seeing with respect to partnering with the program?
So just for the benefit of the audience, so we ran a 15-patient study in APOE4 homozygous Alzheimer's disease where we delivered the APOE2 gene. This was a dose escalation study, so four patients per dose, a total of 15 patients. We enrolled patients in this study across the range of the disease, so everywhere from MCI to moderate dementia, to get an understanding of how a gene therapy that addresses the genetics of Alzheimer's disease could impact various biomarkers that are associated with the disease. So these patients that are at the MCI stage have very little amyloid and very little tau. Then on the other end, you have moderate patients who have significant amyloid and significant tau. So as you would imagine, you can expect a differential effect across patients that are sitting in the range of the disease. And that is what we saw.
I think we saw that we had the most significant effect on key biomarkers such as tau within the moderate population that presented with the most significant tau burden. So we saw this across various tau assays in cerebrospinal fluid. We also saw this impact in tau PET scans. So I think that's what's important that I would note for this therapy is that we were able to impact tau within an APOE4 population without instances of ARIA, or the brain-swelling disease that typically leads to death. As many would be aware, the existing commercially approved treatments, lecanemab and donanemab, within this E4 population have very significant rates of ARIA, in some cases 30% to 40%. So an ability to impact a biomarker such as tau with no instances of ARIA is something we think that deserves further exploration.
Now, from a perspective of a small company, it's a challenge for us to take forward several cardiac programs and an Alzheimer's portfolio. And for that reason, we're seeking partners to work with on the Alzheimer's front. And so those conversations are advancing. I think we'll have an update on this within 2025.
With your cash balance, what is your cash runway? And how do you think about OpEx in 2025?
Kyle, do you want to take that one?
Yeah. No, I think the good news is we're more than sufficiently funded to get through each of the events that Nolan's talked about, $157 million at the end of the third quarter. And I think it depends on the pace and how aggressive we want to advance into a pivotal trial. And at what point we begin that will be impactful to OpEx. But we've got plenty of cash runway to get into 2027 and a lot of really important catalysts still to come this year.
I think that might be a good place to leave it. Thank you so much, Lexeo, and thanks for.