Good morning, everyone, and thank you for joining the 2024 H.C. Wainwright 26th Annual Global Investment Conference. I'm Dr. Jade Montgomery, an associate biotech research analyst at the firm, and I'd like you to please join me in welcoming Nolan Townsend, CEO of Lexeo Therapeutics, a clinical-stage company developing precision genetic medicines in the cardiovascular and neurological space. Nolan?
Thank you for having us this morning. I'll go through some slides, and then I'll have a colleague of mine join us for questions if we do have time for that. Thanks everyone for taking the time to listen. To start with, you know, the fundamental thesis behind, you know, Lexeo's pipeline is the ability to apply precision medicine to diseases that have seen limited or no penetration of precision medicine to date. First, starting with our core focus in the cardiac disease area, there are, you know, fewer than 10 precision medicines approved, and several of these are focused on the same disease. This is very different from oncology, where you see, you know, 50%-60% of the treatments are precision medicines.
And the difference between these two is fundamentally related to the evolution of the regulatory landscape. Historically, the FDA has required cardiovascular outcome studies to support the approval of CV treatments. However, this has been changing, first with the approval of mavacamten, and then more recently with the development of other cardiac precision medicines that have used biomarker-based endpoints in their pivotal studies. So we're seeing evolving of the regulatory construct around cardiovascular treatments. That's opening the window, opening the door to a number of precision medicines in this disease area, very similar to what you have seen develop in oncology. We actually also believe that the AAV vector will play a unique role in this treatment landscape for cardiovascular disease. For the moment, there's no more efficient way to deliver a genetic payload to the cardiomyocyte.
We've not seen lipid nanoparticles able to access the cardiomyocyte. ASOs have a challenging time accessing them as well. So for the moment, the AAV vector is the most efficient way to deliver a genetic payload, and we believe we're working with the most efficient AAV vector for cardiac tropism, AAVrh10. There's a similar thesis on the Alzheimer's side, although it's not obvious, in that there are no precision medicines approved in the Alzheimer's treatment landscape. However, if you looked at the data from the amyloid antibodies that have been approved, you see different response rates between the different genotypes for the APOE gene, which implies that precision medicine is likely to play an important role in the evolving Alzheimer's treatment landscape as well.
We have the most advanced precision medicine for APOE4 homozygotes in the clinic today. The commonality across our pipeline is the lack of introduction of precision medicines, both in the cardiac space and the Alzheimer's space, and we believe the AAV vector will play an important role in the treatment landscape in both disease areas. In terms of the company itself, first starting with the cardiac side, we have two cardiac programs in the clinical stage. The first is treating the cardiac pathology of a disease called Friedreich's ataxia. Here, we've read out data in July 2024, showing a reduction in key biomarkers that are commonly associated with Friedreich's ataxia cardiomyopathy. This program, we are advancing towards regulatory alignment within 2024.
Our next most advanced program is treating arrhythmogenic cardiomyopathy, and here we're focused on the plakophilin-2 mutation. This is a disease of about 60,000 patients in the U.S., making it one of the largest targets in cardioskeletal gene therapy, and here we also have an ongoing phase I/II clinical trial. On the other side of our pipeline, in APOE4 homozygous Alzheimer's disease, we have a phase I study that's completed enrollment. We're working towards a data readout for this program by the end of 2024, so a busy year of clinical data catalysts for Lexeo between our cardiac and Alzheimer's pipelines. In terms of our pipeline, here's a snapshot of where we are. As I mentioned, the two cardiac programs for FA cardiomyopathy and plakophilin-2 arrhythmogenic cardiomyopathy are at clinical stage.
And then the third program in APOE4 homozygous Alzheimer's disease is also at clinical stage. And so, for all programs, either we've read out data or have data coming in the forthcoming few months. So switching gears to our cardiovascular diseases, which is the core focus of the company, I'd first say that each program in our pipeline is addressing a different organelle within the cardiomyocyte. So for example, frataxin is a mitochondrial disease, plakophilin-2 is a disease of the desmosome, TNNI3 is a troponin mutation in the sarcomere.
So our ability to deliver gene therapy to treat these different components of disease mediated by the cardiomyocyte give us a readthrough to other cardiac diseases we can target beyond the four that are shown on this page. So we think of this as both proof of concept for these individual therapies, but also proof of concept for our ability to treat these components of disease within the cardiomyocyte. Therefore, this is really the tip of the iceberg of what we think can be achieved with genetic medicines in cardiac disease. In terms of the capsids that we're using to achieve this, we're utilizing the AAVrh10 capsid, and in our hands, of the known vectors, we believe this has the most compelling cardiac tropism profile out there.
This is a study that's comparing AAVrh10 to AAV9, which is another commonly used vector, and what we've observed is a one and a half to two times greater biodistribution in the heart compared to AAV9, and this is across multiple large animal models, so minipigs and non-human primates at the top, and this is showing expression of the therapeutic transgene or vector copy number as well. But on the bottom, what's being demonstrated is improvement in a disease model, the plakophilin-2 arrhythmogenic cardiomyopathy model in AAVrh10 versus AAV9. Here you see a greater reduction in ejection fraction with AAVrh10, a greater reduction in end-diastolic volume, and a greater reduction in end-systolic volume, so you see these functional improvements as well when comparing the two capsids.
So we believe that what this allows us to do is to transduce the heart at doses that are relatively low for systemic gene therapy, but still achieve protein expression that allows us to correct the disease in question. And as I talk through some of the data behind our FA program, you'll see that the doses we're achieving these therapeutic results in are quite low for systemic gene therapy, thereby validating the therapeutic and efficacy profile of the capsid in clinical studies as well. So switching gears to our FA program, many would probably know Friedreich's ataxia. It's one of the rare diseases that have been studied by a number of different companies and academic groups. You would note as a neurologic disease, it develops in childhood.
These are patients that are, you know, between five, eight years old, but at adulthood, a cardiomyopathy associated with the disease emerges, and it's this cardiac disease that is the cause of death for 70% of FA patients, so while addressing the neurologic disease can improve quality of life in FA, you can really only impact mortality in the disease by addressing the cardiomyopathy associated with the disease, and this is the component of the disease that our therapy is focused on, and for those that don't know, in terms of some of the biology of the disease, the cause of the disease is a missing frataxin. This is due to an expansion of GAA repeats in the genome. This results in low levels of frataxin being expressed within the FA patients.
This leads to mitochondrial dysfunction, deficiency, and energy production, and this is the cause of the disease. The two organs that require the most energy, the brain and the heart, are the two that are the most impacted by the disease. The disease progression from a cardiac perspective starts with normal left ventricular mass index for patients, and this typically progresses into elevated wall thickness, and then elevations in left ventricular mass, so this is the continuum of the disease from a phenotypic standpoint, so patients that are earlier in the disease continuum may present with elevated wall thickness, but without elevated LVMI. Patients that are further along in the disease continuum will present with elevated LVMI, and the study that we've been advancing is a 52-week study evaluating adult patients with FA cardiomyopathy.
Our primary objective is to evaluate the safety profile of the therapy, but we also have some efficacy endpoints as part of the study. The inclusion criteria, as you can see here, are adults with evidence of FA cardiomyopathy. Importantly, the key measurements we're evaluating from an efficacy standpoint, you know, left ventricular mass index, which is a measure of the heart's weight relative to the body weight, high-sensitivity troponin, which is a measure of cardiac cell death, and some other measures from a biomarker standpoint. We're evaluating functional capacity via cardiopulmonary exercise testing, and then we're evaluating frataxin protein expression in the heart via LC-MS and immunohistochemistry. In terms of the results we have presented to date, they are summarized on this slide. From a safety perspective, this therapy has been well tolerated with no treatment-related serious adverse events.
And from a left ventricular mass index perspective, so this is evaluating the heart's thickness and its response to the therapy. Among patients that presented with elevated LVMI at baseline, we saw that 75% of them achieved a 10% or greater reduction at 12 months, and with the mean reduction of 11.4% at 12 months. So we saw a pretty material reduction in left ventricular mass for the patients that were at 12 months in the data we reported. And noting that by natural history, which shows that the LVMI would be stable to increasing over time, so the ability to achieve this level of reduction in patients with elevated LVMI, we believe, demonstrated an effect size that was meaningful in this disease.
We also evaluated lateral wall thickness. As I mentioned earlier, patients start in the disease continuum with elevations in wall thickness, then progress to elevated LVMI. We saw a reduction of 14% in of left lateral wall thickness across six patients that had reached 12 months in the study. And then for troponin I, which is a measure of myocardial injury, we saw about a 50% reduction for patients that had reached 12 months. So we saw material reductions across three different endpoints that are relevant, you know, for this disease. From a frataxin expression standpoint, in terms of cardiac biopsies, we saw increase in frataxin in three of three patients via LC-MS and two of two patients via IHC.
So across all of the biomarkers that we've evaluated in the study, we've either seen improvement in disease-related biomarkers or increases in expression of the therapeutic transgene. This is some of the detail behind the frataxin expression biomarkers. On the left, you see LC-MS, on the right, you see immunohistochemistry. You can see that we saw a dose response between cohorts one and two from the frataxin expression standpoint on the left, and on the right, you can see staining across the two patients, where we've achieved about a 50% post-dose staining area, which is a proxy for the percent of cells transduced.
In some studies, there's estimates that treating up to 40% of the cells in the heart or in the brain can correct the FA disease. Here you're seeing that we're transducing about 50% of the heart, and this is in the doses that we have reported to date. We have since moved into a cohort three dose. That's another about half log higher than the cohort two dose. So we're expecting to see even greater frataxin expression across the third dose. In terms of the data itself from a left ventricular mass index standpoint, what we're showing on the left is the mean change versus the patient's pre-treatment baseline.
You see this 11.4% improvement at 12 months that I mentioned, but you can also see a deepening of effect for patients that are at longer time points, so the patients that are 18 months are showing an 18% reduction in left ventricular mass, and the median change in the middle, very similar trend there, and what we're showing on the right are the patients that did not have elevated LVMI at baseline and the changes there, and what's important to note are the patients that did not have elevated LVMI at baseline, so they were normal. They all stayed in the normal range, and you can see this across the data for the patients in the study.
Those with elevated wall thickness, but without elevated LVMI, stayed in the normal range from an elevated LVMI perspective, which may mean that we are preventing patients from progressing in the disease that are, you know, earlier in the disease course. What's shown here are the changes in lateral wall thickness. As I mentioned, the 13% improvement at 12 months. This is sustained out to 18 months for the patients that have reached that time point, and as well, the reductions in troponin of about 53%, and this is also sustained out to 18 months for the patients that have reached that time point. Again, across all biomarkers, we're seeing a sustained or greater improvement as the time course of the therapy sort of takes shape.
So just to summarize, the data that we have reported, we've shown transgene expression via two different independent assays, LC-MS and IHC. We've shown left ventricular mass improvement, greater than 10%, across all the patients that have reached 12 months, and then 18% for those that have reached 18 months. We've shown improvements in lateral wall thickness, which is an independent endpoint from LVMI. We've also shown improvement in troponin I of about 50%, which is a third independent endpoint. So we're excited about these results and where we take the program further from here. The next steps for this program is that we are working to reach alignment with the FDA on surrogate endpoints for a pivotal study.
We expect to make an update on these regulatory conversations by the end of the year, switching gears here with about five minutes left to the PKP2 arrhythmogenic cardiomyopathy program. This is a very different disease. It's a disease that patients present with arrhythmias or premature ventricular contractions, which is a precursor to major arrhythmic events. This is a disease that impacts desmosomal integrity, so the desmosome separates, and this is the cause of the arrhythmias that are commonplace in this disease. Our approach is delivering a functional copy of the plakophilin-2 gene, restoring desmosomal integrity and has addressed these symptoms in murine models.
As you can see on the top right, the introduction of the therapy has resulted in a significant reduction in the premature ventricular contractions, which is a precursor to arrhythmic events. We've been able to get the vector into all regions of the heart, including the right ventricle, which is what's most relevant for this disease. Importantly, as you can see on the left, we've seen pretty significant improvements in survival versus the untreated group across all the doses that we studied. Importantly, in this disease, we've begun to think about what are important endpoints to evaluate in our preclinical studies and our clinical studies that may give us a read to what would be most important for a pivotal study.
Importantly, we believe premature ventricular contractions will be an important endpoint for us as we look at the treatment results, but there are others, T-wave inversions, cardiac contractility, and others that we'll be looking at as part of this study. We're in an ongoing phase I/II study associated with the disease. We have a cohort one that's treating patients at 2 E 13 vector genomes per kilogram, and the cohort two, treating patients at 6 E 13 vector genomes per kilogram. I mentioned the endpoints we're evaluating as part of the study. Obviously, it's a safety study as a phase I, but we're looking at other measures of arrhythmia, frataxin expression and other MRI and echo measures that I think will be relevant for the disease.
So last but not least, is our APOE4 homozygous Alzheimer's disease program. You know, for just some short background on this program, E4 is the gene that's most associated with the early and most severe onset of Alzheimer's disease. E4s have a fifteen times higher likelihood of developing the disease than other genotypes associated with APOE, and this is fifteen times higher than normal, which is APOE3. But interestingly, APOE2s have the lowest risk of developing the disease if they develop it at all within their lifetime. So our therapeutic approach is simple: we're delivering the APOE2 gene to the CNS of APOE4 homozygotes, thereby seeking to alter their CNS to become closer to E2, E4 heterozygotes. And despite the approval of Alzheimer's treatments, substantial unmet need remains within the APOE4 patient population.
As you can see, both lecanemab and donanemab did not see statistically significant improvement in efficacy versus the untreated groups, but they had a much higher risk of ARIA, which is the brain swelling disease, than the other APOE genotypes. For example, with donanemab, 40% of the patients had incidents of ARIA. This means almost half of the population there, which means that, you know, one could argue that the risk-benefit for an APOE4 being treated with an amyloid antibody is questionable, and therefore, the unmet need remains within this population. Our therapy is focused on treating the APOE4 homozygote population today. This is the design of the clinical trial. It was four cohorts. The trial has been fully enrolled. It's a dose escalation study, so about three patients per dose.
We've completed enrollment across the study, and this is the data readout we're working towards in Q4 of this year. We're looking at both safety as part of this study, but also other biomarkers that are commonly associated with Alzheimer's disease. So CSF biomarkers are amyloid beta 42, tau, and phospho-tau. We're also looking at amyloid and tau PET scans, and some other biomarkers commonly associated with Alzheimer's disease. So the readout we're working towards will be a read on safety, but also the ability of this gene therapy to fundamentally impact some of the biomarkers that are commonly associated with the disease. Amyloid, tau, and phospho-tau are the key ones that are commonly evaluated as in a study of this profile.
This is a fifteen-patient study, so it's not powered to show an improvement in cognitive decline, but we will report cognitive decline data for the patients in the clinical trial. This was the data that was presented at CTAD in 2022 for the patients that had reached twelve months at that point in time, and you can see across these first three patients that have reached twelve months, we saw reductions in amyloid across those three patients shown. We also saw reductions in phospho-tau for the patients that have reached twelve months.
You can see across three different independent endpoints, we've shown a reduction in CSF for these key biomarkers. The data we'll be reporting at the end of the year will have the same biomarkers across all the patients in the study that have reached either six and twelve months. With that, I'll conclude. We have about a minute left here just with what's upcoming for Lexeo. I described the FA data readout. We're working on an update on regulatory engagements by the end of the year. For the plakophilin-2 arrhythmogenic cardiomyopathy program, we're expecting to have data read out in the coming few months. We're still looking for the appropriate venue in which to present that data.
For the APOE4 program, we're working towards a data readout at likely the CTAD conference this year. And for the desmoplakin cardiomyopathy program, we're looking to initiate IND-enabling studies shortly. We have a cash runway into 2027 with about $175 million of cash. So with that, we probably have a minute or two for a question, if there are any, and if not, we'll conclude here.
Yeah. So unfortunately, we are out of time for questions. But Nolan and his team will be around, so if you would like to ask him questions, I'm sure they'll be happy to talk with you. Otherwise, there is also the form online where you can ask questions. Thank you so much, Nolan, and have a good rest of your day.
Thanks for having us. Appreciate it.