Okay, let's go ahead and get started. My name is Chris Raymond. I am one of the senior biotech analysts here at Piper Sandler. It's my pleasure to introduce our next presenting company, which is Lexeo Therapeutics. I have with me Nolan Townsend, who is the CEO. So maybe just to kind of go through the format here, I think folks generally should know the drill here. This is a fireside chat. It's meant to be very informal. So if there's a question in the audience, please raise your hand. I'll make sure it gets asked and answered. So thanks for being here, Nolan.
Maybe just before we dive into Q&A, if you could, for folks who may not be familiar with the Lexeo story, walk us through sort of the setup and the premise and the investment thesis and a little bit of what you guys are working on, and then we'll jump into questions.
Sure, so first, thanks for having us, so Lexeo is a clinical stage gene therapy company focused in genetic cardiovascular diseases and a gene variant associated with Alzheimer's disease. We have three clinical stage programs, two focused in the genetic cardiovascular space, the most advanced of which is treating the cardiac pathology of Friedreich's ataxia. This program has read out interim data at mid-year, advancing towards other meaningful clinical milestones in the future years, and I'm sure we'll spend some time talking about it, but we're focused there on the cardiac pathology of the disease, which is the cause of death for 70% of the Friedreich's ataxia patients, so while many may know it as a neurologic disease, it can really only impact mortality and FA by treating the cardiac component of the disease, which is where our gene therapy candidate is focused.
Our next most advanced cardiac program is treating arrhythmogenic cardiomyopathy. And here we're focused on the PKP2 mutation, which represents a population of about 60,000 patients in the U.S., making this one of the largest targets for cardioskeletal gene therapy today. This program is also clinical stage. We've reported completion of enrollment of the first cohort of patients. And we're working towards a data readout of that first cohort by the end of Q1 or beginning of Q2 of next year. So we have a pretty robust pipeline of cardiac gene therapies, all with material data readouts in 2025. We really think this is the tip of the iceberg for the opportunity set in cardiac genetic medicines. And these are really compelling proof of concepts. Each opportunity is compelling in its own way, but also the proof of concept that it represents is important for the field.
On the CNS side of the house, we have a clinical stage program that's read out data in Q4 of this year. We're treating APOE4 homozygous Alzheimer's disease with the APOE2 gene. This readout demonstrated an improvement in certain biomarkers that are correlated to the disease. And we're looking forward to the next steps for that program as well. So in total, the three programs represent the bulk of the focus of Lexeo. But we also have some preclinical programs, which we may not get time to discuss today, but also represent either continuations of an existing treatment approach or new strategies focused on certain cardiac genetic diseases.
Awesome. Okay, so lots going on, lots to jump into. Maybe before we talk about specific programs, I wanted to ask a little bit about the state of the art, if you will, in AAV gene therapy. We've been following the space, Nolan, for a long time, and we've seen a decent amount of success, also some challenges, actually, in the space, and maybe more topical or recent has been commercial challenges of some of these therapies. So I guess a pretty tried and true belief is that if you're adding clinical value, the therapy is going to get used. There's obviously some nuances to that, but just maybe give us a sort of sense of your take on the field, Lexeo's approach, especially when it comes to your specific constructs and the vector that you're using, and why you are so confident.
Yeah, so you mentioned commercial. I'll start there and then talk about some of the clinical side of that question. So, first, I think commercially, there have been commercial successes in gene therapy. I would point to Zolgensma. I think there's an expectation that Sarepta's Duchenne muscular dystrophy gene therapy will also be a commercial success. There's a common theme across those two treatments in that they're focused on a disease of very high unmet need. That either doesn't have an existing treatment or the existing treatment is sort of insufficient relative to the nature of the disease that it's treating. That's different and apart from some of the treatments, for example, in the hemophilia space, where there's a dozen or more treatments that exist in that disease.
The increment of what a gene therapy may provide would be nominal from either efficacy, safety, or just ease of use perspective. If you focus on the types of diseases that have high unmet need, no existing treatment ahead of them, that have been commercial successes, this is exactly the type of pipeline we've constructed at Lexeo. We're focused on the cardiac pathology of Friedreich's ataxia. There's no treatment for this disease. We're focused on arrhythmogenic cardiomyopathy. There's no commercially approved treatment for this disease either. The same is the case for the rest of the pipeline that we're advancing at the company. I think commercially, our pipeline fits with the model of the gene therapies that have been or are expected to be commercial successes. That's why we're confident in that picture from a gene therapy perspective with our particular pipeline.
So let's.
Oh, go ahead. Sorry.
No, please. Oh, okay. So maybe let's talk about 2006, your FA program. So you have a vector that has shown a tropism, a greater tropism to the heart. Maybe just talk about your discovery, your development of this capsid as it relates to cardiac gene therapy. Would seem to make a ton of sense to have a vector that wants to go to the heart.
Yeah, so at the outset, we did a lot of work to evaluate the cardiac tropism profile of various capsids. We know that the field had coalesced around AAV9 as a capsid that was being utilized for cardiac disease, but the early work we did was to validate which capsid actually is most efficient to deliver to the heart, and that work led us to AAVrh.10 as the capsid, which was demonstrating the most compelling cardiac tropism profile, and we validated this through several different studies. One was a non-human primate study, a study in porcine models. We've also done this in several small animal disease models, and pretty consistently, we saw this picture of 1.5 to 2x greater biodistribution when treating these different animals with AAVrh.10 relative to other commonly used vectors. What we've begun to see here clinically is also that translating as well in our FA study.
We're seeing a very compelling cardiac tropism profile in that program. And we're also using the same serotype for our Plakophilin-2 program. So there's a good read-through effect across them. So I think we're seeing a good preclinical to clinical translation in terms of the cardiac tropism. And it's the capsid that we believe will allow us to treat these diseases safely, therefore, let's say at a lower dose for systemic gene therapy than one would expect, and do so in a way that we can deliver efficacious therapy to patients.
Okay, so let's talk a little bit about Friedreich's ataxia. So we cover Biogen, which obviously has Skyclarys. It's the only approved therapy for FA. Yours, obviously, it treats specifically FA-associated cardiomyopathy. Maybe just give us an overview, I guess. We know a little bit, maybe enough to be dangerous somewhat on FA. But specifically, maybe talk about the burden of cardiomyopathy in FA.
Yeah. So FA is a mitochondrial disease. Deficiency of the frataxin is the cause of the disease. This leads to mitochondrial dysfunction and deficiency in energy production, the two organs that are the most impacted by the disease, therefore the two that require the most energy, so the brain and the heart. The way this disease presents from a cardiac perspective is with cardiac hypertrophy, which is thickening of the heart wall. And this progressive hypertrophy leads to cardiomyopathy and therefore leads to heart failure if untreated. The neurologic disease, as you rightly pointed out, presents earlier for the patients. So this is childhood patients that are five, eight years old. They typically progress until this cardiomyopathy emerges, most typically in adulthood. So the shortened life expectancy associated with Friedreich's ataxia is typically related to the cardiac disease.
At roughly 70% of the patients, their cause of death is the cardiac disease. You can really only impact mortality in FA by addressing the cardiac component of the disease. Now, we look at the treatment of Skyclarys, which I think was a major step forward in the treatment landscape for Friedreich's ataxia patients in that it does have an impact on the neurologic disease. For some of these patients, it comes along with a negative side effect of an increase in NT-proBNP. It could be that that therapy is even potentially worsening the cardiac disease. We think that this makes the unmet need greater than ever for patients with Friedreich's ataxia in terms of treating the cardiac disease, that there is a neurologic treatment. Presumably, this is slowing the rate of decline of the neurologic disease in many of these patients.
But I think the focus would turn to how can they live longer? How can you improve the cause of mortality in this disease? And this is what this gene therapy is focused on doing, is by delivering frataxin to the heart, expressing the functional protein. And that functional protein should impact the hypertrophy of the disease and ultimately be in a position to impact mortality associated with FA.
Okay, so there's two studies ongoing. There's the Lexeo-sponsored SUNRISE- FA, and then there's an investigator-initiated study, I think, at Weill Cornell, an investigator there, is running it. Just by our take, these are relatively similar trials. Maybe just talk about the reason for the two separate trials and how you plan to leverage the data.
Yeah, so the Cornell-sponsored study is our scientific founder, Ron Crystal, running it out of his lab. Ron's had over a decade of experience in Friedreich's ataxia, both from a basic science perspective but also in clinical research. Ron was able to access a large NIH grant, which was non-dilutive funding, that allowed us to evaluate this clinical candidate in just a broader number of patients. So, in total, across the two studies, it's the same drug product that we're using in both. We have a total of 16 patients enrolled, for which we have access to data for all of them. We've been able to utilize the data from the Cornell study in our regulatory conversations as well. The only difference in the two studies is that the Lexeo study has included cardiac biopsies in it. So, we're actually evaluating for frataxin expression in tissue from the heart itself.
The Cornell study does not have that endpoint in it. The other endpoints are common to the two studies. We're looking at cardiac MRI. This is left ventricular mass index, wall thickness, blood-based biomarker called troponin. Those biomarkers and readouts are common to both studies and are part of the readout that we presented earlier in the year and will be part of future readouts as well.
Okay, great. And so as with most gene therapy trials, you have to screen for pre-existing neutralizing antibodies. How often are patients excluded, I guess, based on having too high antibody titers? And maybe sort of how do we think about this from a market standpoint? And what % of patients would ultimately be ineligible?
Yeah, I think the neutralizing antibodies associated with AAVrh.10 are no different than they are for the other serotypes. So we're looking in that similar range to what you would see with AAV8 or AAV9 in the, call it, 15% range or thereabouts. So that's the presumed cut that I would take from a commercial standpoint for neutralizing antibodies is that same range that you would expect to see with the other serotypes.
Okay, so you had data in June. I'm sorry, it was July, actually, with I think it was eight patients total from the two trials. Safety looked good. No treatment-related SAEs. No signs of immunogenicity. I think it was updated. Maybe one patient had grade 2 asymptomatic myocarditis. I'm not sure if that was related to treatment. This seems pretty good for an AAV therapy. So just maybe so far, so good, I guess. So if you would attribute to the design of the vector, is it the capsid? Is it the dose? Or all of the above that sort of I'm not asking you to wave the victory flag just yet, but just how you feel about it.
Yeah, and we provided a safety update very recently within the quarter, which gave a safety update that's encompassing all the patients that have been enrolled in the study. This is a total of 16 that represents the safety profile. But what I would say is it's likely related to the dose. The dose that we're using is in the 10^11 to 10^12 vector genomes per kilogram range. As you'd be aware, this is two logs lower than where you typically would expect to see safety events in systemic gene therapy. So that's why I believe we have the safety profile that you just described. And we're also using prophylactic immune suppression, prednisone, for patients in the study. So that's where I would attribute the safety profile to. And interestingly, at that safety profile, we're getting what we feel are very compelling efficacy results.
We're reducing left ventricular mass at a level beyond what we believe is clinically relevant for the disease at 11%. In the patients that we presented in July, we've seen about a 50% reduction in troponin, which is a measure of cardiac cell death. We've also seen a 14% reduction in lateral wall thickness. So three different independent endpoints. Two are MRI-based. One's a blood-based biomarker where we're demonstrating efficacy that clears a clinical significance bar. And we're doing so with the safety profile you mentioned. So you're right. I think from that perspective, we think the profile and balance there in terms of efficacy and safety is a very compelling one.
Yeah, so you mentioned a lot of measures you got with a relatively small number of patients. Pretty impressive. So it looks like it's working. If you were to pick maybe one of, and this is maybe not a fair question, but sometimes all of these in totality are really what's the most impressive. But is there any one particular measure here that you think physicians are most focused on or will be when ultimately you have a label?
Yeah, I think for cardiologists, especially those that work in heart failure and deal with hypertrophic cardiomyopathy, MRI measures that evaluate hypertrophy are probably the most relevant for them. The most prominent one, I think, is left ventricular mass index. This is a measure commonly used in cardiac practice. This is also the measure that we've reached alignment with the FDA, will be one of the co-primary endpoints in the pivotal study for this therapy. So that's the one that I would choose that I would say both would resonate with cardiologists, but also will be one of the co-primary endpoints for the pivotal study for this therapy. So that's probably the if we said we had to focus on one, that would probably be the best one to focus on now.
Got it, and you've just finished enrollment, I think, at the highest dose, right, in SUNRISE- FA.
Right.
Not asking you to set a bar here, but how should investors be thinking about once we ultimately have the data from that cohort?
Yeah, so I would look at it as the likelihood of achieving the thresholds that are relevant for the future pivotal study in this disease. And so the thresholds and the endpoints we've aligned on with the FDA, and this is part of an update we gave a couple of weeks back, is a 10% improvement and 10% reduction in left ventricular mass index. There's one co-primary endpoint in the threshold. And on the frataxin side, frataxin expression via immunohistochemistry assay of 40%. So that 40% is a proxy for percent of cells transduced or coverage of the vector in that tissue sample. So if I look at the data to date and the data that we reported in July, we achieved an 11.4% reduction in left ventricular mass index. And this is relative to the 10% threshold that I described earlier.
On the frataxin side via IHC, we're at an average of a 44% IHC staining level of frataxin relative to the 40% bar that I described, the alignment we reached with the FDA. So as we look forward to the future data, I think we would like to see that we maintain an efficacy profile that exceeds those thresholds. And that's the goal of the future dose and all the existing data that we'll present at a future time point is to demonstrate that we continue to exceed those thresholds. And I think that should give investors confidence that this therapy is already achieving the efficacy profile that will be needed for an accelerated approval of the therapy, therefore giving confidence that such a study would have a likelihood of success when completed.
Without having your high-dose data.
Without having the high-dose data. So the point you're making, the high dose just needs to not be worse than the lower doses.
Yeah, yeah.
Correct.
So I think you're, as we understand it, it sounds like you're waiting for the cardiac biopsies, right, from the high-dose cohort before the dose selection?
That's correct.
Have you disclosed or talked about the timing for when that will be in? And I know that you've gained alignment with the FDA on the endpoints, but that seems to be a gating, I guess, or one of the gating factors.
Yeah, the dose selection will be focused on the biopsies. As you rightly mentioned, at the cohort three, biopsies will be an important part of that discussion. We completed enrollment of the high-dose cohort of the study in Q4. So we'll have the biopsies in the first half of next year. We're not guiding yet on the timing of the data readout associated with cohort three. I think that's forthcoming guidance. But I'd say it's not in the distant future in 2025.
Okay. Okay, your other clinical program or the next one in line, I guess, is the LX2020, which is for ACM. So you're specifically targeting ACM patients with mutations in the PKP2 gene. Maybe just give us a background on the disease and the Lexeo approach here to treating it?
Yeah, first, I just would reiterate the size of the disease. This is 60,000 patients in the U.S. It's more than twice the size of Duchenne's muscular dystrophy, making it a very impactful disease both for patients but also the healthcare system in general. This is the disease that presents with life-threatening arrhythmias, typically. And the biology of the disease is that the lack of plakophilin-2 protein leads to desmosomal disintegrity. The desmosomes sort of separate, and they become islands. And this is sort of the driver behind the pathology of the disease in terms of causing arrhythmias. The therapeutic approach is relatively straightforward. We're expressing the plakophilin-2 gene. This is restoring desmosomal integrity and therefore reducing the life-threatening arrhythmias. There's another important biomarker that's a good surrogate endpoint for the disease, which is the name premature ventricular contractions.
These are typically extra heartbeats that patients will experience, and they can be precursors to these sudden arrhythmic events. So this is something that can be observed non-invasively. It's also something that can be evaluated in preclinical studies. So in our murine studies, we were able to both dramatically increase survival of the mice that were in the study, but we also suppressed the premature ventricular contractions with this therapy. So from a biologic standpoint, the preclinical models are pretty resounding. And the only question now is, do we see the same translation into the clinic? Our data readout that we're focused on at the end of Q1 or beginning of Q2 is really focused on protein expression. So what level of protein expression are we achieving via these cardiac biopsies and also evaluating the safety profile of the therapy?
So as we understand it, PKP2 is the most common mutation in ACM?
Yes, that's right.
So it would seem to be obvious that going after the most common mutation, but is there a read-through, I guess, if you establish proof of concept for going after some other ACM mutation to drive ACM?
Yeah, I think there could be. We have a program in our pipeline focused on desmoplakin-mediated cardiomyopathy preclinically, and this also presents with arrhythmia as well, so I think we've demonstrated via the FA program that adding what is a relatively small amount of frataxin can meaningfully reduce cardiac hypertrophy, so this is a demonstration of a proof of concept of AAV gene therapy and hypertrophic cardiomyopathy. I think the ACM program would be a proof of concept in treating arrhythmogenic disease with gene therapy, and therefore, other arrhythmogenic diseases like desmoplakin-mediated cardiomyopathy could be opportunity sets, but I would say on its own, this is a pretty substantial opportunity. I think the type of disease that, as it presents, represents a very significant treatment burden. Many of these patients go on to receive cardiac transplants, so obviously, the cost of the healthcare system is meaningful.
Obviously, the patient burden of that is also meaningful. So to the extent we can advance treatment for these patients and do so in a meaningful way, we think that could have a big impact on the broader cardiac treatment landscape.
Okay, so you're running a phase 1-2. It's called HEROIC- PKP2. I think you're working with two dose levels. Just talk about the setup and the timing. It looks like you're expecting data early 2025. Just give us the setup and what to expect.
So it's a two classic dose escalation study. There's a 2E13 vector genomes per kilogram dose, which we've completed enrollment of. We're moving now to the second dose cohort, which is 6E13 vector genomes per kilogram. There's a third dose cohort, an expansion cohort at the chosen dose between the two. The first readout will again be focused on biodistribution and safety. The biodistribution will be plakophilin expression via cardiac biopsies that we're taking. We'll be collecting other efficacy measures, but I would say three months is early to expect to see any impact on efficacy-related endpoints. And so the focus there really will be on biodistribution and understanding both the pretreatment baseline levels of these patients, but also the plakophilin expression that the 2E13 dose is able to achieve.
Over the longer term, I think we will be looking at certain endpoints like premature ventricular contractions, T-wave inversions, QRS interval, endpoints that are highly relevant for the disease and relevant for the cardiac treatment landscape as well.
Okay, and I'm giving this last program short shrift because we only have about a minute. But we're really intrigued by your Alzheimer's program targeting APOE4. I think a lot of folks are familiar with that given the issues associated with amyloid targeting agents. But maybe just talk about the setup. And I know it sounds like you're fully enrolled in your phase 1-2 trial. And these have a 52-week follow-up. So just talk about the unmet need here and really there's a massive void, obviously, but the setup and the premise behind this program.
Yeah, so the data that we presented at the CTAD conference back, I think it was last month, demonstrated an ability that this therapy could reduce Tau via several different measures of Tau at a level that was similar to many of the commercially approved therapies, but do so without any instances of ARIA, which is the brain swelling disease, a serious side effect associated with those therapies. So I think we understand that APOE4s have a higher side effect risk when treated with amyloid antibodies. It seems that there needs to be a different therapeutic approach for those patients.
We would suggest that this treatment focused on APOE4s and an alternate treatment approach could be one of the solutions for this population, given that we're able to impact Tau at a similar level to some of the commercially approved therapies, but then we do so without that serious side effect of ARIA. So I think more to come on this one. We're certainly thinking about the next steps of the program. It's likely that we take it forward alongside a partner because the opportunity set is large and capital-intensive. But I think the early data suggests that we can impact Tau and certainly can do so within the moderate patients, which are the ones that have the highest unmet need in that population.
Okay, excellent. Well, lots of important data coming in the next year. We're unfortunately out of time, though. But thank you for your time.
All right, thank you so much. Appreciate it.