Hello, everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at H.C. Wainwright. I'd like to welcome you to our Genetic Medicines Conference. Today I have the pleasure of having Lexeo Therapeutics with us. From the company, I have R. Nolan Townsend, the CEO, and Dr. Eric Adler, the CSO. Gentlemen, thank you for joining us today.
Thank you for having us. It's great to be here.
Maybe to start off, you could just give us a little bit of an update on where Lexeo is at today, the key initiatives, but most importantly, the recent update that you all shared that may frame the first half at least of the discussion.
Sure. I'll spend a few minutes, just in general, giving some background on Lexeo and then talking about the Friedreich's ataxia program update. Lexeo is a cardiac genetic medicines company. Our most advanced programs are AAV gene therapy mediated drug treatments for Friedreich's ataxia and arrhythmogenic cardiomyopathy. Both are clinical stage programs. The Friedreich's ataxia program, we've completed enrollment of our Phase 1/2 study and we're moving rapidly to a registrational study next year. Our arrhythmogenic cardiomyopathy program is not that far behind that, where we intend to complete enrollment of the Phase 1/2 study this year. We'll be thinking about next steps for that program in 2026 and beyond. From the perspective of our lead asset in FA, we had a recent update of both clinical data showing significant improvements in certain endpoints that are important for the cardiovascular disease associated with Friedreich's ataxia.
We also showed improvement on the neurologic scale that is typically used to evaluate progression of Friedreich's ataxia. We're really excited about these developments in the program, obviously representing what we believe is a very compelling product profile that's impacting both the cause of death in this disease, which is cardiomyopathy, but also impacting the other aspect of the disease that's very challenging for patients, which is this progressive decline in neurologic function. We'll spend some time probably talking about that data. Associated with that, we have reached an agreement with the FDA on an expedited path to an accelerated approval. Part of this agreement includes pooling of our Phase 1/2 data.
From our earlier.
Study with data from a pivotal study in order to support a BLA in this indication. This represents a more accelerated path versus what we previously guided. The FDA also showed an openness to evaluating the endpoints earlier than 12 months of follow up, which will likely lead to a shorter length study from a pivotal perspective. These are both, in our view, positive developments on the regulatory front. I think it represents the FDA trying to collaborate with us to find a way to get this therapy to patients faster. This all comes on the back of the breakthrough therapy designation that we achieved for this therapy earlier this year. I think things are moving rapidly and we're seeing a very supportive FDA and a very compelling product profile emerging in this disease.
Sorry, I was on mute. Thank you. That was a wonderful overview and set the stage for the discussion. I wanted to jump into the trial. Pivotal will enroll abnormal LVMI patients, which I think you all mentioned is around 40% of FA cardiomyopathy with LVMI and Fritaxon as the co-primaries. Can you talk a little bit more about the design, how many patients are planned, and how did the FDA feedback shape the powering assumptions around the 10% LVMI reduction target or anything else you can share on how those discussions went?
I'll say one word and then I'll maybe pass it to Eric. We can't guide yet on the size of the pivotal study. We can just more talk in generalities about some of the considerations. Maybe I'll pass it to Eric just to speak to that.
Yeah, yeah. To clarify, we're powering this study to detect a 10% reduction in ejection fraction—I mean in LV mass. The rationale for doing that, that the FDA understood and agrees to, is across cardiomyopathy, increasing LV mass is a sign of progression of disease, certainly across hypertrophic cardiomyopathies and hypertrophic cardiomyopathy phenocopies. If you look at—now switch gears and look at FA specifically—if you have a 10% increase in your LV mass indexed to your body size, you have a 20% increased risk of death. In recognition of that, and using a tool like MRI, which is very precise, we powered a study to detect that 10% difference because that's meaningful for patients and for providers to lower their mortality and certainly for regulators and obviously the commercial program as well.
Across the board, this number is important that we can deliver a medicine that improves the lives of our patients. That's how the study works backwards from there.
Can you remind us from the data we've seen today how many are already hitting that threshold to kind of set the stage for what the data look like today and how achievable that is?
Thankfully you're talking about the patients. Let me recap. The patients with elevated LVMI in our Phase 1 studies had a reduction far beyond the 10%, closer to 20%, 25% at six months, even getting above 10%. What you see is that we're above this threshold. We saw some patients that had 50% reduction, another patient with 35% reduction. These dramatic decreases in LV mass and, a little off topic, but for someone in gene therapy for 15 years or so, it reminds you the power of precision medicine. You never see 50% reduction in LV mass. You have to, you wipe your eyes twice when you see something like that in clinic. It's only when we develop this next generation of therapies that we can deliver to patient where you treat the root cause of disease that you can talk about things, about curing, dramatically changing the disease. Dramatic.
That's like a transplant, right, to get a 50% reduction in the weight of your heart. It's really amazing to be part of that program and see, in our patients with the heaviest hearts in our Cohort 2, we saw a patient go from 110 to 54, in terms of grams per meter squared of heart rate, that is, and that's over multiple measurements, you see these dramatic reductions. Confirmed. Very exciting to see.
The other thing I'd add on top of that, in addition to the reductions, these six patients that started with abnormal LVMI, all of them moved into the normal range. This represents the hallmark of this disease, which is hypertrophy, thickening of the heart wall. We've nor.
Hello, everyone. My name is Mitchell Kapoor. I'm a Senior Biotech Analyst at H.C. Wainwright. I'd like to welcome you to our Genetic Medicines Conference. Today I have the pleasure of having Lexeo Therapeutics with us. From the company, I have R. Nolan Townsend, the CEO, and Dr. Eric Adler, the CSO. Gentlemen, thank you for joining us today.
Thank you for having us. It's great to be here.
Maybe to start off, you could just give us a little bit of an update on where Lexeo is at today, the key initiatives, but most importantly, the recent update that you all shared that may frame the first half at least of the discussion.
Sure. I'll spend a few minutes, just in general, giving some background on Lexeo and then talking about the Friedreich's ataxia program update. Lexeo is a cardiac genetic medicines company. Our most advanced programs are AAV gene therapy mediated treatments for Friedreich's ataxia and arrhythmogenic cardiomyopathy. Both are clinical stage programs. The Friedreich's ataxia program, we've completed enrollment of our Phase 1/2 study and we're moving rapidly to a registrational study next year. Our arrhythmogenic cardiomyopathy program is not that far behind that, where we intend to complete enrollment of the Phase 1/2 study this year. We'll be thinking about next steps for that program in 2026 and beyond. From the perspective of our lead asset in FA, we had a recent update of both clinical data showing significant improvements in certain endpoints that are important for the cardiovascular disease associated with Friedreich's ataxia.
We also showed improvement on the neurologic scale that is typically used to evaluate progression of Friedreich's ataxia. We're really excited about these developments in the program, obviously representing what we believe is a very compelling product profile that's impacting both the cause of death in this disease, which is cardiomyopathy, but also impacting the other aspect of the disease that's very challenging for patients, which is this progressive decline in neurologic function. We'll spend some time probably talking about that data. Associated with that, we have reached an agreement with the U.S. Food and Drug Administration on an expedited path to an accelerated approval. Part of this agreement includes pooling of our Phase 1/2 data from our earlier study with data from the pivotal study in order to support a BLA in this indication. This represents a more accelerated path versus what we previously guided.
The FDA also showed an openness to evaluating the endpoints earlier than 12 months of follow up. It will likely lead to a shorter length study from a pivotal perspective. These are both, in our view, positive developments on the regulatory front. I think it represents the FDA trying to collaborate with us to find a way to get this therapy to patients faster. This all comes on the back of the breakthrough therapy designation that we achieved for this therapy earlier this year. I think things are moving rapidly and we're seeing a very supportive FDA and a very compelling product profile emerging in this disease.
Sorry, I was on mute. Thank you. That was a wonderful overview and set the stage for the discussion. Wanted to jump into the trial. The pivotal will enroll abnormal LVMI patients, which I think you all mentioned is around 40% of Friedreich’s ataxia cardiomyopathy with LVMI and mFARS as the co-primaries. Can you talk a little bit more about the design, how many patients are planned, and how did the FDA feedback shape the powering assumptions around the 10% LVMI reduction target or anything else you can share on how those discussions went?
I'll say one word and then I'll maybe pass it to Eric. We can't guide yet on the size of the pivotal study. We can just more talk in generalities about some of the considerations. Maybe I'll pass it to Eric just to speak to that.
Yeah, yeah. To clarify, we're powering this study to detect a 10% reduction in ejection fraction, I mean, in LV mass. The rationale for doing that, that the FDA understood and agrees to, is across cardiomyopathy, increasing LV mass is a sign of progression of disease, certainly across hypertrophic cardiomyopathies and hypertrophic cardiomyopathy phenocopies. If you look at, now switch gears and look at Friedreich’s ataxia specifically, if you have a 10% increase in your left ventricular mass index to your body size, you have a 20% increased risk of death. In recognition of that, and using a tool like MRI, which is very precise, we powered a study to detect that 10% difference because that's meaningful for patients and for providers to lower their mortality and certainly for regulators and obviously the commercial program as well.
Across the board, this number is important that we can deliver a medicine that improves the lives of our patients. That's how the study works backwards from there.
Can you remind us from the data we've seen today, how many are already hitting that threshold to kind of set the stage for what the data look like today and how achievable that is?
Yeah, thankfully you're talking about the patients. Let me recap. The patients with elevated LVMI in our Phase 1 studies had a reduction far beyond the 10%, closer to 20%, 25% at six months, even getting above 10%. What you see is that we're above this threshold. We saw some patients that had 50% reduction, another patient with 35% reduction. These dramatic decreases in LV mass and, a little off topic, but for someone in gene therapy for 15 years or so, remind you the power of precision medicine. You never see 50% reduction LV mass. You have to, you wipe your eyes twice when you see something like that in clinic. It's only when we develop this next generation of therapies that we can deliver to patient where you treat the root cause of disease that you can talk about things about curing, dramatically changing the disease.
That's like a transplant, right, to get a 50% reduction in the weight of your heart. It's really amazing to be part of that program and see, in our patients with the heaviest hearts in our Cohort 2, we saw a patient go from 110 to 54, in terms of grams per meter squared of heart rate, that is, and that's over multiple measurements, you see these dramatic reductions. Confirmed. Very exciting to see.
The other thing I'd add on top of that, in addition to the reductions, these six patients that started with abnormal LVMI, all of them moved into the normal range. This represents the hallmark of this disease is hypertrophy, thickening of the heart wall. We've normalized the cardiac hypertrophy. I think that's a very important milestone to have achieved in this group to have all of the patients achieve not only the degree of reduction that Eric described, but also normalization of their, you know, of their heart mass.
Right, absolutely. We find obviously that that's a significant risk mitigating feature as you all move forward, and with such dramatic reductions that you all have seen, this is probably not a problem. I wanted to kind of just understand a little bit more about maintaining MRI consistency across different sites and how that looks so investors can understand, you know, from a site to site basis, how you can ensure reproducibility of standardization.
In the registrational study, we're using a central reader core lab. In the Phase 1/2 study, there's two different sites that are reading the scans, but we've had them over read in a single place. I think consistent with how I think studies, registration studies are run, we're using a single reader or single site to do that.
Okay, great. You've begun enrolling this natural history study that serves as the external comparator here. How do you ensure demographic and baseline LVMI balance between clarity and the treatment arm so that this is the best design for regulators?
Eric, do you want to speak to that one?
You're referring to how we design the pivotal trial, is that right? Just to clarify.
Exactly.
Yeah. I think, you know, obviously, this is.
This.
This is work. We haven't presented our finalized statistical plan yet, so I want to clarify that. That being said, we believe the best way is to propensity match a study. That way you have a natural history arm with patients that are equally, equally matched, and you over enroll in a natural history study. I don't know if you have any other comments, Nolan.
Oh, yeah, sorry. Yeah, yeah.
We're conducting propensity matching. The inclusion criteria is identical. We'll be enrolling patients for the treatment study from the same sites as the prospective natural history study. These are some of the steps we're taking to ensure comparability across the two as well.
I mean, one thing I want to mention, and no one jump in here, but I think something that our cardiology experts recognize is that if you look across cardiomyopathy, LV mass does not change, is not subject to a placebo effect. Your heart, you know, if you look across the HCM trials of myosin inhibitors, et cetera, decades, and you look in the tabs and you look at LV mass, which isn't always a primary endpoint, what you will notice is, like, no impact of placebo. We're taking advantage of that because the natural history of this disease and, frankly, all of these genetic cardiomyopathies, the hearts continue to get heavier and heavier until they reach this kind of end stage of disease in which then the hearts start to fibrose and at that point dilate.
We're avoiding those patients by not enrolling patients with low ejection fraction and high BNP's, end stage patients. We're far from that. Any effect on LVMI is assumed to be a drug effect because, you know, the natural history study is robust. Hearts, again, without a change in treatment, just don't spontaneously start to get better in these genetic diseases.
Great. Okay. While it's relatively early, can you describe kind of these roles between frataxin expression and ongoing cardiac remodeling for patients and what you think the contribution of each would be? If there's anything we're seeing now that we can kind of attribute to either.
I'm trying to understand this. Let me try to answer your question. If I didn't answer it, let me know. I think that FA cardiomyopathy is unique. It's among a class of what I would call mitochondrial cardiomyopathies, where because of the lack of frataxin, you have mitochondrial dysfunction because frataxin is critical for mitochondrial function, which, remember, is the engine of the cell. When you don't have enough frataxin, your mitochondria don't produce enough oxygen. What they end up doing is they start replicating. The weight of the heart in FA is at least partially, if not significantly, contributed to just simply the number of mitochondria. You start expanding these even in you and I; the weight of our heart is like a quarter or a third just mitochondria, which is hard to imagine, but it's such an energy-consuming organ.
In FA that goes up because the mitochondria are trying to compensate, right? It's like, oh, we don't have enough oxygen, so make more mitochondria. By giving more frataxin, you're restoring the ability of mitochondria to work and turning off that trigger for mitochondria's hyperplasia. That's what we think. Obviously, this is based on preclinical work and studies and somewhat hypothesizing that leads to the decrease in LVMI, is this reduction in mitochondrial content within the cell. You also see some decrease in sarcomere content as well because as the hearts start to work better, you don't need to have heavier, have more sarcomeres, you know, the contractile unit of the heart. We think there's a direct relationship between frataxin that plays itself out in natural history studies when you look at the number of repeats, GA repeats, and the weight of the heart, which are inversely correlated.
The less frataxin you have, and the surrogate for that is GA repeats, the heavier your heart as well. All those hypotheses line up for more frataxin, less heavy heart.
Okay, I think what I'm trying to get at is I wonder a little bit about transgene expression versus permanent cardiac remodeling long term. Are we thinking about the durability of the transgene expression, or are you seeing signs of cardiac remodeling that says, hey, even if five, six years down the line, transgene expression, I think.
In a non-dividing cell, the evidence across in gene therapy is the robustness of gene expression over time. If you look at other cardiac gene therapy programs, biopsies, five, six years out, you're still detecting things. If you're looking at, you know, SMA, obviously that's a neurologic condition and not a cardiac condition, but again, not a post-mitotic cell. What you see is durable gene expression. I suspect that the gains we're seeing are from durable expression. We certainly are seeing that at a year out and expect to see that ongoing. There may be some reduction in fibrosis and things as well. That's additive benefit, but I think it's primarily the continuous expression of frataxin.
Okay, very helpful. With the potential for accelerated approval filing based on these surrogate endpoints, thinking about what a full approval could look like, can you talk about the role of mFARS and KCCQ, how we should think about that as data evolves? Also, any feedback from regulators you've had on those two endpoints as they relate to maintaining approval.
Maybe I'll let Nolan start with his take on it, and then I'll add regarding mFARS. Nolan.
Yeah. I think what's interesting about the profile of how this therapy is evolving is it is treating both components of Friedreich's ataxia that are relevant. We talked a lot about cardiac and the benefit we're seeing there, normalization of the hypertrophy picture, reduction in troponin and so on. The other side of the disease is this progressive neurologic decline. To see a 1 to 2 point improvement in the modified Friedreich’s Ataxia Rating Scale is roughly similar to the degree of benefit that the commercially approved treatment for Friedreich's ataxia achieved in their registrational study. We broke up the data not only in aggregate, but also at a patient level where you can see that we appear to be having a more significant improvement in mFARS at our higher doses.
We intend to take the highest dose evaluated in our Phase 1 forward into the pivotal study and into commercialization. Patients should benefit from that higher dose effect in mFARS. The other thing that we showed as part of this data was obviously for some patients, with the existing commercially approved treatment being the standard of care, some patients came into our study on that treatment ahead of being dosed with LX2006 and others started at least eight months after treatment with LX2006. We broke those cohorts into patient level data showing patients that were on Skyclarys entering our study, those that added Skyclarys later in our study, but those that were never, never treated with Skyclarys throughout the entire duration of the LX2006 Phase 1 study.
I think through that data you can see that patients that have never been treated with Skyclarys are benefiting from a neurologic disease progression perspective. We're seeing roughly similar improvements in those Skyclarys-naive patients as we're seeing in some of the other cohorts. I think overall that picture is a very interesting one. I also think we're seeing a deepening effect in neurologic benefit over time. If you look at the patients that are 18, 24 months, we're seeing an even deeper improvement from a neurologic disease progression perspective. I think in totality, we're seeing an evolving product profile that can deliver value for patients across the range of Friedreich's ataxia, whether it's a patient that's earlier in the disease with some of the neurologic complications, or those that are later in the disease that have both neurologic and cardiac complications.
I think this therapy has value for all segments of patients struggling with this disease.
Absolutely. That's great. Congrats on this recent progress here. I do want to spend a few minutes on PKP2 since that is also a huge value inflection point for you all coming up as well. Just to jump into it, you've shown cardiac PKP2 protein restoration and impressive PVC improvements over time. What magnitude and consistency of improvement across different patients would you imagine in this population would define a true proof of concept for these patients?
I'll just take that one from maybe an expectations point of view. Just take a step back. We're working towards a readout which I think will have the majority of our high dose patients included in it for this disease. Because it's a heterozygous disease, the patients present with variable levels of baseline protein anywhere, let's say from 20% to 40%. The increment of protein that we're adding on top of that baseline, I think it's going to be much harder to determine what benefit that could ultimately result in from a clinical perspective. For this disease, I think we're much more focused on the clinical endpoints, surrogate endpoints, and some of those biomarkers that we're evaluating, and those include premature ventricular contractions, non-sustained ventricular tachycardia, EKG, T wave inversions, QRS restoration.
There's a range of endpoints that are relevant in this disease, and I think we're trying to understand the effect size in each or the mix of effect that we can observe. There are some that may be closer to the disease than others. I think non-sustained VT is a good one. PVC, premature ventricular contractions, is another one. Ideally, we would like to see more than one of those surrogate endpoints moving in a positive direction. That's what will give us some confidence that we're beginning to see the clinical benefit that we're looking for. That's really the picture as I would see it, and probably the expectation that I would set here is that it's the majority of the high dose patients and we hope to see more than one of the endpoints I described moving into a positive direction.
Okay, great. That's very helpful. Can you help us understand a little bit about the dialogue with regulators at this point and any precedents that help us define what a true surrogate could be? Obviously you're exploring these different endpoints, but wondering what the FDA has said of what could be meaningful.
Yeah, I'll take the first one and maybe Eric can talk about some analogous studies. We have not engaged the FDA in this program. We take the view that we want to see the clinical data at a sufficient stage of maturity to be able to support productive conversation with the FDA. I think if you go too early or go with too few patients, you may draw conclusions that are not ultimately supportive of the right path to registration. We have eight patients treated. We expect to have a total of 10 patients treated in this Phase 1 study that will ultimately include seven patients at our high dose.
We'd like to see all of those patients, for example, at six months at least, before we go and speak to the FDA so we can have a view of the clinical picture across the disease with the relevant number of patients. That's probably a 2026 event for us, that FDA conversation. That's probably something we will focus on in our guidance for next year. I know, Eric, if you want to speak to some of the analogous studies and some of the antiarrhythmics.
Yeah, I mean, certainly in the antiarrhythmic space we're seeing PVCs have been used in at least two studies as a primary endpoint. There haven't been, to my knowledge, studies in arrhythmogenic cardiomyopathy that look at treatments like this. For me, I think we want to have an informed discussion, which means we have a mature data set, as Nolan was saying, and you could think about the totality of evidence in regards to your first question as being the most compelling, as opposed to putting your weight in any one endpoint when you have small ends. What we like to look for is across multiple domains, some of them orthogonal and unrelated. Do you see movement in the right direction? In FA we see troponins and LV mass improve, not necessarily related, and both of them improving suggests that this is not just noise.
The same thing with FA, we're looking at multiple different structural and electrophysiologic endpoints. That's what we're waiting for to have that discussion with the FDA.
Okay, could you talk about kind of the heterogeneity of the patient population and how that affects how you're looking at these different surrogates and what could be meaningful or if there could be multiple things that could be meaningful?
I would look at the baseline amounts of PVCs. Now, I think in terms of understanding how sick your patients are, that would be something where I think less than 500 is not really even, you know, that's a well-controlled patient compared to someone, you know, that comparing someone like that who starts versus, you know, and then lowering their PVCs when they're super low to begin with may not be as meaningful as looking at patient populations where PVCs are like around 1,000 a day, 2,000, 5,000 a day. If you can find patients that are above 1,000 PVCs, that's more of a homogeneous population than I would say in general. Then look at the structural impact on the heart. Is there RV dysfunction? Because that's another stage of the disease.
Is the RV totally normal is a very different patient than a patient whose RV ejection fraction is getting below 50, certainly above 40. Those are patients who have aneurysms. You can use both structural and then the PVCs as a tool for understanding the patient population. We designed our enrollment criteria to reflect that and frankly reflect the consensus documents on what is ARVC. Does this patient truly have it? It usually has multiple domains. It has an electrophysiologic domain, it has an EKG domain, it has a structural function domain. Those are all included in our enrollment.
Okay, great. What's the process like of finding these patients and genetic testing for them? At what point do they get genetically tested? What does that say about their disease?
Yeah, so if you look at the kind of trajectory that these patients have and the patient journey, it usually starts in a few different ways. One is they have a sudden death event and they're resuscitated. One is that they have lots of palpitations and start to feel awful. Then they show up to the primary care doctor, who sends them to the cardiologist, who then sends them to the specialist. Thirdly, they're identified from a family member that has a genetic condition. Usually now, thankfully, we're really evolving in the now by the 2000s where cardiologists recognize these diseases and recognize the importance of genetic testing. When the patients have an ARBC phenotype, it'll be class one, you'll be classified guideline directed to now do a genetic test to identify both for them and for their family members.
Super helpful. Okay. In the last minute or two, I want to open up the floor to you guys to maybe touch upon anything we didn't get to that you feel is important or just give a look ahead for the next 12 to 18 months.
For Lexeo, I think important is just the context of what we're now seeing in cardiac gene therapy more broadly. I think that this field of cardiac precision medicine really began to gather some steam with the introduction of the amyloid treatments, like Tifamidis and some of the other silencers that have come along. I think both pharma and biotech community have begun to see the potential of cardiac precision medicines and what they can deliver for patients and ultimately the commercial potential that they can achieve. We believe that the AAV vector is the most efficient way to deliver a genetic payload to the heart. It's likely to be the tip of the spear in treating a range of genetically mediated cardiac conditions.
I think the effect sizes that we're seeing in our Friedreich’s ataxia program and the type of benefit that we could ultimately achieve in the arrhythmogenic cardiomyopathy (PKP2) program is really just the tip of the iceberg for cardiac genetic medicines. I see this as where the field will grow and expand in a very dramatic way. It could look a lot like oncology some decades ago, where precision medicines became the standard of care across a range of diseases. I think the cardiac field will evolve in that direction. We're excited to have multiple clinical stage programs that are kind of following this thesis, and we're excited to see them reach some stage of maturity where we can ultimately deliver this kind of value to patients that we're describing. I think that's a broader context that hopefully is helpful as well.
Great. Gentlemen, thank you so much. Really appreciate your time today. Very helpful. I just want to send a special thank you to all the investors that dialed in. On the topic of cardiology, I will be at AHA for anyone who wants to meet up there. Looking forward to it.
Thanks so much.
I'll see you there, Mitch.
All right, see you there.