Good afternoon, and thank you for joining Guggenheim's 2026 Emerging Outlook Biotech Summit. I'm Debjit, one of the therapeutic analysts, and my privilege to welcome my next presenting company, Lexeo Therapeutics. And from Lexeo, I have Nolan Townsend, the CEO, and Louis Tamayo, the CFO. Thank you, gentlemen.
Thank you. It's great to be here. And thank you for having us at the conference.
Thank you for hosting. If I could ask you to just do a quick intro, before we get into the Q&A.
Yeah, sure. So Lexeo is a cardiac genetic medicines company. Our most advanced programs are utilizing AAV gene therapy to correct genetic cardiovascular diseases of high unmet need. Our most advanced program is treating Friedreich's ataxia. Our gene therapy is having a meaningful impact on both the cardiac pathology of the disease, and it's showing signals of improvement in the neurologic disease. You know, we'll spend some time talking about the data, but on the cardiac side, for all of the patients that presented with abnormal heart mass, they've all returned into the normal range. We've also seen an effect size on the neurologic scales for Friedreich's ataxia that are similar to the commercially approved therapy.
So we think this treatment has the potential to change the standard of care in, in that disease, and we're moving this program into a registrational study this year, which, which I think we'll spend some time, you know, talking more about. But this is obviously a disease of high unmet need. For most of the patients, the cause of death is cardio- cardiovascular disease, so to see this type of, you know, treatment effect across the totality of the, of the disease, we're, you know, we're very excited about. Our next most advanced program is treating arrhythmogenic cardiomyopathy. Here we're focused on the, the most common genetic mutation causing arrhythmogenic cardiomyopathy, which is the plakophilin-2 gene, or PKP2.
This is a 60,000 patient rare disease in the U.S., so it's more than twice the size of a disease like Duchenne's muscular dystrophy, you know, making this one of the largest commercial opportunities in, systemically administered, gene therapy. We completed the enrollment of a phase I/II study last year. We have, 10 patients total enrolled, seven patients at our high dose. We had a data readout earlier this year, with data at early time points for our high-dose cohort. This showed a meaningful improvement on endpoints like ventricular tachycardia, both relative to the patient's baseline, but also relative to a natural history study that we have running alongside it.
We'll have, you know, conversations with the FDA, and then a future data readout at more mature time points associated with that program. But I think it's showing some very interesting early signals of clinical benefit against some very important endpoints in the disease. And we have a preclinical pipeline also focused on genetic cardiomyopathies. So, we're making a lot of progress in this, you know, new and evolving field within the broader cardiovascular treatment landscape, where you've seen very few precision medicines approved in cardiovascular disease. And we think the AAV vector has unique properties that allows it to treat genetically mediated cardiac disease, and we're really at the tip of the spear in some of that work with our clinical-stage programs.
Well, thanks for that. And let's start on the regulatory side in terms of interactions with the FDA. The FDA was open to pooling phase I/II data and also using an earlier time point. When should we expect a definitive update on that?
Yeah. So we're. So maybe I'll, you know, just take a step back and, kind of, you know, walk through, walk through where we are. So, as you mentioned, a prior meeting with the FDA, they were open to pooling patients from our phase I/II study with a, you know, yet-to-be-conducted, registrational study. It was left to us to, come back with a statistical plan that could allow for pooling in that picture. It's not, it, it's a relatively complicated exercise, but that's part of the alignment that we're working to reach. We are expecting to give an update on, the, you know, final statistical plan and, and study design in early 2026. I think from a guidance perspective, in terms of study size, study length, we remain, you know, in line with the prior guidance.
The work that we're doing with the FDA now is really on a couple of fronts from a statistical perspective. I think one is trying to minimize sources of bias in the forthcoming study relative to the control. And the second is trying to give some visibility into the future confirmatory endpoints. We do not have to design the confirmatory study in order to reach alignment on the accelerated approval study, but I think the CBER would like to have a lens into where we're headed from a confirmatory perspective, and we're likely to have, you know, important cardiac endpoints that as confirmatory study endpoints here. Those are a few of the things we're working on, and we expect to give an update in the time frames that we previously guided in terms of, you know, final study size, study length, and other attributes of the statistical plan.
Given that LVMI is not necessarily a subjective biomarker, it's a hard clinical endpoint, you should be fairly confident that there should be no walk back from the FDA-
Yeah, I-
... like some of the recent CRLs we have seen, which are more sort of biomarker.
Yeah, I think LVMI is clearly cardiac hypertrophy is the hallmark of this disease. LVMI is the most. And cardiac MRI is the most sensitive measure for it. Left ventricular mass is a commonly used biomarker by cardiologists that evaluate the hypertrophic cardiomyopathy. So it is really the best and most efficient and most sensitive way to evaluate disease progression in Friedreich's ataxia cardiomyopathy. We've agreed on a 10% improvement in left ventricular mass as a clinically meaningful threshold. There's literature that links this to a 20% risk of mortality, so it's very much a surrogate that's linked to the disease and has a clear link to mortality. No guidance changed with respect to LVMI.
Where do you think the duration of follow-up could land up? ... you know, would you prefer a six-month study or a nine-month study?
There's trade-offs. The FDA is open to a time point shorter than 12 months. We have, at the higher dose, a 28% reduction in left ventricular mass. At six months, we have a 30% reduction in left ventricular mass at 12 months. So there is some difference in effect between the two, so there are obviously trade-offs in looking at an earlier time point with potentially a less deep treatment effect. So we're working through all of that in terms of the alignment on the statistical plan, and we'll be able to give a final conclusion on that when we provide the update. I mean, our goal is to, you know, have the fastest, most de-risked path to an accelerated approval. So, the design that we land on will, you know, take all of this into account to get us there in the most efficient way possible.
Got it. Now, the company has two late breakers at the ACC. Are we expecting substantial new data from the two programs? Or, I mean, given that it's a late breaker, people are expecting something different.
Yeah. So, you know, I think for FA, the last data update, we had, you know, all of the abnormal LVMI patients were at 12 months. We had most of the other patients with normal left ventricular mass, you know, at 12 months. We saw a consistent improvement in left ventricular mass. We saw consistent improvement in troponin. I wouldn't expect a materially incremental picture to that. I mean, there may be some additional data there, but I think the story for FA in terms of the treatment effect, the relevance of the endpoints, I think that's all clear from, you know, from prior data updates.
I think it's important that this, therapy, this LX2006 has not been presented in an academic conference, so this will be the first one. We'd like to ensure that this therapy is being introduced to cardiologists, that they understand the treatment effect, they understand the relevance of gene therapy for this type of disease. So I think the focus is more, you know, the audience and ensuring cardiologists have awareness of what this therapy is achieving in this, you know, in this very, you know, this very serious disease.
In your discussions with KOLs, the LVMI greater than two standard deviations, is that the threshold for treating? Or if your data look anything like your earlier data set, there is gonna be an urgency to treat no matter what.
Yeah. So I think obviously, the patients with two standard deviations and above will likely be the early adopters for this therapy. Those are the ones that are, you know, closest to the latest stages of heart disease. But also looking at the phase I data, we had 11 patients that did not have abnormal LVMI at baseline. Many of these had elevated troponin, many of these had elevated wall thickness. We saw improvements in lateral wall thickness. We saw meaningful improvements in troponin. So there is a case to be made to treat patients that do not yet have this two standard deviations or greater of left ventricular mass disease burden, potentially on the basis of troponin.
I would, I would agree that probably the more urgent, you know, treatment, those seeking treatment would be for that abnormal LVMI population, but we do not expect the label to be limited to that population. I think we can look across a number of rare diseases, including within Friedreich's ataxia, where the label of the commercially available treatment does not match the inclusion criteria of their, of their pivotal study, to say that we're likely to have a label that's broader than just the abnormal LVMI population. And then looking at biomarkers like troponin, that may be the right trigger point to consider, a therapy like this could be the pathway to treat patients earlier in the disease. And what we've not talked much about is the benefit on the neurologic side.
So we're getting about a 2-point improvement in the Modified Friedreich's Ataxia Rating Scale, which is the neurologic functional scale that evaluates disease progression in Friedreich's ataxia. It was also the clinical endpoint used for the approval of the existing, you know, commercial treatment. That treatment was seeing roughly a 2-point improvement in the mFARS scale. So, you know, for patients that even have earlier stages of cardiac disease or do not have, do not yet have cardiac disease, the potential benefit of a 2-point improvement in the Modified Friedreich's Ataxia Rating Scale is also clinically meaningful. If you remember, at the outset of the approval of SKYCLARYS, there were, I don't know, up to 4,000 patients on treatment, seeking exactly that treatment effect of this 2-point improvement in mFARS.
So there's a case to be made here for patients that are even much earlier in the cardiac disease and the potential neurologic benefit that they could experience from LX2006. So I think we'll... You know, the story will play out over time here, but I think we have a strong case to be made for, you know, a range of patients across the disease and treatment of this profile.
This is a complicated disease. You've got neurologists on one side, cardiologists on the other side.
Yeah.
Who's your primary target, and, you know, where does the intervention need to occur?
Yeah. So I think the early adopters are likely to be cardiologists. There are a range of patients that are under the care of a cardiologist. They're under the care of a cardiologist for a reason. They will probably have some form of, you know, discernible cardiac disease. Some of the sites we're working with are already doing cardiac MRIs on their patients, so they're tracking the progression of the disease in a pretty robust way. So I think the early adopters for treatment are likely to be cardiologists, but I think for the points that I just made about the benefits on the neurologic side, we're likely to see neurologists that also engage in therapy.
In our sites from our phase I, actually, all of our PIs were neurologists, so a lot of the patients that have been treated to date have been under the care of neurologists and have considered LX2006 for, you know, for their patients.
So maybe talk about the ease of administration, corticosteroids, et cetera, which adds to the commercial appeal.
... Yeah. So our immune suppression, we're using a 1 × 10^12 vector genomes per kilogram dose, and that's a dose we'll take forward into our pivotal study and into our into the commercial setting. Associated with that, we're using a relatively low dose of prednisone as the immune suppression. So as you're pointing out, I think it's a, you know, a not very onerous treatment course. We've had a very compelling safety profile associated with this therapy. I think that's to be expected at this dose. So the expectation would be that this would be, you know, a gene therapy that is amenable to the range of patients across the disease. We also have adolescent and pediatric cohorts that we're expecting to have in the study. So from an age group perspective, we would expect to potentially be able to treat the range of the disease as well.
From a CMC perspective, do you have end-to-end control of the product? In terms of purity, empty-to-full capsids about IU versus-
Yep. So, we have, you know, completed production of the, you know, clinical batch for the pivotal study using our final commercial process. This is a high-yielding process, and we have information on our website, but in effect, yeah, you can back into what we're looking at, cost of goods in some cases that are close to biologics. And this process, we transitioned from a HEK293 adherent process to Sf9 suspension for our clinical and commercial material. This required a comparability study for us to complete. That study is complete. The FDA has approved the comparability protocol, so we're clear to move forward with dosing in our pivotal study from a comparability and FDA perspective.
We also received a CDRP designation, which is a designation designed to advance innovation in what's required from a PPQ process validation perspective for, you know, for a BLA. That conversation is running alongside our conversation about finalization of the clinical trial. We hope to align with the FDA on a PPQ process validation requirements that could allow for a rapid path to a BLA following the completion of the pivotal study and then that top-line readout.
What role do you think natural history is going to play in your BLA submission for accelerated approval?
Yeah, so that's a good question. We have the natural history study, the prospective natural history study, already running. So that natural history study has identical inclusion criteria to the treatment study. So we already have sites up and running that are looking for patients that are the identical profile to what we need for the, for the treatment study. So that study will be a feeder of patients into the ultimate treatment study, allows us to get, you know, the sites up and running earlier, allows us to look for the patients that will ultimately, you know, be part of the treatment study, as well. So I think it'll play an important role, and as we align with the FDA, it allows us to, you know, to advance from a site operations and enrollment screening perspective as well.
Got it. Now, you guys are clearly well ahead, but the competitive landscape is changing, so are you thinking about the dual approach or the dual AAV approach going after CNS and cardiac?
Yeah. So I think there's, you know, obviously, there's different approaches here. What we're seeing from our systemically administered therapy is it's having an impact across a pretty broad swath of this disease. So, you know, I mentioned the improvement on the mFARS scale. We're seeing, you know, very definitive and very important improvements in the cardiovascular, you know, component of the disease. It's not likely that a substantial amount of our therapy is actually getting into the brain itself. And in the brain, there's aspects of Friedreich's ataxia that are mediated by the deep cerebellum or the dentate nucleus. And there is, as you're, you know, pointing out, a therapy that's, you know, evaluating intraparenchymal injection of, you know, frataxin gene therapy, combined with the systemic injection.
So, however, it's not exactly clear to us that these therapies are will be direct competitors over the long term. And what I mean by that is there's a possibility that a patient who receives a systemically administered dose of gene therapy may still be eligible for an intraparenchymally administered dose or CNS-administered dose of gene therapy. So there's not been definitive preclinical or non-clinical work completed to really flush that concept out. We'd like to understand that a lot better, but in a world where a patient can be sequentially dosed first systemically and then later in a direct CNS administration, it would mean that these therapies are not necessarily direct competitors, that there's an aspect of that therapy that may be amenable to patients that have been treated with LX2006.
I think, you know, more to come on the competitive landscape. I think as I look at all the therapies out there today, whether it's protein therapies and others, there may be a world where these all coexist, as they do in some of the other disease areas that are out there.
So let's talk about the PKP2 program. I mean, in general, people were expecting variability in the PVC side, but you had pretty, you had some variability on the NSVT endpoint as well. How do we address this going forward?
Yeah. So I think, you know, going into this, what we understood is that the endpoints are likely to improve at different rates, that you won't see at the same exact time point in the same patient, improvements in non-sustained VT, PVCs, and ejection fraction, that likely the remodeling that's occurred, the remodeling that we would expect to occur will cause those endpoints to improve at different rates. So that was expected. We did see a 22% reduction in non-sustained ventricular tachycardia. If you look at our natural history study running alongside the treatment study, patients saw a 20% worsening in non-sustained VT.
So there's a 42% delta between the treated patients and untreated cohort, and that's with several of the patients at the earliest time point where we can evaluate efficacy. If we look at the nine-month time point, there's a 65% reduction in non-sustained VT, again, versus this 22% worsening, so you're looking at an 85% delta. So I think we're seeing the early signals of a treatment effect in non-sustained VT, and I would draw a comparison to the existing, you know, let's say, commercially available treatments, amiodarone, for example, there is a mid-twenties treatment effect in reducing VT, about, about a 24%. So already, at the earliest time point for many of the patients, we're already seeing a treatment effect that's similar to what's available today for patients.
What's also corresponding to this is that the patient at the longest duration of treatment follow-up is showing a 30% improvement in their ejection fraction. And one could say if a 3%-5% improvement in ejection fraction could be noise, but I think any cardiologist would say a 30% improvement in ejection fraction is likely to be clinically meaningful. So with that improvement in non-sustained VT, we're showing signals of an improvement in an important structural endpoint like ejection fraction. There is no therapy today that is approving or improving arrhythmia burden at that effect size, and also showing any signal of improvement in structural elements of the disease. So at this early data readout, we're already seeing that. You're pointing out we had one patient who saw an increase in their non-sustained VT burden.
This patient was at an early time point at six months. It's not clear to us, is this a non-responder or is this a patient that is yet to respond? But if you look at the overall picture of this early data, we're actually very encouraged by it. The question from here is, what's the right pathway to a registrational study? What are the right registrational endpoints? Ventricular tachycardia is frankly the hallmark of this disease. It's not even a surrogate. It is a clinical endpoint. So we think that'll play an important role in our, you know, the future alignment with the FDA. And I think the only question is, is sort of the one you're asking, which is: What is sort of the final treatment effect that we can expect to see at longer time points?
Is it something more similar to the nine-month patient, is it something more similar to the average of what we're seeing today, and then how much variability is there in the endpoint over time? I think we'll have that answer as we look at the data later in the year and see more of the patients at these longer time points, such as 12 months.
How do you... When you think about the PKP2 expression versus mRNA or the protein, I mean, there wasn't a direct correlation there or even versus VCN.
Yeah.
Why do you think that is, and is there a way to sort of address that?
Yeah. So, just, you know, taking a step back, what we did see. So we saw a dose-dependent response in every one of our biopsy endpoints. So we saw greater vector copy in our high dose than our low dose. We saw greater mRNA in our high dose versus our low dose, and the same with protein. We saw more protein in our high dose versus our low dose. And we got, in some cases, between three and five vector copies per cell, which we think is a great outcome to achieve that kind of result and do so with no classic gene therapy-related SAEs, so no SAEs related to complement activation, no SAEs related to liver injury. So we define a very clear therapeutic window. We're getting a great payload.
In fact, this validates the use of AAVrh.10 for the heart, in that I have not seen another capsid demonstrate that type of distribution into the heart, but do so with the safety profile. So that's, I think, a very positive picture that, you know, that we're happy with. In terms of the direct correlation on a patient-to-patient basis between VCN mRNA to protein, you remember these all come from different tissue samples. So you would like to see the high dose with more protein than the low dose across all these measures, which we did see, but you wouldn't expect an exact correlation patient to patient because you're looking at a different tissue sample for each one of those endpoints.
So for us, the usefulness of this data is sort of as, as I was describing, I think we know we're at the right dose. To get between three and five VCN implies, you know, we don't need more than five copies of the gene, you know, per cell. We're seeing protein expression. We're seeing protein expression actually localized to the right place in the desmosome, so we know functionally, from, you know, validating the biology, it's going to the right place. I think this is... What this data is, is, you know, helpful for is to understand all of that. I think it's unlikely to be a pivotal study endpoint, both because of tissue quality issues with the disease itself results in fatty fibrotic tissue to accumulate in the heart.
So if you end up with tissue samples that are primarily fibrosis, you will see a kind of variable picture. The other challenge with using plakophilin-2 as an endpoint or biopsies in a future study is the patients are presenting with a pretty wide range of pre-treatment baseline, so anywhere from, let's say, 20%-50%. So it'll be a lot harder to understand how much more PKP2 do you need to add to have a clinically meaningful benefit. So I think the usefulness of the biopsies is as, you know, as we described. I think we know we're at the right dose. I think we know it's getting to the right, the right place in the desmosome. This validates all the biology that we saw preclinically, and now I think we're more focused on the clinical endpoints, like non-sustained VT, for the future of the program.
In terms of the three SAEs of sustained ventricular arrhythmias that you had, how do you go about addressing that? Does it... Do you need any changes to-
Just to correct, there's one SAE.
Sorry.
Yeah, one SAE. We had one SAE of a sustained ventricular tachycardia. This is actually an endpoint that we're measuring in the disease. This patient had a prior treatment, prior history of sustained VT, prior to entering the study. So while it was assessed as possibly treatment-related, it looks very much like arrhythmogenic cardiomyopathy. I would note that over the course of this treatment, none of the patients in the trial have had their ICDs fire. So not only are we seeing improvement in non-sustained VT, we're also seeing no ICDs fire. And so it, that endpoint looks like the disease, and I would point out, you know, we've not had any SAEs related to complement or any SAEs related to liver injury, which is what you would typically see in some of the higher dose gene therapies.
I think we're in a very positive place from a safety perspective, in particular for a disease like this one, where, you know, many of the patients will experience sudden death arrhythmias, many of the patients will go on to require transplants. From a benefit-risk perspective, we think this is, you know, a very attractive picture that's, you know, developing for this therapy.
... Well, awesome. Unfortunately, we have run the clock, and looking forward to the data updates, especially on the regulatory side, and wishing you guys the very best for this year. All right, thank you.