Great. Perfect. Everyone, welcome back to the next session of the second day of the 2026 Leerink Partners Global Healthcare Conference. Welcome everybody here to Miami, Florida. I am Mani Foroohar, Senior Analyst for Genetic Medicines, and I am, for this session, hosting Lexeo Therapeutics. Guys, how are you doing, and how was the trip down from New York?
Great to be here. It's always nice to enjoy the beautiful Florida weather relative to, you know, New York. Great to be here.
You could always relocate the whole company. We are happy to have you. Redomiciling the company aside, you guys have obviously made tremendous amounts of progress, both on your lead Friedreich's ataxia program, you gave us an update on PKP2 earlier this year. Obviously a busy year for you across two programs at different levels of maturity.
Yes
Versus a registrational study. I do wanna touch base on a question I've spoken to a number of my companies about over the course of this conference and throughout the year. Obviously topical. How much consistency have you seen and constancy in terms of both personnel and process have you seen in your discussions with the agency? Have you seen any evidence of disruption from turnover, changes in policy, et cetera? Like, from the outside, it appears that the agency is navigating a period of great turmoil, but it's not clear to us as investors and analysts if that's filtering down into your program-level discussions. Can you give us a little color on what your experience has been?
Yeah. T hanks for the question, and obviously it's, given some of the recent news, an important topic. I think there are, you know, some differences that we're observing in how this team at CBER thinks relative to the prior one. I could, you know, kind of frame those in the context of the ongoing discussion we're having to finalize the protocol and statistical plan around our pivotal study for FA to get it started. Before I do that, let me just, you know, take a step back. Our Friedreich's ataxia program, we read out data in October of last year, which was a pretty definitive update showing a consistent improvement in left ventricular mass index at a pretty meaningful effect size.
What we're working to do now is finalize the pivotal study and statistical plan for the registrational path around that program. What we know from all of the interactions with the FDA, things that have not changed, left ventricular mass index is the key, you know, surrogate endpoint in this disease. It's linked to mortality. Obviously, a very relevant endpoint in this study. The study will be powered on the LVMI endpoint. We will, you know, give an update on this pivotal study and statistical plan in early 2026. We still remain within early 2026. We intend to start the study within the first half of this year. We remain on track from a guidance perspective with respect to starting the study.
I think two of the areas where this CBER puts a little bit more focus than the prior group is on eliminating sources of bias in the accelerated approval study design. They also put more focus on the link between the accelerated approval endpoint and the future confirmatory endpoints. Meaning, if the accelerated approval endpoint is left ventricular mass index, that's clearly a cardiac endpoint, then the full approval endpoint therefore needs to be a cardiac endpoint as well. We've all talked about the effect size that we're observing on the neurologic scale of modified Friedreich's ataxia rating scale, and the link between that improvement and the cardiovascular surrogate endpoint is less clear.
The question is how to fit mFARS into the picture from a label perspective, given that the confirmatory endpoint will ultimately be a cardiac one. There's conversations like that that are occurring. The prior group at CBER, we never really discussed to any great degree confirmatory endpoints. The prior group at CBER probably had less focus on bias in the study design or in the statistical plan, and that's sort of some of the topics that this group's been focused on now.
Let's dive into the dynamics around that labeling. The conversation around mFARS, as you've mentioned, is, it's quite nuanced.
Yeah
Since what you're pursuing primarily is the cause of death for these patients, which is the cardiomyopathy side of Friedreich's ataxia. Talk to us about how necessary mFARS benefit is, in your view from a clinical and commercial standpoint versus from a registrational standpoint, and are those answers different?
I think to some extent they could be. Just, you know, taking a step back, in our phase I data, we saw at six months, at the high dose, a 28% reduction in left ventricular mass at six months, a 33% reduction in left ventricular mass at 12 months. We saw significant reductions, about 60% in troponin, which is another blood-based biomarker. It's a biomarker so sensitive that cardiologists use it to predict heart attacks. We saw also reductions in lateral wall thickness, and we saw improvements in the modified Friedreich's ataxia rating scale relative to an untreated, you know, natural history group. We saw a range of improvement across endpoints. Some of them are much earlier in the disease course than where you would begin to see cardiac hypertrophy.
If you look at the totality of evidence here, I think you see a treatment that could theoretically change the standard of care relative to the existing commercially approved treatment. However, in our pivotal study, we are studying patients that have two standard deviations or greater of left ventricular mass index, meaning they have hypertrophy and they are on the, let's say, the mid to later stages of the cardiac disease.
Well, you say, what about all of the other patients who have elevated troponin or who have elevated wall thickness or who have abnormalities in the mFARS scale, can they also benefit from treatment? I think our goal here is to show that treatment benefit not only for the population that has two standard deviations above of heart mass, but also find a way with the existing data or potentially other future data sets to show a benefit across mFARS, troponin, and wall thickness for patients that are earlier in the disease course. This will allow us to commercially have a credible case to treat patients across a range of the disease. I mean, what we'd want first is cardiologists that are treating patients with abnormal heart mass to, you know, obviously select this therapy for those patients.
Ultimately, we'd like to see neurologists that are treating patients earlier in the disease course to consider this as a treatment option as well. I think that's kind of a commercial question as much as it is a label question.
Let's talk about patients and patient stratification out in the real commercial world presumed moving forward. To what extent does patients being a concomitant therapy, I mean there are approvals for Friedreich's ataxia, though not for cardiomyopathy. To what extent does Skyclarys use affect how you think about a patient should be on this study, should not be on this study, should receive therapy commercially, should not receive therapy commercially? Do you view that as totally orthogonal to whether or not the patient should receive gene therapy, or does that combination therapy change how you think about the benefit?
Yeah. You know, our understanding of the existing evidence around Skyclarys is that it shows some improvement in the neurologic disease, but it has not shown an improvement in the cardiovascular disease course. In fact, it has a side effect of increasing NT-proBNP, so maybe that it's even worsening the cardiovascular disease course. I think at its outset, just you know, fundamentally, the cause of death for 70% of the patients is cardiovascular disease. Obviously, that's our first focus from a patient perspective is the 40% or so of patients, adult patients that have abnormal LVMI. I think these will be early adopters for treatment.
When we looked at the mFARS data, we broke it out in a prior data update by, you know, patients that had been treated with Skyclarys or an ongoing treatment with Skyclarys while also having been treated with our gene therapy, and the patients who had not been treated with Skyclarys and were treated with our gene therapy. I thought we saw no difference in the effect size across those groups on the mFARS scale, meaning that patients that had not been treated with Skyclarys are benefiting from a neurologic, you know, reduction in the rate of decline. I think there's a strong case to be made for, you know, Skyclarys naive patients.
There's also a case to be made for those patients that are being treated with Skyclarys because they're unlikely to benefit from any kind of cardiovascular, you know, treatment effect. We have, I think, a case for both sets of patients, irrespective of whether they're untreated with Skyclarys or treated with Skyclarys. Our study design will have to take all of that into account.
Let's move forward a little bit to think about one of the conversations we've had around PKP2, if I may slide over to another program. I'm sure we're gonna bounce back and forth a little bit. Let's talk when we're gonna get data for PKP2, your next update, and the state of your consideration around what will eventually be the commercial positioning of PKP2. Obviously it's a population with variable penetrance, though that's a pretty fairly common abnormal genotype.
Yeah.
How that translates to abnormal phenotype, clinical manifestations, ICD, residual shocks, et cetera. Obviously, the funnel is quite wide and narrows. When are we gonna get data from you, the next slug of data, and how is that gonna inform our consideration of who should be enrolled and who should be treated?
Right. Maybe I'll say a few words, and I'll pass this to Nani. One, we've guided to data in Q4 of this year. We will have most of, if not all of, the patients at 12 months of treatment follow-up. That, you know, will be a time point where we'll have relatively mature data to be able to look at the entirety of the treatment effect. We've also guided to a regulatory update this year where we'll have a discussion with the FDA about the appropriate endpoints for either a future accelerated approval or potentially a full approval study. You know, taking a step back with the data set that we presented earlier this year, we saw a 22% reduction in the non-sustained ventricular tachycardia endpoint.
This is with the majority of patients just at six months of treatment follow-up, so this is the earliest time point where we can look at efficacy. For the couple of patients that were beyond six months, that were at nine months, we saw an average of 65% reduction in non-sustained VT, so we're seeing a trend of a deepening effect over time. We'd like to observe the data to see if that trend continues, but I think that's a very promising signal. If you look at that 22% effect size, you're looking at other treatments around other antiarrhythmic treatments like amiodarone is achieving roughly a similar effect size, and this is an approved therapy doing that.
I think we're hopeful that with the safety profile we've observed, the treatment effect we're already seeing in non-sustained VT and this deepening effect over time, we'll have a compelling therapeutic option here. Importantly, we're seeing it around probably the most important endpoint in this disease. I mean, the ventricular tachycardia is something patients can feel. It's also something that leads to the sudden ICD shock events, which is a sudden cardiac death event. It is something patients can feel. We view it to be a clinical endpoint, and it's right in the middle of the disease. That's sort of what we're working towards as we think could be the most important endpoint in a future registrational study.
Let's talk about the impact of ICD shocks on these patients. Clinically, I think there's no question the ICD shock is potentially preventing a fatal event. I don't think there's a question about the value to the patient. Let's talk about the quality of life cost of frequent shocks, and to what extent that plays into the value proposition for your therapy and how, like, patients experience these shocks from a QOL perspective and how they experience the threat of a shock.
Yeah. The threat of the shock, I mean, that's always the anticipatory thing, right? Nolan was saying, you know, the patients can feel the PVCs, they can feel the NSVT, and then it's kinda just this waiting game of saying, "Is this gonna deteriorate to a point where I'm gonna get shocked or not?" Because remember that the ICD can be set to multiple treatments, not just shocks. It can be set to anti-tachycardia pacing zones, and so they can get paced out of it, but they don't know which one's gonna work or not work, based on the drug they might be on, et cetera.
Definitely from a shock perspective, it's a concern to the patients and this fear of when it's gonna happen and how it's gonna happen. Just think about someone who may be doing a daily activity, et cetera. It's not even that they you know have to be just sitting on a chair or something, but they could be driving, for example, or something like that. This is definitely something that lives in constant. Each time the shock occurs, that leads to a whole monitoring session. It leads to an interrogation of the device. It leads to reprogramming the device, potentially looking at the trend, the history, et cetera.
It leads to that utilization of healthcare and then further and then could even lead to ablations and things like that because you're like, "Okay, your character of the arrhythmia is changing," so now you're going through multiple procedures like ablations, et cetera. Definitely that is a thing that just feeds into itself over time because the condition doesn't necessarily improve from a structural perspective. The arrhythmia burden doesn't suddenly get better or go away. It just progresses over time to a point where they can progress to a structural issue with heart failure, et cetera, and then have even worse arrhythmias. That's where the value proposition would come in from an HCRU perspective.
Yeah. I would add, I mean, the cost offsets, as Nani just described, are significant. By the way, many of these patients go on to require heart transplants, which are a $2 million healthcare intervention, and this is after a lifetime of ICDs ICDs being reset, ablations, things like that. I mean, we're you know, for the healthcare system, this is millions of dollars of cost that could potentially be replaced by a gene therapy with the right effect size. Imagine, you know, you can improve non-sustained VT or ventricular tachycardia. This is a clinical endpoint. Imagine you can reduce ICD shocks, which would be natural if you can reduce VT. Then we saw for our patient with the longest treatment follow-up a 30% improvement in right ventricular ejection fraction.
For those that follow that endpoint, you would know that a 30% improvement is not noise. We're seeing some signs of improvement on the structural front as well. A therapy that can reduce arrhythmia burden, improve structural outcomes, prevent progression into heart failure, and do so with a safety profile of no, you know, classic gene therapy-related SAEs. There's been no complement activation SAEs, been no liver injury SAEs. We think that, you know, sort of product profile is very, very compelling against a, you know, 60,000-patient, you know, rare disease in the U.S. I think we're very excited about the opportunity for this therapy. Obviously, there's a regulatory conversation we need to have. Obviously, we wanna see the data be consistent and mature from where it is today.
I think this will all play out this year, and I think there's some very, you know, interesting opportunities in the PKP2 front for us.
Let's talk about something that the company. I just had another company in this space maybe an hour ago. There is sort of a received wisdom at this point that the right answer, quote-unquote, for an AAV company is to drive your capsid purity and your full-to-empty ratio as high as possible, deliver as much genetic ordnance on target, vector genomes per targeted cell.
Yeah
Avoid de-target the liver if you can, unless you have a liver indication, of course, and drive your dose as low as possible. To what extent is that, in fact, the path to have the cleanest safety efficacy profile and other cases where that is not true?
Yeah, no, I mean, that concept has been the fundamental strategy for Lexeo from the outset. If you look at our Friedreich's ataxia program, the highest dose we're using is one E12 vector genomes per kilogram. I think some of the bear thesis on this program, at least initially, was, well, how could you ever correct a disease of the heart at that dose? Well, our preclinical evidence suggested that we could. That's the dose we took forward. We never kind of fell into the into the trap of trying to pursue higher doses, and we've achieved a, you know, 30% effect size at a one E12 per kilogram dose just because we understand the biology of the disease, the enzymatic function, and therefore how much protein you need to correct it.
We didn't need to get to 100% of normal frataxin in order to correct the disease. We've been able to thread the needle on safety and efficacy with that program. I think we're doing the same for PKP2. We're at one of the lowest starting doses. We're at one of the low, our high dose is relatively low. We've seen we have relatively modest immune suppression, just rapamycin and prednisone and rapamycin in that program as well. We've had no classic gene therapy related SAEs in either program, so no SAE related to complement, no SAE related to liver injury. I think it's one of few that's had that across two different programs.
This is across 27 patients we've dosed in a range of different conditions. I think we're at a very good place from a safety profile perspective relative to efficacy, and this all comes from choosing the right dose, and that comes from having a right understanding of the tropism profile of the capsid and the function of the protein that you're actually trying to replace. I think that's the themes we've taken forward into the programs we're working on.
Talk to us a little bit about your manufacturing infrastructure while we're on this topic, where we are on empty capsid ratio, how your strategy is in terms of scale up. Obviously, the number of patients one could treat, especially since we're talking about PKP2, this starts to become a lot of patients, although absolute dose-
Yeah.
Per patient matters.
Yeah.
Talk to us about where you are in manufacturing footprint now and how you think about scale up strategy as you transition into pivotal over the course of the next year and a half, eventually commercial, et cetera.
Yeah. No, this is something we're, you know, very happy to talk about. We're utilizing the baculovirus Sf9 process at 200-liter scale. We're getting greater than 1E15 vg per liter yield. We're doing so with less than 20% empty capsid ratio. I think we're one of few companies that would disclose those numbers. Why we disclose them? Because we're actually very happy with both the yields and the low empty capsid ratios that we're getting. What this means, if you back into the numbers of the doses we're utilizing, you're looking at cost of goods that could be close to biologics for a commercial treatment, which means a very compelling profitability profile once we get to that stage. That also factors into the clinical supply cost.
It's unknown what size of trial we could be considering for PKP2. We'll have to have that conversation with the FDA. Whatever size it ends up being, we have the ability to supply vector at a relatively modest clinical supply cost into that trial. It's not to say if the trial ends up being larger than, for example, what we're contemplating for FA, that it's an overly expensive trial. The expense will be driven by the number of patients, not by the vector supply. I think we're really excited about our CMC platform and where we are with it. We're in our commercial process for FA. We've manufactured the batch for the pivotal study. We're in our commercial manufacturing process also for PKP2.
The last batch that the patients received in our phase I study was in our commercial process. You know, for both, we are in a place where we can move quickly, for FA from pivotal study into commercial and for PKP2 from phase I into pivotal and then into commercial, given the readiness of the process and kind of where we are in that.
I wanna hop over to a quick financial question while we're talking about CapEx infrastructure, et cetera. Can you remind me where you guys are in terms of runway versus the sort of some of these key catalysts we're seeing for Friedreich's ataxia, et cetera, and versus the anticipated timing of the pivotal in particular?
Yeah. We're very well capitalized. We're sitting with a number in the mid $200 cash and equivalents. That gives us runway through 2028. Our burn rate is roughly in the mid $20 per quarter. Included in that runway, you can think about the FA program through the BLA filing, and you can think about the PKP2 program through the conclusion of phase I, too. You know, very happy where we are. We did a capital raise in October on the back of the compelling FA data that Nolan described, so we're in a good place.
We've talked about build out and manufacturing. We talked about some of that CapEx spend, obviously, in build out. Talk to us about how you think about the transition towards eventual pivotal commercial. What kind of footprint would you need to commercialize a product like this in Friedreich's ataxia with a label for cardiomyopathy, but presumably some mFARS data on there, but certainly not a primary?
Right.
Like what does the footprint for that look like U.S., what is the strategy OUS, to sort of maximize access to these patients, but also to make sure that you have, you know, the strongest commercial position?
Yeah. There are 5,000 FA patients in the U.S. A lot of these are collected around a small number of centers of excellence. I'd say twenty or less. Most of these are current clinical trial sites. I think in the U.S., the commercial organization that needs to be built around FA is relatively modest. It resembles a rare disease commercial infrastructure given where the patients sit today. The fact that they're treated by a neurologist and a cardiologist, typically these are in the same treatment center, so these aren't in different kinds of centers of excellence typically.
I think from a commercial perspective, this is the type of rare disease that a company of our size and stage could theoretically launch ourselves. Outside of the U.S., it's actually even a little bit simpler, in that most countries there is a single treatment center in each country where you know where the FA patients are treated with the same structure of cardiologists, neurologists working together around the course of treatment. I think the commercial picture as we're you know developing our strategy for U.S. and ex-U.S. appears to be one that's feasible for a company at our size and stage to launch.
We have experience, including myself and our organization for launching rare disease drugs, including rare cardiac drugs, so I think we have the right, you know, skill sets in the company, to achieve this successfully. I was involved with the launch of tafamidis for ATTR cardiomyopathy. Nani was involved with the launch of mavacamten. Some of the most successful rare cardiac drugs, you have a team literally on the stage today that's been responsible for those launches.
Let's talk a little bit about that exact commercial dynamic. How much overlap is there in infrastructure, and how much synergy, I guess, do you get from the progress you're seeing in Friedreich's versus PKP2? These are very different indications, but there is some overlap in terms of physicians that address these patients.
Yeah, no, definitely. I think the broader concept, taking a step back, is around designing therapies that are typically treated by heart failure specialists, right? There are, call it four to five thousand heart failure specialists in the U.S. These are primarily at tertiary care centers. These heart specialists, heart failure specialists are seeing the most complex cases, and those are the types of diseases that Lexeo was focused on. If you go to a site like UC San Diego, where our former chief medical officer, Eric Adler, continues to have a clinic, he is seeing Friedreich's ataxia patients, he's seeing PKP2 patients, he's seeing desmoplakin patients, he's seeing BAG3 patients, you know, and so on. That is not uncommon.
You have a number of heart failure specialists that are seeing a range of these genetic cardiovascular diseases, and that's the population of physicians that we're focused on. Those are the same clinical sites that we're working with across multiple of our programs. The entire pipeline is set up for exactly that population of physicians, of which there's only 4,000 to 5,000. I would argue that, again, even for PKP2, it's a larger disease, but there is an ability to set up a commercial infrastructure around that. I mean, you see companies, biotech companies like BridgeBio and Alnylam are launching products in TTR amyloid. That's a substantially larger disease than any one that we're focused on, and yet they can successfully commercialize into that landscape.
I think you're seeing in rare cardiac potentially some different trends than what you may observe in other areas. You know, more to come on that as we kinda build out the strategy, but that's, you know, what we're seeing in the rare cardiac field today.
I wanna sort of touch back on the back half of my prior question. At what stage of maturity do you think it's appropriate then to make a decision regarding OUS strategy for each of these assets? Is it different for PKP2 versus ?
It may be, but they need to be looked at in concert. I think the biggest question will be the EU approval path. So that would be on the back of a productive meeting with the EMA to understand what elements of our existing, you know, clinical development plans would fit with an EMA approval, would allow us to make that decision. I mean, we need to know the timelines, we need to know the possible label endpoints and so on in order to understand the, you know, the true opportunity set there. It would be hard to make a decision about ex-U.S. commercialization in the absence of having that regulatory feedback across these programs.
On the back of that is probably when we'll have a clearer picture about our ex-U.S. plans. For now, for FA, we're very much focused on this accelerated approval study in the U.S., getting the protocol and the SAP finalized, getting the study started. We see the effect size we're observing, so we wanna find the fastest, most de-risked path to a U.S. accelerated approval first, assess the U.S. opportunity and use that data and potentially others to support EMA and other jurisdictions and the approval there.
Great. On that note, we are coming down out of time momentarily. This will be an exciting year for you guys. Obviously, a lot of moving parts. Looking forward to continuing the conversation.
Thank you so much. It's great to be here.
A pleasure.