All right, good afternoon, and thank you for joining Guggenheim Therapeutics team on our second SMID Cap conference. I am Devjit, one of the therapeutic analysts, and joining me on stage from Lexeo Therapeutics are Sandi See Tai, Chief Development Officer, and Kyle Rasbach, CFO. Thank you for making time for us today. Maybe we can get started on the fundamental platform. First, on the vector, the choice of the vector for cardiac indications, and not just for the first one, but also for the PKP2 program. Okay. Do you want me to start, Sandi? Yeah. I think one of the fundamental underpinnings of this company really was the vector technology that we're using, and specifically, we're talking about RH10 here, where we believe this is a best-in-class technology with superior cardiac tropism that allows us to dose these products at doses that are meaningfully lower than where we've seen safety issues emerge with other vectors while still delivering meaningful amounts of protein to the target tissue. It becomes especially important in diseases where you're delivering a structural component where you may need to deliver higher amounts of protein. The ability to deliver, have a lower dose becomes very important from a safety perspective. Given the translational work that you guys did and what you're seeing from the preclinical models into the clinic, how well has that translated? Yeah, so we've been very pleased by what we've seen, as Kyle alluded to, utilization of the RH10 vectors when we're delivering lower doses to achieve the protein expression. For what we've seen in the FA patients to date on their cardiac biopsies, we're seeing this translate quite well in terms of the frataxin expression, where on the biopsies that we've done to date pre-treatment in terms of frataxin positive area, we're starting out at about 19%, and by three months after dosing, we're seeing that increase to about 44% on average. Overall, that translation in terms of utilizing that cardiotropic vector seems to be playing out quite nicely in the biopsies. Great. Can you remind me what the, given that the agreement with the FDA on the expression and LVMI change, what's the scale-up in terms of the dose from cohort 2 to cohort 3? Yeah, so cohort 2 to cohort 3, we have it's about a twofold increase in dose. With that, if we look at it in terms of the threshold from a couple different angles, one, in terms of LVMI, where we're looking at a threshold of seeing at least a 10% reduction in LVMI, we know that with the lower doses, we're already seeing that we're able to achieve that. In terms of the frataxin expression, we're certainly getting to the thresholds that we need to see, which is around the 40% positive area by immunohistochemistry when we look at the patients who start out with an abnormal or elevated LVMI at baseline. Given that you have a very close, even on a per-patient basis with the last cohort, you guys are completely comfortable with that next-dose cohort, you'll hit it out of the park? You know, based on what we've seen in the preclinical models, certainly there seems to be an increase that is non-linear, so we expect to really achieve that. Of course, we're looking forward to that readout later this year where we'll have the cohort 3 biopsies and be able to see the levels that we're achieving in the post-treatment biopsies. Maybe, Kyle, could you sort of frame the commercial opportunity here in FA cardiomyopathy? Yeah, I mean, I think, first of all, from a commercial perspective, this is a disease where there are no available therapies today. It is not like we are looking to displace an existing standard of care. You think about, I will call it 5,000 or so patients in this country with FA cardiomyopathy, and it becomes a pretty substantial commercial opportunity. I think we also have to recognize that there are some emerging therapies for FA in general, where probably the most bothersome early symptom for these patients is their ataxia, but these patients will die from their cardiac disease. 80% of these patients will ultimately succumb to the disease from the cardiac manifestations. If you are a patient, you are able to treat some of the neurological conditions, it stands to reason that you are pretty quickly going to transition to, how do I live, how do I live longer? We think this is the opportunity to give patients the opportunity to extend their life. If the next cohort, you get what you want to see, could you sort of give us some timelines from the next data set into what could be either a unit filing or registration study? Yeah, I mean, I think we're really motivated to move as quickly as possible from the next data set into a pivotal. We need to get this third cohort of biopsies in hand, really, to inform what dose we are going to choose to move forward with. We'll quickly engage with the FDA around that dosing discussion. The size of the treatment effect we're seeing will also inform how large that pivotal study needs to be. We think it can be 2,025 patients, and we think we should be able to begin that study by the end of this year. From a recruitment perspective, how quickly can you get to full enrollment? Yeah, this is still a little bit of an open-ended question, but I think that we're doing a couple of things. One, we're going to begin a natural history study relatively soon. We're going to plan to over-enroll that study so that patients with the baseline characteristics that are appropriate for our pivotal study can choose to enroll in the pivotal out of natural history. It is a way to begin to recruit patients for that study today to give us a little bit of a head start when we do begin the pivotal. I think we can tell you expect data for that study sometime in around 2027. Got it. How quickly do these patients normally progress? Because if you enroll a natural history cohort, how many of those patients will become eligible, given that the enrollment criteria probably is going to be strict? Yeah, we plan to recruit, we plan to have similar inclusion criteria for what would be in the natural history study versus what would be in the pivotal study. It should be the similar patients, and the majority would be able to qualify. We're talking about patients with high. High LVMI. High LVMI base. [crosstalk] Where we're really, and the goal of our study is to decrease their left ventricular mass index in patients at baseline with abnormal LVMIs. We wouldn't expect those to spontaneously regress. If anything, we'd expect them to modestly increase in size. That's really what we're comparing against. Got it. Just put the, call it 10-11% change in LVMI, put that in context of natural history. What does it actually mean? Yeah, sure. The natural history data has shown us that these patients generally progress over time, whether it's in terms of their LV mass or wall thickness. Their hearts are certainly enlarging over time. From our perspective, when we look at what our treatment has the potential to do in terms of not just stabilizing, but actually reducing LVMI, it comes down to what threshold is clinically meaningful. Looking at at least a 10% reduction is what we believe is clinically meaningful. That is based on some natural history data that has been published, where about a 10% reduction or 10% lower LVMI has been associated with a 20% lower risk for mortality. Vice versa, a 10% increase in LVMI is associated with a 20% increase in risk for mortality. I think getting to that threshold is not just one that's numerically meaningful, but really clinically meaningful for this patient population. When you do have the update from the cohort 3, are you, as a company, also thinking about updating on the earlier cohorts to see if the response deepens, or could that data come earlier? No, no, no. We'll give you a pretty comprehensive update. You'll see continued progression from the patients that you've seen already in cohort 1 and 2, some additional patients there as well. We'll give you any patient who's out to six months and beyond, you'll see that data. If you look at where we are from some of the earlier patients, some of those will go out to 24 months, for example. The data set should be anywhere from 6 to 24. If the response does deepen with follow-up, then it automatically sort of takes some pressure off the next cohort, right? I mean, if, let's say, instead of 40%, you're at 39%, or instead of the 10% threshold, you're at 9.5%. Yeah, I mean, I think when we look at the pivotal, we're going to be looking at 52-week endpoints. What we have seen is some deepening of responses over time. Monitoring data beyond just one year is going to be important from a clinical perspective. I think you also need to remember that we're trying to bring these hearts from abnormal into a normal range. Once those patients' hearts become a more normal size, they're not going to continue to shrink. You're not going to take a normal heart and make it smaller. Once we've kind of come down into that normal range, the rate of decline over time should then probably stop progressing as much as these patients' hearts become normal in size. Got it. For the pivotal study, how long do you think it has to be? Going to be six months, or does it have to be a 12-month study? We'll be taking biopsies at three months, looking at protein expression with an LVMI endpoint at 12 months. Got it. You can't file on the protein expression data. You have to wait for the LVMI. I mean, I think the LVMI data is really what's going to be most predictive of the overall outcomes for these patients. Got it. In terms of CMC, because that's absolutely pivotal for any of the gene therapy programs, where are you and where do you need to be from here? Yeah, so we're well positioned to begin that study by the end of the year. The process is underway. We're using an Sf9 baculovirus production system, which will be the same in our clinical trials, our pivotal clinical trials, and our commercial product. That process is well underway to get us to where we need to be to begin that trial by the end of this year. Does the financial guidance include all the work that needs to be done for the pivotal and subsequent registration? Correct. What about the second program then? Uses the same system. Got it. That's already included in the. Right. Got it. Maybe you can touch upon the PKP2 program, especially how it compares versus competition. Yeah, I think PKP2 is a really large opportunity, 60,000 patients in the US may make it the largest potential opportunity in systemic gene therapy. That's two times the size of Duchenne, for example. It's also, Sandi can talk about what a comorbid kind of condition this is. It's really an area of high unmet medical need for these patients. We think it's a great commercial opportunity combined with a great unmet need and that the value proposition is relatively straightforward and that preclinically, if you replace a functional PKP2 protein, you can have pretty dramatic impact on the disease. We think the biology is hopefully somewhat de-risked. That said, that's why we're doing the experiment. This is the first time this experiment is being done in humans. We are going to present a number of data points across the remainder of this year that will hopefully be de-risking this program moving forward. You mentioned there are a couple of other programs that are in the clinic as well. We have two competitors. Really, the main difference between all three programs is the vector that we are using. This is where the Lexeo platform is really important, especially in a disease that is as large as 60,000 patients. A lot of these patients will not die from their disease. They have implantable cardiac defibrillators to prevent them from having sudden death. In a disease that may not have as high of a mortality, safety becomes really, really important for these patients. Having the lowest starting dose and the lowest finishing dose of any program in development and staying below total doses that we know are associated with adverse events is really an important differentiator for our program. When are we expected to see some initial data from this in 2025? What we've guided to is some initial data at the end of the Q1, beginning of the Q2. That is going to be restricted to protein expression. We will give you baseline and post-dose biopsy expression. We will also give you a safety update at that time. This is a disease where you are replacing a component of the desmosome, and it is a structural component that probably results in the heart probably taking a little bit more time to remodel. Three months may not be the appropriate time point to look at functional changes. We have also guided to giving a more clinically focused update in the back half of the year where we can start to see how different levels of protein expression may translate into some more functional outcomes. Got it. To wrap it up then, you also have an Alzheimer's program where you had data last year, or was it this year? Forgot. At the end of last year. Yeah. Should we sort of view that as source of funds going forward? Yeah, I think what we've said is that we no longer have any meaningful financial obligations to that program. Some additional monitoring requirements that from a capital perspective are very minor, but that we're not going to be investing any more Lexeo capital into this program. We are looking for a good home for that program where we can advance the science behind what we've pioneered there and hopefully bring some economics into the company that help us develop our other programs. Awesome. Looking forward to the clinical updates both in the end of the Q1 and then the big frataxin story coming up. Yep. Thank you so much for making time for us. No problem. Great. Thank you. Great. Thank you.