I'll talk about it afterwards. Afternoon, everyone. Thank you very much for joining us. I'm Brian Skornie. I'm one of the Senior Biotech Analysts here at Baird. Really happy to have presenting in a fireside chat format with us next: Lexeo Therapeutics Management Team. It is a company I cover. I'm very excited about it. It was one of my top picks for this year on Baird's 2025 top pick list. Very exciting gene therapy company covering a number of cardiac diseases led by a Friedreich’s Ataxia program. Maybe to start, Nolan, can you give us a brief introduction to the company, how it started, and what areas you're focused on?
Yeah, so Lexeo Therapeutics is a cardiac genetic medicines company. The foundational science for the company was actually sourced from Weill Cornell University here in New York City. This came out of Ron Kristol's lab. Ron is one of the early scientific pioneers in the gene therapy field. We've since expanded our work in the cardiac space to include other indications beyond Friedreich’s Ataxia, including arrhythmogenic cardiomyopathy and other indications, working closely with Eric and his colleagues at UC San Diego. Our most advanced program, as mentioned, is treating Friedreich’s Ataxia. The therapy originally was focused on the cardiac component of the disease, but I think we're seeing pretty interesting data with the ability for that therapy to address the neurologic component of Friedreich’s Ataxia. Our next most advanced program is treating arrhythmogenic cardiomyopathy. This is a disease of life-threatening arrhythmias.
It's also a 60,000 patient rare disease in the U.S. For example, more than twice the size of Duchenne muscular dystrophy, making it one of the largest commercial opportunities in clinical-stage gene therapy. We've had a data readout for the Friedreich’s Ataxia program in the first half of 2025. We would expect to have a data readout for the PKP2 program in the second half of this year, and moving quickly towards a pivotal study for the Friedreich’s Ataxia program in 2026. I think a lot of very exciting developments and catalysts to come.
Yeah, great, agreed. Maybe start with some background on the vector that you're using for gene therapies. How do you sort of think of it as differentiated, particularly for cardiac indications versus some of the other ones that are in development, be it AAV9 or AAVRH74?
Yeah, sure. I think, as you mentioned, when you look at the adeno-associated viruses, those clearly are becoming the preferred viral therapy for cardiovascular targets. The three kind of furthest along in the clinic are using AAV9, AAVRH10, and AAVRH74. What differentiates AAVRH10 and why there was some intention in selecting that for all our clinical programs thus far is AAVRH10 has superior cardiac tropism compared to AAV9. We've done that head-to-head, and that's on our website and our deck, that it's about double the cardiac tropism. That is critical because, as we all know, the headwinds in gene therapy are around toxicity, and toxicity is directly related to dose. The lower you can go, the less likely you are to have any toxicity, clinical holds, all these things that keep people up at night.
It also affects manufacturing and cost of goods, which is the other headwinds in gene therapy. What I think is unique about AAVRH10 is we kind of think of it as kind of like a Goldilocks capsid. It gives us low enough doses where we've at least avoided clinically significant, or I should say, SAEs for LFT abnormalities across our programs, and we report out our quarterly safety events so we can stand by that. AAVRH10 has some similarities to AAVRH74 in that it doesn't appear to activate complement in the same way that AAV9. You're avoiding the two principal adverse events with gene therapy. One is the LFT abnormalities, and two is TMA, so complement-mediated toxicities. AAVRH10 seems to avoid both.
Great. Maybe starting on the Friedreich’s Ataxia program, can you tell us a little bit about the disease itself and how LX2006 really seeks to address the underlying pathophysiology?
Sure. Friedreich’s Ataxia is a disease due to deficiency in frataxin. Frataxin is a critical protein for mitochondrial function, which, remember, are the engines of every cell. It turns out that the heart of all tissues has the most mitochondria per square inch or per ounce. In fact, a third of the weight of the heart is just mitochondria alone. It is a huge energy-requiring organ. It is not surprising then that the leading cause of death for patients with Friedreich’s Ataxia is, in fact, cardiomyopathy. Clearly, people recognize that it has a neurologic component, a devastating neurologic component as well, but in this case, because of the capsid that we are using and the leading cause of death of cardiomyopathy, we are focused on that. As Nolan alluded to, we have some preliminary evidence that also suggests that we are addressing some of the neurologic components as well.
We think we are addressing both what the leading killer is for patients as well as what drives symptoms for them.
Yeah, and just expanding further on that, you know, our construct for Friedreich’s Ataxia is reintroducing frataxin to the heart, but also to the skeletal muscle, dorsal root ganglia. We think skeletal muscle transduction could result in benefits on the neurologic scales for Friedreich’s Ataxia. We believe that dorsal root ganglia transduction as well. We’ve seen DRG transduction in our preclinical studies. I think there’s an emerging body of evidence to suggest that this therapy is not only a cardiac therapy, but also one that could benefit patients from a neurologic perspective as well.
Great. Maybe run through a little bit of the clinical results that we've seen so far in terms of both functional measurements and some of the biomarkers that you're looking at.
Sure. I'll start with the cardiac endpoints, which were the principal endpoints that we're looking at in our clinical trial. When you're thinking about cardiovascular endpoints that are relevant to Friedreich’s Ataxia, probably the most important one is LV mass, which is simply the weight of the heart. We know that the heavier your heart, the more likely you are to die across all of cardiovascular diseases, cardiomyopathy. In this case, it's particularly true in Friedreich’s Ataxia, where a 10% increase in the weight of your heart is associated with a 20% increased risk of death. The FDA recognized that and agreed for us that to be a primary endpoint in a subsequent clinical trial. What we've shown is that collectively across our phase one clinical trial, in fact, we're getting closer to a 24% reduction in LV mass among patients that have elevated LV mass in our trial.
Far above that threshold of 10%, which the FDA suggested to be a primary endpoint in the pivotal trial. That's LV mass affecting the main primary clinical endpoint. The second thing the FDA wanted us to look at, and which we agreed to, is just the expression of frataxin. If your thesis is that you're restoring frataxin, they wanted us to show it. Where we landed with them is that any increase in frataxin from baseline to the second biopsy after therapy is sufficient to show that we're expressing frataxin. What we've done in our phase one trials is that 100% of the patients that we've biopsied have shown an increase from baseline to second biopsy after getting therapy.
If you think about the two endpoints that we talked about with the FDA, we've gone above and beyond what both of them could potentially be in our phase one as we look into our pivotal trial. The third thing I'll mention is troponin. Troponin is something every cardiologist is familiar with. They order that test multiple times a day, probably. Troponin is a bloodborne biomarker that predicts death. In our case, we're reducing troponin, I would say, drastically. We see some patients where it's a 90% reduction in troponin. That gives us biologic confidence that we're having an effect that's not just some kind of noise, that it would be very unlikely for a placebo, in fact, to lower troponin or LV mass index from that standpoint.
The three cardiac biomarkers that look very promising, I don't know, Nolan, if you want to talk about the neurologic biomarkers as well.
Yeah, so we have, you know, 17 patients treated with the disease. We've looked at two functional scales as part of our phase one two study. One is the mFARS scale, which is the Friedreich’s Ataxia neurologic scale. This was set behind the approval of Skyclarys, which is the only commercially approved treatment available for Friedreich’s Ataxia. We've also looked at the Kansas City Cardiomyopathy Questionnaire. It's another functional scale, more specific to cardiomyopathy. I think we're seeing a greater than three-point improvement in the mFARS scale in the patients we've evaluated to date, which I think exceeds the effect size that was observed in some of the pivotal studies with Skyclarys. I think we're seeing a pretty meaningful improvement in mFARS.
As we look at this picture, we're able to address the component of the disease that could be the cause of death for up to 70% of Friedreich’s Ataxia patients, and this is the cardiac component. We also appear to be benefiting the neurologic component of the disease at an effect size that's similar to the commercially approved therapy. I think it's a very good picture that could ultimately potentially evolve the standard of care for Friedreich’s Ataxia patients today.
Great. Eric, you mentioned a little bit about the favorable safety profile that you've seen so far. Maybe you could just kind of help contextualize that in terms of the dosing that you're exploring. What you think sort of brings the liver profile down relative to, you know, maybe it's just the capsid?
Yeah, as I was saying, there are a number of factors that predict toxicity, but one thing that's clear is total dose, over and over again, across multiple programs. The first thing to align on is that we're logarithmically lower in the dose we're giving here because you don't need much frataxin to improve the biology. With intention, we're giving E12, E11 in our first cohort, now E12 doses, which are far below where we see LFT abnormalities, which are usually, frankly, E14 range, sometimes E13. It's not surprising we haven't seen LFT abnormalities. It would be surprising if we had. It allows us to give lower immunosuppression as well because we're not as worried about an immune response to the virus. If you look closely, a lot of the adverse events that we see in gene therapy are actually from the immunosuppression.
Over-immunosuppressing patients and having them have risk of infections and other things. By avoiding having to give these big doses of immunosuppressant, that's another reason why we're not seeing adverse events. Frankly, we've seen one of the adverse events across our entire cohorts. It's not entirely clear whether it's drug-related or not. A case of myocarditis that occurred one year after drug administration, that patient is still alive, doing well two years now after drug administration, and that's it. I'd say one of the cleanest profiles in gene therapy.
Yeah, and I'd add to that, the 1E12 vector genomes per kilogram dose, it's a dose we're taking forward into the pivotal study. We have had no treatment-related SAEs at all at that dose. We are giving quarterly updates on the ongoing safety profile for both programs. I think there's a body of evidence out there supporting the safety profile of AAVRH10 across the two studies that we're currently running.
Got it. What are the next steps in terms of what needs to be done before starting the pivotal study?
I'd say there's two things we're focused on. The first is completion of the statistical analysis plan in collaboration with the FDA. We've guided to 12 to 16 patients in the pivotal study. I think the alignment around this will give us the final number of patients. We're also completing vector production, release testing, steps like this operationally, getting sites up and running. Some operational steps we're taking, but we're on track to have the study starting in early 2026 as we've guided to.
Got it. Are there any more formal meetings that you need to have with the FDA? In particular, a lot of the controversy in the gene therapy space has been around the CBER Director, Vinay Prasad, and his view on utilization of controlled groups. Have you had a chance to be able to discuss with him directly?
Yeah, I think we're in ongoing discussions with the FDA. The one note I'd make is while we reached alignment on this pivotal study and accelerated approval path under Peter Marks' leadership of CBER, we have since received a breakthrough therapy designation in July of this year, which follows the Vinay Prasad leadership of CBER. I think this speaks to their interest in the therapeutic profile of what we're developing. I can say we're, again, in ongoing discussions with the FDA, and our guidance around where we think we'll land has not changed. I think the picture is evolving in the way that we would expect.
Great. We probably last six months ago talked a lot about it as sort of cardiomyopathy due to Friedreich’s Ataxia, but obviously you have sort of evolving data showing that there might be a benefit on the mFARS components as well. Does that sort of change the dynamic in terms of who you want to enroll in the pivotal study? When we think about label down the road, does that have any impact, or is there a chance to have sort of a broad FA label?
Yeah, I think ideally, first, we utilize the same study for accelerated and for full approval. The accelerated approval, as we've described, is focused on left ventricular mass and frataxin expression as the co-primary endpoints. We would still be focused there. We understand the effect size, and I think we can obviously design and power a study around those endpoints. As we look at mFARS as a secondary endpoint in this study, we'd ideally like to use it for full approval. This may need a different picture in terms of the number of patients and the effect size that we're experiencing there. That's some detail that we're working through. In general, I would expect the early adopters commercially for this therapy to be those patients with more advanced heart disease.
Probably the patients that are more so in that abnormal LV mass population would be the early adopters or those with any cardiac involvement. I think over time, as we treat those patients, we demonstrate a consistent, compelling safety profile. We would look to expand to the broader set of patients, and the mFARS data would be obviously a helpful corroborating data for those patients with neurologic involvement that do not have cardiac involvement. I think what this does is it offers us the opportunity to confidently treat the entirety of the Friedreich’s Ataxia patient population. Obviously, we have both adolescent and pediatric patients in the study as well. I think the optimistic case here is that we have a label that covers the entire population in all age groups across Friedreich’s Ataxia.
Great. I mean, I guess you kind of went over the numbers a little bit in terms of patients who have cardiomyopathy, but maybe kind of paint a commercial picture here. What do you think the opportunity is for sort of just the cardiomyopathy subgroup versus kind of more broader FA?
Yeah, just to break it down, you have 5,000 FA patients in the U.S. 40% of those patients have what we call abnormal LVMI, which is greater than two standard deviations from a left ventricular mass index perspective. Those are the patients that are closest to heart failure, so I think would be most urgently seeking therapy. That's 40% of the population. 70% of the Friedreich’s Ataxia population will ultimately experience mortality from cardiomyopathy. That's another 30% that will have some form of cardiac involvement within their lifetime. I think they would also be patients that are ultimately eligible for therapy and would be interested in it, obviously, given that that would be their cause of death.
You have another 30% that may not experience cardiac involvement in their lifetime, but given the benefit we're showing on the neurologic scales for mFARS, I think there would be a strong case that this therapy ultimately could address that population as well. That's kind of how the market breaks down across the different patient segments and phenotypes across the FA population.
Great. That's moving into pivotal, but we're not really that far behind. You have LX2020, which I think is a really interesting program in PKP2 ACM. Can you walk us through this disease and the potential that 2020 has in this indication?
Yeah, sure. Arrhythmogenic cardiomyopathy broadly is a leading cause of inherited premature death. The leading cause of arrhythmogenic cardiomyopathy genetically is this loss of this protein, PKP2. PKP2 is critical for allowing cardiomyocytes to stick together, to adhere to each other. When you don't have enough PKP2, cardiomyocytes start drifting apart, and you get this infiltration of scar tissue and fat. That infiltration is why people die suddenly when they do sport or they feel like their heart is skipping, or often when patients just develop heart failure and need heart transplants. That roughly occurs in 50,000 to 70,000 U.S. patients. That makes this loss of PKP2, this disease, probably the leading target for gene therapy currently across all diseases right now, frankly, and certainly in the cardiomyopathy space. We think it's a high unmet need. The patients obviously have this high mortality. They have a lot of morbidity.
They feel like their heart is skipping all the time. They have a lot of PTSD and anxiety because they often have these defibrillators, and they don't know when they're going to get a shock. It can happen unexpectedly. One of the benefits here is that they have, in terms of a target, these extra heartbeats or premature ventricular contractions, and those are very quantifiable measures that we can use as part of a study.
You're in a clinical study now, and it seems like you enrolled very quickly. I mean,
Months ago, I did.
Maybe paint the picture of the clinical trial design, the different dose levels that you've tested so far, what small amount of data we've had so far, and what expectations.
This is a cross-dermal protein, so we need more protein than we need in our FA patients. We tested two doses at 2E13 and 6E13 doses using AAVRH10 with the full-length protein and a cardiac-specific promoter this time because we just want this protein expressed in the heart. The trial, we're collecting a whole host of data that includes extra heartbeats. I think an important endpoint for these patients is when these extra heartbeats are grouped together. We would call that either sustained or non-sustained ventricular tachycardia and/or sudden death. We'll be able to measure that. We're measuring cardiac function by MRI so we can look at structure, a bunch of clinical questionnaires and endpoints around anxiety, depression, the things that are relevant for these patients. We've enrolled eight patients thus far, three at the first dose and five at the second dose.
We're going to have data forthcoming on those patients by the end of the year.
The intention is in totality to have 10 patients enrolled. We're interested to enroll two more, which we'd expect to be completed this year. A total of 10 patients, of which eight are enrolled today.
We are biopsying these patients as well, I forgot to mention. We will have some histopathologic data, including gene expression after this year.
Okay. On the expression side of things, I mean, as you said, you need very small amounts of frataxin to show meaningful benefit, but this being a structural protein, what's the target threshold you're looking for here?
You know, the target threshold is one that makes patients feel better and live longer. We hate to box ourselves into some quantifiable amount because, frankly, we don't know. That being said, in our preclinical models, the doses that we gave were leading to a wild type or above levels of protein. I'm not saying we'll see that. I'm not sure how much you need, but that's what we saw preclinically.
I would also mention, I think this is a different picture of what the biopsies will be able to tell us from the Friedreich’s Ataxia program. At baseline, FA patients have very low levels of frataxin, call it 1% to 2%. This is a very different disease. It's a heterozygous disease. At baseline, the patients present with very varying levels of protein. It could be 20%, it could be 40%, and so on. It's a lot harder to understand how that incremental protein above the pretreatment baseline ultimately impacts efficacy. I think the goal here is to evaluate the biopsies, but I think the efficacy data is going to tell us a lot more about the disease pathology and our ability to impact it than the biopsies will, given these differences in the patient's pretreatment baselines.
I agree, and we heard that from some of our colleagues also investigating this. You have scar tissue, fat, and you're biopsying these, and you can't always be exacting on where you get the biopsy. You can end up with some contamination with scar tissue that could affect how you read out protein and things. There are a bunch of caveats here that are different when you're measuring these in mice.
Great. Maybe comparing and contrasting between left ventricular mass volume, which has a very obvious benefit outside of control, how do you kind of interpret PVCs? Could you see resolution of PVCs spontaneously?
I think the good thing about PVCs is it's both a feel endpoint and it's a survival endpoint. People, it bothers them, and it really affects their quality of life. They feel like they're at any moment could get a shock when they start feeling PVCs. It predicts death. The more PVCs you have, the worse. Finally, it's very quantifiable, and there's precedent. There are other cardiac trials which have used PVCs as the primary endpoint. It checks a lot of boxes for us. The variability in PVCs in patients, that thing we're doing a lot of natural history work to elucidate that. We're measuring them over a week, and then look at it per 24-hour measurement. We average over seven days per 24 hours. We think even if there's some ups and downs, we're getting a seven-day look at it.
I think the data will tell us between our natural history data. The nice thing is this is a very important topic right now to multiple companies. We're going to be getting a lot of information about variability of that endpoint.
Yeah, I think as well, maybe Eric can speak to it. NSVT is another interesting endpoint that we're evaluating as part of the picture here.
Thanks for mentioning that. When you have more than three of these PVCs in a row, that's non-sustained ventricular tachycardia. When you have it for more than 30 seconds, that's sustained ventricular tachycardia. That's essentially like dying or close to dying. Those are endpoints that we can measure that probably have less fluctuation. If you have it for more than 30 seconds, you shouldn't be having that kind of ups and downs as a normal person. We'll measure those. That's very relevant. That's a mortality endpoint, essentially. We'll measure those, and if we can have a, depending on the incident rates, that could be a very insightful look at if we're affecting the biology of disease. That shouldn't be affected by placebo. Let's put it that way.
Okay. On the safety side of things, it's kind of early to give much of an indication of safety, but you are stepping up into a systemic dose that's higher than FA. Have you changed your immunosuppression protocol to do that?
Yeah, comparing FA to PKP2 and FA, we're just using steroids. In PKP2, we're using steroids plus rapamycin in the therapeutic dose. Thus far, we've given safety reports. As you would, you could expect to see LFT abnormalities, but we haven't seen any SAEs related to this drug thus far, and we're reporting them out quarterly.
Yeah, I think that's an important note. I think we're giving regular safety updates across both programs, including this one. We know that safety is an important theme in gene therapy. We're offering a level of consistent transparency on the safety profile so that investors can follow along with that picture as the therapy evolves. As mentioned, we've now treated eight patients, five patients in our higher dose. You typically would expect to see safety events in gene therapy a few weeks or months after patients are dosed. Based on the cadence of enrollment, as you could follow from our quarterly filings, we've started enrolling patients in our higher dose roughly five months ago. You can sort of follow along with where the safety picture is evolving to date. We've had no treatment-related SAEs that we've reported.
In terms of a pivotal start, would you anticipate that's something that could be done around this time next year, or is it about a year behind?
I think it's early to comment on timing. I think what we'd like to see is our data reach a certain stage of maturity that can allow us to have a conversation with the FDA. That's probably a 2026 event. I think it's important to have the data at a stage of maturity to understand both the clinical profile, but also the variability across these endpoints so we can design the appropriate study. We have a pretty robust data set that's evolving here with eight patients and soon to be 10. Following that FDA discussion, it'll put us in a position to guide on timing for the next study.
Great. I don't want to leave Luca out here for his first time here. Could you just review the cash balance and what the burn looks like at Lexeo Therapeutics and how you think about getting these programs to sort of a break even? Is it through public market financing? Are you guys active in looking at partnerships?
We raised recently in May around excitement for our program updates that happened in April. We are very well capitalized at this point. We closed Q2 with $153 million in cash and marketable securities. That gets us runway into 2028, inclusive of the FA pivotal. We feel comfortable around our capitalization. On our burn rate, we did see some elevated G&A in Q2 into Q3, related mainly to some litigation charges that are now completely behind us. That matter was resolved amicably with claims being withdrawn voluntarily. That is completely behind us, and we expect our G&A to normalize after Q3.
Great. The last question I'll just ask, is there anything I didn't ask that you think is particularly important for investors to walk away with?
I think there's a lot of noise in the gene therapy field around safety, but I think, importantly, safety in gene therapy is related to dose, and it's related to the immunosuppression protocols. You could think of Lexeo Therapeutics as the company that has been able to achieve these clinical results, for example, in Friedreich’s Ataxia, but do so at low doses. What this confers is a favorable safety profile relative to maybe some of the other gene therapies that are out there today. I think our willingness to give these regular safety updates is a testament to the confidence that we have in the safety profile of our gene therapy treatments. You can think of Lexeo Therapeutics as the company that's able to thread the needle on efficacy and safety in the gene therapy field.
All right, great. Nolan, Eric, Luca, thanks for being here today.
Appreciate the time.
Thank you for having us.