Good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts here, and my privilege to host our next presenting company, Lexeo Therapeutics. Joining us from Lexeo are Nolan Townsend, its CEO, and Louis Tamayo, CFO. Thank you, gentlemen. Thank you for making time for us.
Thanks for having us.
Thanks for having us.
Appreciate it.
Why don't we do a very quick intro of the company before we dive into the Q&A?
Yes. Lexeo is a cardiac genetic medicines company. Our primary focus is two clinical stage programs. The most advanced is treating Friedreich's ataxia, both the cardiovascular and neurologic components of that disease. That program will be entering a pivotal study in 2026. Our next most advanced program is treating PKP2, Arrhythmogenic Cardiomyopathy. PKP2 is the gene mutation most commonly responsible for Arrhythmogenic Cardiomyopathy. We've completed enrollment of our phase one two study associated with that indication, and we'll be presenting data in early January associated with the first set of patients at our higher dose. In general, the company's science was originated from Weill Cornell. It was built around the work of Ron Crystal, who's our scientific founder. We've advanced programs across both cardiac and neurologic disease historically. Today, our focus is on the cardiovascular indication.
On 2006, you had a recent alignment with the FDA. Could you just walk us through what the primary endpoint now is, the number of patients you need? Then we can get into specifics around the endpoint.
Yeah. Just taking a step back, this therapy for Friedreich's Ataxia received a breakthrough therapy designation in July of this year, I think on the back of some very compelling data, both on the cardiovascular front, while showing that patients that presented with abnormal left ventricular mass index, which is the biomarker we're using to evaluate Hypertrophy, which is the hallmark of this disease, all of the patients that started with abnormal left ventricular mass at baseline returned to the normal range, which means we were able to reverse or correct the Cardiovascular Disease Pathology, or at least the hallmark of this disease. On the neurologic front, we showed an improvement in the Neurologic Functional Scale, mFARS, which is the same functional scale used to approve the commercially available treatment, SKYCLARYS, for Friedreich's ataxia.
What that meant is that we were showing very significant clinical benefit on the cardiovascular component of the disease and also the neurologic component of the disease, which may allow for a change in the standard of care within Friedreich's ataxia more in totality. On the back of this data, we engaged in a conversation with the FDA about are there opportunities to accelerate our pathway to a BLA. The solution that was discussed in order to achieve that was pooling data from our phase one two study with data from the forthcoming pivotal study. What this would potentially lead to is a smaller pivotal study, and obviously that could accelerate the pathway to a BLA. The FDA was also open to considering a time point earlier than 12 months to evaluate efficacy.
In total, we think this puts us on a more rapid path to a BLA. In general, I think by the fact of receiving the breakthrough therapy designation, I think the FDA was very, let's say, excited or comfortable with the data that we were presenting. We are working towards finalizing that pivotal study design and then entering the pivotal study within 2026.
Given that this happened over the last month and a half-ish, you don't expect the FDA to walk this back suddenly.
Yeah, I know you're probably referring to some recent examples. I agree that there are some maybe differences versus the circumstances that we've seen play out over the last few weeks. The first that you're highlighting is that our meeting with the FDA was relatively recent. It was in September, so, I think this reflects the most recent thinking of the FDA with respect to endpoints and also the control. The second thing I'd note is the endpoints that we're evaluating for Friedreich's ataxia are very objective endpoints. Left Ventricular Mass Index is evaluated via cardiac MRI. This is a very objective measure. There's no effort-based, there's no placebo effect in a cardiac MRI or in left ventricular mass. The second co-primary endpoint is frataxin expression. This is an LCMS assay. Again, there's no effort-based or no, I'd say, subjectivity to that assay as well.
I think by virtue of the recency of the meeting that we've had with the FDA, but also the nature of the endpoints that we're evaluating, we think this puts us in a good position to drive towards where we've guided with respect to where the study should land. I'd also note that the final alignment on the study will come via another meeting, so we'll have another opportunity to reconfirm our understanding with respect to where the FDA stands on study design, control group, endpoints, all of that. We have not seen any change or discussed any change versus our prior alignment with the FDA with respect to where we're headed.
Got it. The mFARS data really stand out. Could you sort of, how are you getting there? Is it because of dorsal root ganglia transduction? Is it because of dramatic improvements in left ventricular mass index, which is translating into improvements in function? How do we think about the mFARS data?
Yeah. This construct was designed with the ubiquitous promoter, which means with our gene therapy, we are expressing frataxin in all organs. The heart, this is a cardiotropic capsid. There is differential transduction in the heart, but we are also transducing skeletal muscle and other organs. I think first, the benefit we are seeing is likely related to skeletal muscle transduction, where that transduction should yield some neurologic benefit. We have also seen in preclinical studies that this same construct in mice was able to transduce dorsal root ganglia. We may be seeing some DRG transduction as well within patients. We have a sub-study evaluating with skeletal muscle biopsies, and we should have skeletal muscle protein expression data available next year so we can validate what I said via data.
We believe that those elements are what is likely leading to the neurologic benefit that we're seeing in mFARS. And it's a pretty meaningful benefit. I mean, we're getting a one and a half to two point change in the mFARS scale. This is roughly the same change that was used to approve the commercially available treatment. So the combination of the cardiovascular benefit, which is the cause of mortality in this disease, combined with the neurologic benefit that we're observing, we believe could change the overall standard of care in this disease in a commercially available treatment.
How are you guys thinking about the commercial opportunity then, given the mFARS benefit that you're now capturing along with the profound LVMI changes, et cetera?
Yeah. The abnormal LVMI, which is the hallmark of the disease or the patients that are getting closest to the latest stages of cardiomyopathy, is about 40% of the adult population. We would see those as the early adopters for any therapy that we launch here. As you're pointing out, we're seeing other benefits beyond just the reduction in cardiac hypertrophy. You could first see in the cardiovascular data, we are reducing wall thickness, which is, I'd say, the precursor to elevations in left ventricular mass. We're also seeing pretty significant reductions in troponin, which is a blood-based biomarker that's so sensitive that cardiologists use it to predict the onset of heart attacks. We're seeing reductions in both of those biomarkers, even in patients that do not yet have elevated LVMI.
The point I'm making is that there's an approach of potentially treating patients that are earlier in the cardiovascular disease. This goes beyond the 40% of the adult population that I mentioned. Roughly 70% of FA patients have cardiac involvement or ultimately will experience mortality from the cardiovascular disease. That's another 30% beyond the elevated LVMI population that we think would be eligible to treat with our therapy. There's the last 30% where they will obviously suffer from the neurologic component of the disease, where we think showing a compelling neurologic data set with the right safety profile would make that patient population eligible as well. We have planned for cohorts in our study that are looking at adolescent and pediatric patients. We should, down to, I think, two years of age, so we should have all age groups eligible for treatment there as well.
I think we're looking at this treatment now as one that can potentially address the totality of the disease across patients of all age ranges and certainly those that have both neurologic and cardiovascular disease. I think, admittedly, the earliest adopters will likely be the cardiac patients, and then we would progressively move to treat patients that are earlier in the cardiac disease and then the neurologic disease as well.
There are multiple care points in that discussion, right? There are pediatric patients managed by pediatric neurologists, there are adult neurologists, there are cardiologists. Who's your initial target from a care point perspective? As these patients progress, they are sort of multifactorially managed?
Yeah. Most adult patients are seen by both a cardiologist and a neurologist. Typically, the disease is diagnosed when patients are five or eight years old, so they're under the care of a neurologist at that stage. The cardiac disease most typically emerges in adulthood. You would have a patient who's treated with a neurologist from childhood, and then the cardiac disease becomes more evident, and they're treated by a cardiologist. In our pivotal study, we will have both cardiologist PIs and neurologist PIs. I think both sets of physicians will have experience with this therapy. As I mentioned earlier, I think the earliest adopters will likely be those with the cardiac disease. That's the most urgency to treat, obviously, because they will experience mortality the soonest. There will be a component of our focus that will be cardiologists that treat this disease.
Now, there's not a lot of them. There's maybe a dozen or so in the U.S. that really are the focus of our work and our clinical study. As we move from there to neurologists, I think we will expand our focus as well. There's a number of neurologists that are PIs in our study as well. They treat patients both looking at the neurologic component of the disease, but also the cardiac component of the disease. I would see both as being relevant as treating physicians that would ultimately prescribe this gene therapy. I would liken this to the amyloid field, to ATTR, that therapy and that disease obviously has a neurologic component and a cardiovascular component. There's neurologists involved in treating TTR amyloid. There's cardiologists involved in treating it as well.
I think with the therapies that have advanced, have been able to demonstrate an ability to address both sets of physicians successfully. I would see this playing out in a very similar way to the way we saw the amyloid field play out, which had both a cardiac and neurologic component to that disease as well.
Other than the LVMI thresholds, does the patient or does the FDA want to see a finite number of patients going through the initial program plus the pivotal study before you can file for BLA?
I wouldn't be able to guide to a specific number, but I would say the first thing is we have come up with an approach allowing us to pool data from our phase one two study with our pivotal study, and we need to achieve and enhance comparability sort of requirements in order to do that. There are six patients that have abnormal LVMI that are relevant for efficacy in terms of pooling. But you could also imagine we have 17 patients treated across the phase one study. To the extent that data is in totality relevant for pooling, we then have 17 patients that are relevant from a safety database point of view. I think we would see that study as being relevant for the safety database.
In terms of the increment of patients we need to add to that safety database in order to achieve a BLA, that's a discussion that's ongoing currently.
Given that the disease impacts relatively early in life, how are you thinking about pricing? Is this going to be a flat price across the board or because you have different doses across, total vector volume is very different?
Yeah. I think the price, in our view at least, one is a function of the ultimate treatment benefit that we achieve. It is difficult to speculate on price in a very accurate way this early. I would not expect that we would have a price difference based on the number, the amount of genomes we are delivering or the dose. I would say it would be more so linked to the clinical benefit that we are providing to patients. I would look at pricing in a very similar way to some of the other rare disease gene therapies that have been commercialized over the last couple of years. Something in that range is likely where we would land from a pricing point of view.
Got it. What role do you think natural history is going to play in your BLA submission?
Yeah. We have an ongoing natural history study with patients with abnormal left ventricular mass. The natural history study, the goal is to use it as a control, as an external control. What we are able to demonstrate is that hypertrophy does not spontaneously improve in patients that are untreated. What we have seen via existing natural history data sources is that the hypertrophy in this disease will be stable or increase over time. We would expect to see that in the natural history data set. The clinically meaningful threshold improvement in left ventricular mass that we have agreed with the FDA is 10%. If you look at that 10% relative to this external control that should increase over time, you may need to achieve less than 10% in terms of treatment effect in order to reach that efficacy threshold with the FDA.
Now, I'd note that we're achieving something in the 30% range or 28% in left ventricular mass versus the patient's baseline in our phase one study. We are very readily clearing the efficacy threshold even without an external control that is worsening over time. That external control does give us even a little bit more room from an efficacy perspective as well.
Maybe a few minutes on the manufacturing switch and where you are and what kind of comparability you're getting currently.
Sure. The phase one two material for the 17 patients that was treated was manufactured via an adherent HEK293 production line. We have migrated to what is our platform process at Lexeo, which is SF9 Suspension Bioreactor Manufacturing Process. That is a process we have utilized to manufacture the GMP vector for our next program, our PKP2 Arrhythmogenic Cardiomyopathy programs. We have a lot of experience with that process. We have now manufactured vector for our Friedreich's ataxia Pivotal Study using that process. Now, obviously, the conversion from one manufacturing process to another requires achieving comparability. We agreed on a comparability protocol with the FDA with certain parameters that we needed to achieve.
We submitted that comparability report to the FDA in October and received an approval for us to move into dosing patients in our pivotal study, meaning the comparability threshold to start dosing of patients in the pivotal study has been achieved via the report that the FDA has reviewed. In terms of anything else required from a comparability perspective, the FDA has asked for an enhanced comparability threshold, let's say, with respect to being able to pool the data from our phase one study with our pivotal study. The idea there is that we need to show that the product in our phase one is as close as reasonably possible to our commercial material, our commercial vector. The increment of what we need to do is to run a non-clinical study, a mirroring study head-to-head with our HEK material versus our SF9 material demonstrating comparability in that context.
We have put our HEK versus SF9 material in mice ourselves head-to-head. I think we know where that experiment will likely land. I think we have confidence that we will be able to achieve that enhanced comparability threshold in order to submit that data into our BLA.
Got it. Let's switch over to the 2020 PKP2 program. The data are now expected early next year. What prompted that switch there?
Yeah. We had three cohorts in our phase one two study. Cohort one, it's the lowest dose. There were three patients. Cohort two was the high dose, 6013 per kilogram, the three patients. Then an expansion cohort of cohort three at our, let's say, chosen dose. We chose to take forward the higher dose because of the safety profile we were observing in our cohort two patients. We were able to rapidly move from cohort two into cohort three. There was only a couple of week difference between the last patient dosed in cohort two and the first patient dosed in cohort three. We wanted to provide the most robust picture in terms of the number of patients. That picture would allow us to show efficacy across a number of patients at the six-month time point.
If we were to choose a time point in this year, we would have had several patients that were just a couple of weeks behind. The question is, why present data early when you can present more data just a couple of weeks later? What we will have in early January is five patients at the high dose that are beyond six months of treatment follow-up, which is a time point where we can begin to evaluate efficacy. We will have biopsies across all of those patients as well. I think this is a pretty robust data set that can allow us to look both at biodistribution, but also efficacy across a significant number of patients. We will also have safety data from all 10 patients in our study at that January time point.
I think it just allows for the most clear understanding of the efficacy profile of the therapy by choosing that time point.
When you think about the endpoints, at least from my perspective, the PVC endpoint could be variable versus, say, EF or QRS. How should we interpret the data when you start thinking about the January readout?
Yeah. I think there are really five endpoints that are relevant in this disease. You mentioned a few. Premature ventricular contractions is one. Non-sustained ventricular tachycardia is another one. This is probably closest to the disease. The next is QRS duration, T-wave inversions, and then right ventricular and left ventricular ejection fraction. If you look at the way in which the disease is diagnosed, the ARVC risk score, all of those endpoints are relevant in the disease. It is not simply saying this patient has increased PVCs, so therefore they have Arrhythmogenic Cardiomyopathy. You actually look at the totality of the endpoints in order to diagnose this disease. While I think PVCs will be a relevant endpoint here, it is not the only endpoint. The other ones, such as non-sustained VT, T-wave inversion, QRS, will all be relevant in evaluating the efficacy profile of this therapy.
The way I look at it is we'd like to see more than one of these endpoints moving in the right direction versus the patient's pretreatment baselines. We'd also like to see an increase in activity from our low-dose cohort to our higher-dose cohort from a biodistribution and clinical efficacy perspective. That's really our expectations for the upcoming readout.
Given the commercial opportunity out here is significantly larger than FACM, any thoughts as to how many patients you think the FDA is going to ask for here before you can come to some sort of an alignment on what the path forward is?
Yeah. We've not had a discussion with the FDA yet about this program. Our goal is to take a robust data set to the FDA. For example, we'd like to have all of our patients at the high dose at least at six months of treatment follow-up. We will have five of the seven at six months of treatment follow-up by January. Obviously, there's another two patients that we'd like to see reaching that time point in terms of amount of follow-up before we go talk to the FDA. That's probably a 2026 discussion. I would agree with you that this is a different disease with different types of endpoints than for Friedreich's ataxia. I mentioned the objectivity of left ventricular mass index. It doesn't spontaneously improve, so on. I think that yields a certain concept of a pivotal study.
I think the endpoints as we're describing for Arrhythmogenic Cardiomyopathy are different. That's likely to yield a different study design and size than what we saw in FA. I can't speculate now on the numbers, but I know that there are other companies working on progressing conversations with the FDA as well at the same time. I think we'll have a picture both via our discussions and via what some of the other companies are doing as to what the FDA's expectations are for this therapy and its registrational study. I would say for us, that's likely to be a 2026 event where we can guide more specifically on what the FDA is looking for.
Does PKP2 expression need to be controlled very tightly in this indication?
In terms of protein expression, we actually think the biopsies in this disease will be incrementally less helpful than they would be, for example, in a Friedreich's ataxia. The reason is that in FA, patients are presenting with very low levels of frataxin at baseline. They're starting between 1%-2%. Whereas PKP2 Arrhythmogenic Cardiomyopathy is a heterozygous disease, patients are presenting with anywhere from 20%-40% of baseline protein. It is a lot harder with that basis to understand how much the increment of protein that's being added can ultimately benefit clinical efficacy. This is why we're so focused on having a sufficient number of patients that are at the amount of treatment follow-up where we can evaluate efficacy because we're not sure that the biopsies themselves will give that answer.
What I'm describing is that the biopsies may or may not be part of the picture for the purposes of a future pivotal study. It may be that we're much more so focused on the clinical biomarkers that I mentioned, PVCs, non-sustained VT, QRS, T-wave inversion, and ejection fraction are probably more relevant in this disease.
Got it. In the last few seconds, just a quick thought on the safety profile. How do you think that's evolved and how comfortable are you overall?
Yeah. So, I think one of the things we've been doing, and maybe this is unique for a gene therapy company, we've been giving quarterly updates on safety in each one of our quarterly prints as our studies have been enrolling. You could see it even as our last quarterly print, which I think was last week, we gave a safety update. We did the same in prior updates. What we have described as our safety update for Arrhythmogenic Cardiomyopathy is we have a single possibly treatment-related SAE. This is an instance of sustained ventricular tachycardia. This patient had sustained VT in their treatment history, or sorry, had VT in their treatment history previously. This is a hallmark of Arrhythmogenic Cardiomyopathy, that type of event. We have not seen SAEs related that are typical of gene therapy. We've not seen liver injury.
have not seen complement activation SAEs even at this higher dose. We think we are trending well from a safety perspective with this therapy. We think the market has been able to follow along real-time with the safety profile of this therapy. I think you can already see that it is differentiated versus some of the other gene therapies that are out there at a similar dose level.
Thank you so much. Unfortunately, we are out of time. Looking forward to a very exciting 2026.
Thank you so much.
Thanks for having us. Appreciate it.
Thank you.