Great. Good morning, everybody. Thanks so much for listening to this panel with the Lexeo management team. I will maybe just turn it over to Nolan Townsend, CEO and Founder of the company, to give a brief overview of Lexeo's couple lead programs. Maybe, Nolan, you can also review the really interesting deal you guys just did.
Sure.
We will do Q&A. Thanks so much for taking the time.
Thanks, Paul. It is great to be here. Just some background. Lexeo is a clinical stage genetic medicines company. Our lead program is focused in Friedreich's ataxia. As Paul mentioned, we have added additional preclinical programs to the pipeline, which I will spend some time talking about on the FA side. We are also working in a set of genetic cardiomyopathies. The lead program on that side is a gene therapy focused on PKP2 arrhythmogenic cardiomyopathy, which is the most common genetic cause of life-threatening arrhythmias in arrhythmogenic cardiomyopathy. The company is about seven years old, and we have moved into a pivotal study for our Friedreich's ataxia program, and we will be reading our data for our PKP2 arrhythmogenic cardiomyopathy program later this year. As Paul mentioned, we recently completed an acquisition, a small acquisition of a private clinical stage company.
This acquisition added several programs to our Friedreich's ataxia pipeline that are all focused on introducing frataxin into the brain. This is a complementary approach to our current clinical stage program, which is focused on the cardiovascular component of Friedreich's ataxia. We believe that the two together could meaningfully improve the standard of care in this disease. While LX2006, our FA cardiomyopathy program, is likely to be the standard of care for treating the cardiovascular disease, we believe that there are other approaches that can allow us to address the neurologic side of the disease through this expanded pipeline. Excited to spend more time talking about this today, both the FA programs and our PKP2 arrhythmogenic cardiomyopathy program.
Great. Awesome. Well, maybe we can hit a few key points on the LX2006 pivotal study, Nolan. You guys gave an update recently that you have enrolled a whole bunch of patients in a natural history study. Maybe talk about just the effort with the natural history study and the specific population within FA-CM you are trying to enrich your pivotal trial for.
Maybe, Nani, you could speak to the—
Sure.
—the population we are focused on and then the enrollment into CLARITY-FA.
Yeah. I will start with the CLARITY-FA enrollment. Paul, as you mentioned, it is the natural history study that has the same inclusion criteria as our pivotal study. We are recruiting well into that study, from the standpoint of, we are at about 20 + patients, and two others that are kind of eligible and just waiting. All of these patients are eligible to come into the pivotal trial, provided that their neutralizing antibodies and total antibody counts are fine. They could enter into the pivotal trial. The pivotal trial is focused on a cohort of patients that have a left ventricular mass index that is greater or equal to two standard deviations from the mean.
That is where we are focusing on, given the fact that this is the population that as you look at LVMI, and particularly this type of population, there is a significant risk of increased mortality. For every 10% change in LVMI, you have almost a 20% increase in risk of mortality. We feel that that is the population that, given also our phase I, phase II data, we feel that we should be concentrating on to show a very meaningful, clinically meaningful effect size and go from there. That's kind of where we are right now with our CLARITY-FA enrollment and the pivotal focus on the population.
Let me just punctuate—
Great.
—a few points there. As Nani mentioned, 22 patients. Our registrational study is a total of 26 patients in the adult cohort. I'd note that the sites where we have the patients enrolled in the natural history study are the same sites that will ultimately be treatment sites as well. It's a matter of operational steps to move the patients from one study to the other, with the caveat of the existence of neutralizing antibodies would obviously be a factor that makes the patients ineligible for the treatment study and that rate of neutralizing antibodies we've seen roughly consistent with prior literature and prior experiences at about 15% or thereabouts.
Yeah. Okay. Makes sense. Do you guys want to talk about the bar that you've powered the study for, and what gives you confidence that you are likely to meet or exceed that bar?
Yeah, sure. We powered it at a 15% effect size from the baseline, and the trial is the 26 patients is 13 and 13. 13 patients in an untreated arm, 13 patients in a treated arm. The comparator is the change from baseline in the treatment arm versus the untreated arm. The 15% threshold was really arrived upon for a couple of reasons. One, we want to make sure 10% reduction is, as I mentioned earlier, is that clinical bar and the regulators have agreed that that's a clinically meaningful reduction. The 15% was really a threshold that we arrived on for a couple of reasons. One was we wanted to beat that 10% bar and be really clinically meaningful and be in an unquestionable range of effect size, and 15% gives us that.
When we look at also our phase I, phase II data, and we look at the patients who were in the higher two doses and how they progressed at six months, we know that the effect size we saw there was about 28%. So we feel that given that that 15% is we should be able to reach that given our phase I, phase II data, and the fact that we beat that 15% pretty handily in the phase I, phase II data. So that's the rationale for powering it where it is. It also, the couple of other offshoots are that it allows us to get to a reasonable sample size, and also complete the trial in a reasonable amount of time.
I add as well, just Paul, one point I'd add. Obviously with our natural history study, CLARITY-FA, we have visibility into the baselines of the patients that will ultimately end up in the treatment study. We can see those as they're coming in. So I think we understand via that information that there is significant enough disease burden in respect to left ventricular mass index to ultimately meet or frankly exceed the endpoint, given some of the effect sizes we've seen against patient baselines in our phase I/ II study. So I think that gives us additional confidence that we are able to see, as patients are coming in, the existence of cardiac hypertrophy and the degree of that pathology.
Yeah. Okay. That's great. Makes sense. I forgot the other thing. I was just trying to interrupt and ask—
Sorry. I interrupted you. Sorry.
No, it is all good. I think the other, oh yeah, the other piece I was going to ask is just what is your assumption for what we will see in the concurrent untreated arm? Do we have good evidence that there is not going to be any change or any placebo effect from the study?
Yeah, maybe I will start it. We have always seen left ventricular mass index to be a very objective endpoint. Cardiac MRI is not subject to placebo effect. We can look at other HCM studies. You do not see spontaneous improvement of cardiac hypertrophy via left ventricular mass index. The inter user variability is very low. If anything, over a six-month time period, you should see the LVMI trend flat to maybe slightly worsening. You would not expect to see improvement. Again, as mentioned, we are working against a six-month endpoint. I think we are expecting little or no change in left ventricular mass index in that time period, and we have data to support that. Unfortunately, it is not all published, but there are three different natural history data sources.
One at Cornell, one at CHOP in Philadelphia, and one at the FA-COMS data set, all looked at cardiac hypertrophy via MRI. We have access to those data sets. We use them in thinking through our clinical endpoints. I think that helps support the fact that we do not expect to see spontaneous or untreated changes in the endpoint. Frankly, this is why the FDA is supportive of this endpoint, because it does not have a lot of noise or subjectivity associated with it.
Right. Yep. Okay, two more LX2006 questions, and then we can move on to other aspects of the story. Just on the secondary endpoints in the study, what is most important in the pivotal, to you, and how important are the secondary endpoints from a regulatory perspective?
Nani, do you want to take that one?
Yeah, sure. A few secondary endpoints that I think are critical. Staying in the cardiac realm for a moment, certainly you want to look at what's happening to the biomarkers like troponin. We have, again, seen in our phase I, phase II data, remarkable decreases and durability of those decreases in troponin levels in these patients. We feel that's an important one to look at for a couple of reasons. One, not just in this population, but the fact that we should start thinking a little bit more about when do these patients actually start to get their heart disease? Maybe biomarkers like this are important as early signals of the fact that there is something happening. I think that's the other reason why these biomarkers and their trend is going to be important as a secondary endpoint.
We are also looking at some other things like KCCQ, which is a more patient-reported outcome, and trying to look at a functional improvement in those patients. The one that's kind of split away from cardiovascular, but it's still actually very critical in FA and kind of talks to the acquisition that we've just done as well, is mFARS which is the neurologic side of things and is a clinically reported outcome, which is just patients' overall neurologic functional status over time.
Right.
These patients tend to deteriorate by about, t hey get worse, and an increase in mFARS is worsening and a decrease in mFARS actually signals an improvement. These patients worsen from 1 point - 2 points per year on average. We have seen in our phase I/II data extending all the way out to almost two years, that when you compare the treated population with LX2006 versus a propensity matched analysis from the FA-COMS unified data set that Nolan was also mentioning earlier on. We actually see that population in the unified data set worsen by about 1 point per year, and we see our population with almost a little over 2-point improvement over that two-year period. So a net change of 3 points or over.
We feel that's an important secondary endpoint as well to measure and see if we can not just show a cardiac improvement. We know that this vector transduces in peripheral nerves and skeletal muscle and dorsal root ganglion. A re we starting to see some benefit of that in the mFARS data that we have shown so far?
Yeah, I think it's notable just the durability of the improvement in mFARS. This will be the first time we've seen durable improvement of mFARS and maybe even deepening over time, even if you look at this relative to the standard of care. I think we're excited about this data. As you can hear, we're squarely focused on commercialization for this asset. How do we ensure that we can treat the broadest popular cardiovascular population, looking not only at cardiac hypertrophy but also at troponin, and then making the case for the therapy based on improvements we're seeing on the mFARS scale that appear to be at or potentially even greater than the existing standard of care. As you've heard, we've not stopped there.
We're also looking at approaches that can treat the components of FA mediated by the brain, which we know our therapy is not doing today. This will ultimately continue to deepen our effect size even beyond what LX2006 is able to do at launch.
Yeah. Okay. That's great. Commercially, I guess, there's a rationale, right? Most patients die from cardiac disease with FA -CM, so there's a rationale to treat early. What kind of label do you expect if you are successful and you are enriching for this higher LVMI population? Do you expect that to be the label, or do you think this can unlock a broader label?
No, we don't. I think part of what Nani was explaining, I think, is sort of the logic behind why we do not believe the two standard deviations of cardiac hypertrophy would be the label. I think some of the results we've seen with respect to troponin, the 60% reduction in troponin may represent improving patients at the earliest stages of the disease. But frankly, the definition of FA cardiomyopathy, which is what we expect our label to say, is one that we are working with opinion leaders to really define. There has not been a treatment for FA cardiomyopathy, so therefore the definition of what the disease actually is does not formally exist today. In our view, when you begin to see increases in troponin, that may be the early stages of FA cardiomyopathy.
If we have a label that represents that, it should allow us to treat patients across the continuum of the disease, everyone from troponin increases but not yet exhibiting hypertrophy. All the way through to late-stage patients which are beginning to have symptoms of heart failure. Even in that population, we had one patient in our phase I/II study who had a low ejection fraction. We saw a meaningful increase in her ejection fraction that corresponded with improvements in troponin, improvements in left ventricular mass index. So we've been able to show improvement across the range of what is likely to be reflected as our label in the future commercial landscape. Then on top of that, we have the mFARS benefit, which is roughly similar to the existing standard of care.
From our perspective, especially with the safety profile, this will represent a very compelling treatment option for patients, certainly with any cardiac involvement in the disease.
Yeah. Okay, great. Maybe before we talk about PKP2, can we just spend a couple of minutes talking about the deal you guys recently did to bring in a number of other assets. I guess, how would you rank order those assets from lowest risk to highest risk, still early experimental?
Look, I think the deal is interesting in that it gives us clearly a platform to be the leader in this disease. We believe we have what will become the best-in-class treatment for FA cardiomyopathy, and we would like to complement this with one or more treatment approaches that can deliver frataxin into the brain. Which we believe is frankly, a relatively technically challenging target relative to the heart, which is why we think multiple different therapeutic modalities should be attempted to really try to show a benefit there. As we think about risk, one of the programs is already in the clinic, has shown some benefit in increases in frataxin in muscle, which I think is notable. It has shown benefit in mFARS out to 16 weeks. But as you can hear us talking, we think about mFARS benefit in years, not weeks.
We will have to understand the durability of that mFARS benefit. Frankly, whether that mFARS benefit is mediated by skeletal muscle or whether it is mediated by improvements in the brain, s o which domains of mFARS.
Right.
As we discussed, our mFARS benefit is likely mediated by skeletal muscle, and therefore we need an approach that can target the brain and the cerebellum. As I look at the different approaches, I think they all have their pros and cons. Some are very straightforward, some are very novel, unique approaches to treat the disease. But the commonality across many of them is that they are designed to target the brain itself, and this is what makes them complementary to LX2006. Ultimately, as a treatment package here, it is unlikely that there is going to be a single treatment that addresses the totality of the disease, given it is both heart and brain. We now have a portfolio that can potentially allow us to address both with two different therapeutics.
Yeah. That is awesome. What are the next catalysts here for when we will learn more? What are the value inflection points?
In terms of FA, generally, we will have our top-line readout for LX2006 in the second half of next year. I think you can hear the progress on patient finding is going really well. There is a lot of interest in the study. We are able to find patients with these two standard deviations or above of left ventricular mass index at baseline. I think we are well on track for the second half 2027. In terms of the earlier portfolio on the neurologic side, we will give a pipeline prioritization update in early 2027 and expect to have the next IND for that pipeline submitted in 2027.
Awesome. Okay. Well, let us spend the last six or seven minutes here talking about PKP2. Maybe just to level set for people, do you want to talk about the early data you guys disclosed in January of this year? What are we going to get in the fourth quarter of this?
Sure. Just some background, as I mentioned, a disease of life-threatening arrhythmias. There are several endpoints that are likely relevant for the disease. Nonsustained ventricular tachycardia, premature ventricular contractions. Some of the patients at the later stages of the disease have reductions in ejection fraction, so they are entering into heart failure. These are the endpoints that we focused on in our phase I/II study. We presented data in January of this year. I think it was an early data set. Most of the patients at the high dose were at six months of treatment follow-up, which is the earliest time point where you could even begin to evaluate efficacy. In that data set, we saw about a greater than 20% improvement in nonsustained ventricular tachycardia. We saw a 14% improvement in premature ventricular contractions. I would say, as I mentioned, it was an early data set.
There was some inconsistency between the two endpoints in individual patients. I would say the effect size on NSVT was roughly similar to the standard of care today, which are antiarrhythmics. I think as we progress forward here, our expectations are frankly of a very different picture. What I can point to is the two patients at nine months of treatment follow-up, they average about a 65% improvement in nonsustained ventricular tachycardia. We saw a deepening of effect over time. I think the data set that we are working towards presenting later this year will have most, if not all of the patients at 12 months.
Yeah.
This will allow us to show that picture at longer time points.
Yeah. Can I ask you a question? I know that this is probably a total oversimplification. When the data came out, some of the investor discussion on whether we would see improvement over the long term was a thought that in PKP2, these endpoints, they are almost electrical, and there was this questioning of why really would they get better over time—
Yeah.
—with longer follow-up. How would you answer that?
Yeah, very simple. The PKP2 deficiency results in dysfunction in the desmosomal complex, the cell-cell junction. And there becomes fibrotic fatty infiltrates in the desmosomal complex. There's a process from a biologic standpoint to actually reform the desmosomal complex, and this is what reduces the life-threatening arrhythmias. This wouldn't happen immediately. You may see some cells where the desmosomal complex is reformed and other cells where it has not reformed at six months.
I see.
Remember, the gene therapy is just reaching peak expression at three months. That process from a biology standpoint may not have fully occurred, frankly, has not fully occurred three months after that. I think we can absolutely from a just thesis on the biology perspective, expect to see the desmosomal complex reform across more cells in the heart, and that's what should result in improvement over time.
Yeah. Okay, that's great. How many patients will we get in the fourth quarter, and is it all one-year follow-up?
We have a total of 10 patients in the study, seven patients at the high dose, which I think is the more applicable data set to focus on. We should have most, if not all of the patients at 12 months or maybe one or so at nine months. It depends on the time point of when we intend to present the data. But I think the picture will be clear in terms of the treatment effect and the durability of that treatment effect out at these time points.
Yeah.
We'll have data for nonsustained VT, PVCs, RVEF. I think from a nonsustained VT perspective, we're really double-clicking on that endpoint and focused on looking at it in terms of how the guidelines evaluate the endpoint, how the cardiac guidelines look at them. This, we think, is the closest approach to evaluating the clinically meaningful endpoint and mortality with the link to mortality in this disease.
Yeah. Okay, that's great. Maybe the other question around some of these endpoints that I think came up around the initial data disclosure was just that there was a pretty significant variance. Is that just the nature of this disease, the nature of the measure, and does that at all detract from maybe ultimately the regulatory utility of these endpoints, or how do you think about that?
I don't know. Nani, do you want to take that one?
Yeah, sure. PVCs can certainly be influenced by many things, and many normal people walking and talking can have PVCs, coffee, caffeine, just getting nervous, agitated, et cetera. So definitely we can see the many things that can influence PVCs in a patient's life, particularly one that has a substrate for ARVC. I think that is certainly there. NSVT tends to be less influenced by a lot of those things. It is really an organized circuit that needs to be triggered. Probably the main thing in these patients that influence NSVT is level of exercise and things.
As you see the data deepen and the effects deepen, you should hopefully start to see on the NSVT side a tighter control there, and the PVC variability may still be there only because of just all the things that can influence PVCs in general in life than NSVT for that matter.
Yeah. Okay. Just to clarify, you guys expect to have a regulatory update with the data, or what's the timing there?
We've not guided to if it will be with the data or not, but we will have both the clinical data update and the regulatory update in the fourth quarter of this year. We're working rapidly towards that. We received an RMAT designation a few months back and are advancing those discussions alongside collecting and finalizing the data set.
Yeah. Okay. How confident are you guys with safety with this program? I think the high dose is significantly higher than the LX2006 dose.
Yeah, no. That's one of the, I think, highlights here, is that we're at a 6E13 vg/kg dose. If we look at the cardiac biopsies, we got between three and five vector copies per cell, but we did so without any classic gene therapy-related SAEs. There were no—
Yeah.
—SAEs related to complement, liver. Sorry?
Why do you think that is?
I think that this vector has a compelling cardiac tropism profile. I think that was always our thesis around AAVrh10, that it had the most compelling cardiac tropism profile of the known vectors. It's allowed us at a 6E13 vg/kg dose to get a very compelling gene payload to the cells, but do so with limited safety events associated with it. I think that's one of the highlights of this program, that we've been able to really thread the needle on the therapeutic window, get the right amount of gene payload into the cells, and do so without gene therapy-related SAEs.
Okay, great. We're at time, but maybe do you guys want to just wrap up and talk about your cash runway?
Maybe Lou, you want to take that one?
Yeah. We're in a pretty strong cash position. Our last disclosure had us at over $230 million in cash. That gets us into 2028. You've seen historical burn rate in the low to mid-20s per quarter. We expect that to accelerate somewhat in probably the higher end of the $20 million range as we progress our pivotal trial for FA and continue to invest in the pipeline. But we've done some minor financing through the ATM over the course of the last year, and that really allowed us to execute on the Mantle Therapeutics deal without detracting any investment from the core portfolio, which includes LX2006 and LX2020.
Great. Awesome, guys. Thank you for taking the time. Appreciate it.
Thank you.
Thank you.