I'm very happy to be hosting the Lexeo Therapeutics team with me on stage right now. Joining me is Nolan Townsend, the CEO, Dr. Nani Bhalla, the CMO, and Lou Tamayo, the CFO. Thank you all so much for being here. Really appreciate the support.
All right. Thanks for having us.
Thanks for having us.
Maybe just to start from a high level, do you mind providing us with an overview of the company?
Sure. I'll start. Lexeo is a genetic medicines company primarily focused on cardiovascular disease. Our most advanced program is treating Friedreich's ataxia. Here, we're focused on the cardiac pathology of the disease. We're also seeing an improvement in the neurologic component of the disease. Our next most advanced program is treating plakophilin-2 arrhythmogenic cardiomyopathy. This is the most common genetic mutation causing arrhythmogenic cardiomyopathy. There are about 60,000 patients in the U.S. with this disease, making it one of the largest opportunities in clinical stage gene therapy. Here we have a phase I study that we've completed enrollment, and we're working towards a data readout later this year associated with this program. I think we'll probably spend most of the time talking about those programs, but we have other earlier programs in cardiovascular disease as well.
Okay, thanks. Let's start with LX2006 for Friedreich's ataxia. One thing as a company you've really been focused on is disease education. I follow all your socials that you have on this. For the cardiac manifestations of FA in particular, you've showed that there's a disconnect of physicians guiding patients through the importance of the heart health. What work are you doing to help address this issue, and what are you seeing?
Maybe, Nani, to ask you to speak to that.
Yeah, sure. A lot of efforts underway. Certainly, we've been working a lot with our societies and making sure that we're educating through those channels. You mentioned the social media. That's a big part of our education portfolio as well. Then engaging with thought leaders wherever we can to make sure that when they are having their conversations or when they're on the podium, that they're talking through the importance of the cardiac impact of this disease. Then using the advocacy organizations as well. Definitely more work to be done. I think that this whole thing of trying to coordinate care between the various specialties that manage these patients is absolutely critical, and we continue to make sure that these patients are diagnosed early from a cardiac perspective and then are being followed. So that's really where the emphasis has been through all those channels.
We've had great engagement on the social side as well, actually.
I would add, I think the introduction of a treatment for the cardiovascular disease will necessarily lead to more cardiologists engaging. We see this typically in rare diseases when there is no treatment. It's difficult to engage a population of physicians because they would say, "Well, even if I diagnose this disease, what can I do to treat the patients?" I think the introduction of a therapy will change that paradigm. I would draw a corollary to amyloid, where there was polyneuropathy and then cardiomyopathy second, and first there were neurologists involved, and cardiovascular physicians became involved later, and I think we'll see a similar pattern here as well.
Thank you. So why is LVMi the most appropriate cardiac measure to evaluate for FA? What does natural history tell us about its expected progression, and how might that frame your expectation of how the untreated arm is likely going to perform in your registrational trial?
Maybe you can talk about LVMi.
Yeah, sure. LVMi is a hallmark of the disease. All these patients who go on to having their cardiac disease, the first thing is this thickening of the heart walls and left ventricular hypertrophy, so the LVMi goes up. This is a classic hallmark of the disease that they go through this phase. If you look at the population under natural history conditions, again, not a lot of published data out there on the natural history. But looking at the data sets that we have been privy to, there's very negligible change over a year in these patients, no more than 3%-5%. We don't expect a lot of change in the study that we're looking at, which is a six-month duration.
But LVMi and the marker of that as these patients, as we've shown in our earlier data, that as they get treated, we see the LVMi come down towards normal. Definitely an important parameter, and there's data that also links it to mortality risk. We know that every 10 unit increase in left ventricular mass index portends a 20% increased risk in mortality for these patients. All in all, a hallmark of the disease and a key predictor of mortality in these patients.
We chose LVMi also just because of how precise the measurement technique is. There's very limited inter user variability. As Nani said, you typically see this increasing in LVMi over time via the pathology of the disease as a couple percent increase per year. It's an endpoint that very precise, very objective. We don't expect to see spontaneous improvements in LVMi, and we've not seen that across any other cardiac disease.
Okay. For your trial, why is it critical for you to get the right Goldilocks patient population to study? In a real-world setting, what would be the argument to use this therapy before LVMi reads as abnormal?
Yeah, maybe I can add a few words there, Nolan. I think the 70% of the population goes on to have their cause of death be some form of cardiovascular disease. We know that for the vast majority of patients, they will see the onset of cardiovascular pathology at some point of the disease course. The question then is what is the definition of the onset of FA cardiomyopathy, and I think that that's a topic that's still under some debate. The case we would make is that the elevation in troponin, which is a blood-based biomarker that is detecting cardiac cell death, is the first sign of the evolution of the cardiovascular disease for an FA patient. That's something very straightforward to evaluate. It can be evaluated via a blood test. When patients come for their annual visits, they can have a blood test that also looks for troponin.
We think this may be the appropriate trigger point to underwrite the treatment of a therapy such as this for FA cardiomyopathy. What we also know is about 40% of the population has abnormal left ventricular mass or has hypertrophy. We're somewhere between 70% and 40% of the total FA population, which would have some form of cardiac involvement throughout the disease course. The ways to identify that are as described, one would be on one end cardiac MRI, but on the other end, evaluating troponin as the point at which to underwrite treatment of a gene therapy for the cardiac disease.
Okay, thanks. For patients in your trial that didn't present with abnormal LVMi baseline, what did the biomarker data show us about its potential impact of LX2006 on the heart?
Yeah. We had a fair number of patients in the phase I trial who were either just mildly elevated LVMi, so not the abnormal definition of the greater than two standard deviations from the mean or had normal LVMi. Interestingly, all of them had elevated troponin and as they were treated, we saw if they were an increased LVMi subset, their LVMi actually came back towards normal. Those who were normal maintained their normal LVMi and pretty much all the patients had a reduction in their troponin levels. All of that points to the conversation we were just having about how early in the disease can you start to think about these patients as having a marker that points to a cardiomyopathy that's starting and when treatment should be considered and initiated.
This subset shows us that that potential is there in the short-term data that we have so far and we'll follow along.
It would point to the likelihood of not having a label restricted to only the abnormal LVMi population if patients are benefiting that are earlier in the disease via reductions in troponin, reductions in lateral wall thickness. I think importantly, not progressing towards the later stages of the disease, which we've demonstrated through now several years of treatment follow-up data. We had a recent publication in JAMA Cardiology where you can see this trend. I think we're seeing durable effect. We're seeing patients that are not progressing into later stages of the disease. I think that picture certainly would support a label that includes patients that are earlier in the FA cardiomyopathy continuum. Let's not forget the neurologic improvement.
We're getting a 2.5-3-point improvement on the mFARS scale, which is the neurologic endpoint for the disease, which was used to approve the commercially available treatment. Not only are we seeing this reversion of those with abnormal LVMi to normal, we're also slowing the rate of decline of the neurologic disease, which has its own relevance for patients, from a quality of life perspective. I think all of these features together would imply that we can treat patients across the continuum of the disease, provided they have some form of cardiac involvement, which, again, we would argue would be the elevation of troponin.
Okay, and for your registrational trial, is the definition of abnormal LVMi consistent with the subgroup that met this criterion in the phase I/II study?
Yes. Exactly the same. As I just said, the definition is the greater than two standard deviations from the mean, and that's exactly the same population of patients in the phase I, phase II that we were talking about, the six patients. It basically mimics the same criteria into the pivotal trial.
Okay. I think one point of confusion amongst the investor community has been around the powering assumptions of this trial that allow you to detect an effect size of LVMi, both greater than what's deemed the clinical bar of 10%, but also provide you with some cushion to get to that 15%. Could you further elaborate on this, please?
Yeah, maybe I'll say a few words on that. In our phase I/II study, at six months, at our high dose, which is the dose we're taking forward, we achieved a 28% reduction in left ventricular mass index. The study is powered against a 15% effect size, so we believe we have a very comfortable margin of improvement at the six-month time point relative to what we saw in our phase I/II study. And maybe you can speak to some of the other-
Yeah. Using those data sets, by the way, the clinically meaningful bar still remains at 10%.
Right
The 15% was really more on the powering side. We ran those data sets through 10,000 trial simulations to get a sense of how often the result would hit that 15% effect size, and that ends up being 99% of the time it would hit that effect size. That simulation modeling was, if anything, somewhat conservative in how we approached it because there is one patient that we used a three-month MRI for the six-month time point, and that was because this patient had missed their six-month MRI due to a hurricane. They had 10% at three months. We assumed that 10%, but when you look at their nine-month result, it is actually 30%. It is a pretty linear relationship in these patients in this time points, so it is likely that they were more at 20%.
Again, somewhat of a conservative estimate when we powered that to the 15% random simulations.
I know the Lexeo team has a lot of additional natural history data as well, but one other thing that investors bring up is just looking at each of the individual profiles of the phase I/II patients. Is it fair to expect that in the registrational trial we might see some outliers, or do you think their baselines are going to be essentially all identical with each other?
I would say in general, what we saw almost consistently is that the higher the baseline level of left ventricular mass or hypertrophy at the start, the greater the improvement. We had some patients that had up to six standard deviations of left ventricular mass index at baseline, and they improved the most significantly. In our pivotal study, we have a stratification criteria which will ensure that we have patients across the range of the disease. They will, for example, not all be sitting at exactly two standard deviations.
Right.
There will be patients that start at higher baselines than this. We also have CLARITY-FA, which is a natural history study that has been running for the past period of time. In this natural history study, we have been enrolling patients. We have a picture of the baselines of the patients that have come into that study. Many of these patients will ultimately cross over into the treatment study. I think we have a broad picture of the disease severity as evidenced by LVMi of the population that will ultimately be entering the study, and we know that there's sufficient disease burden to achieve the effect size or greater than the effect size that we're hoping for in this trial. That's, I think, something we're very comfortable with as we designed and finalized this study design.
Okay. Certainly the patients aren't all going to look exactly identical at baseline.
They definitely will not.
Okay. Thank you for that clarity. So, another part of that modeling simulation work you did, you looked at three different doses in phase I/II, and you did see a dose response. I am curious how that factors into the simulations and conservatism you did, knowing that there wasn't all patients in just the highest dose, but you do see a dose response.
Yeah.
Yeah. So I can answer that. We did not look at all the doses in the simulations. We really concentrated on the patient with the moderate to high dose, and those six patients that had the high LVMi in those two doses. That's the data that we used to help us with the trial design, the powering assumptions, and the simulations. Then going back to that one patient that I talked about where that's where the conservatism comes in because we really assumed a much lower LVMi change in that patient versus what they likely had in true just because we didn't have that intervening MRI because of him missing that visit. So, yeah. It wasn't based on all the dose. It was just looking at those two doses.
And in general, I think we had a trend towards a deeper and more rapid improvement in LVMi at the higher dose. I think that that's an important feature of the program is that not only is there the correlation to the baseline LVMi level, of which we have an understanding that there is sufficient disease burden. We also know that the higher dose delivered a more rapid and deeper response than the lower doses. But I would even say with that, you include all doses, we achieved an 18% reduction. So we still cleared the 15%, even if you include the low dose where the effect size was lower. No matter which-
Yeah
... way you slice it, we are clearing the 15% effect size in all of the different scenarios that we looked at.
Okay. How has the commercial experience of SKYCLARYS shaped your expectation around the potential TAM for gene therapy, especially since this therapy has the potential to address the cardiac manifestations, the leading cause of mortality?
Yeah. I think what's interesting about where this therapy is evolving is, as we've been describing, we've been able to reverse the hallmark of the cardiac disease, which is hypertrophy. So those that were abnormal have become normal. We've also achieved a 2.5 - 3-point improvement in the mFARS scale, which is roughly similar to the commercially available treatment. What's also interesting is that this improvement has been durable, and it has been deepening over time. So we have patients out to two years of treatment follow-up where they have continued improvement in mFARS. I think that that's an important feature to compare against the commercially available treatment, is durability of improvement from an mFARS perspective.
I think some of the features of the SKYCLARYS launch that we've been watching, one is the speed of uptake or how quickly patients were brought on to treatment from a reimbursement perspective. I think when we look at that was very rapid. So you saw a substantial number of patients out of the total in the U.S. that received very rapid access to treatment, which means payers were motivated to see patients on drug, as were physicians. I think that this is an important feature. What we have noticed is patient dropouts from the commercially available treatment. We've heard that in some cases, this is due to side effects. In other cases, we understand this may be waning disease improvement.
I think the fact that we have both this ability to reverse the disease on the cardiac side, but also achieve this durable improvement in the mFARS scale to us means we could be looking at a step change in the standard of care for this disease with a treatment like this. Obviously, we're doing so with, I think, a compelling safety profile. We've had no overt treatment-related SAEs, and we've had no SAEs at all at the higher doses.
What are your main goals over the next few months and into the next year into the data readout for this program? Any last comments on this before we shift gears in our conversation?
Maybe you could speak to some of the plans we have on the medical affairs side. I will talk maybe to commercial.
Yeah. We continue to rev up the education side of things, making sure the awareness is there. Nolan made a really good point earlier about the fact that when clinicians don't have a treatment choice, the vigor to diagnose and start to get them to treat it, et cetera, is very low. We want to make sure that that is now known to clinicians, that this treatment is available. We are building up our medical affairs team. We have hired the MSL to go out in the field and start doing these programs. The social media is also being revved up from that perspective. Continue to engage with thought leaders. Really doubling down on the medical affairs side to get the education, the word out there from them.
Then, obviously making sure that on the operations side for the clinical trial itself, that we are getting our sites activated quickly and that we are starting to move the process forward for recruitment into the trial.
I think from a commercialization standpoint, as would be typical, we are working on market access and ensuring that with the comprehensive data that we expect to produce at the time of the top-line readout, this will make a credible case to payers. This also will help us to better triangulate towards an appropriate price point for the disease, looking at cost offsets. We are progressively building a commercial organization. We have made the first few commercial hires, and we would expect to see more on the customer-facing side as we get into 2027. So a typical rare disease, a type of preparation. Although I would say for this disease, it is very attractive from a commercial perspective because there is a concentration of patients at a small number of centers in the U.S., so it will not require a large field presence from a commercial infrastructure point of view.
Okay, thanks. Let us move on to LX2020 for PKP2 -ACM.
Great.
Why might conditions like PKP2 -ACM take more time to show clinical benefits? Essentially, what remodeling needs to occur in the heart to start to see these benefits play out over time?
Do you want to speak to that?
Yeah. The PKP2, the disease itself is a disease at the cellular level with the connections that are between cells, the desmosomal connections, and these are the connections that really help the cells communicate with each other and then kind of keep a smooth contractile properties, in addition to all the other things that these connections do. With PKP2 deficiency, these connections start to break down and these cells start to separate. There's a lot of electrical dispersion around these cells, so there's not as coordinated electrical conduction, and that's what starts to give rise to a lot of the arrhythmias that we see. And then that's also what then progresses to fibrofatty deposits that start to form within the cardiac muscle and then actually exacerbate the arrhythmias, exacerbate the disease progressing to a heart failure state down the road.
You can see that when you're starting to treat these patients, you can certainly see some early benefit, maybe with some of the arrhythmia side of things, which then starts to deepen. But as far as remodeling, you're trying to rebuild those connections and really reverse that process. That process is going to take time. So, it's going to be something that we will see over time as to how our effect deepens. And then certainly long -term, we would love to see that we get to a point where we're preventing the progression of this disease to a heart failure state.
I'd add, the data set that we presented earlier in the year, the majority of the patients were at six months of treatment follow-up. This is really the earliest time point where you could even begin to look at efficacy. The gene therapy is just reaching peak expression at three months. Yet you play this forward three more months, there is some remodeling that has occurred, but you would not expect it to have completed the process. I think at 12 months or even nine months, there would be more of the remodeling that's occurred, and I think the place to look for this is actually in the two patients that were at nine months. In the data set we presented earlier in the year, we saw on average 65% improvement in the non-sustained ventricular tachycardia endpoint. Again, relative to the high 20% in the total data set.
I think we're already seeing signs of this deepening and more consistent improvement in NSVT at the later time points, as supported by some of the points that were made about the biology of the disease.
A lot of different things to focus on with this, PVCs, NSVT, and VT. Which endpoint should investors be spending the most time assessing? You have been spending a lot of time with clinicians, talking about the ventricular arrhythmia endpoints, and what do they have to say about what should be evaluated?
You will start, and then I can-
Yeah.
Yeah. I think NSVT is probably the most important of the three. It is one that is central to the disease. I think the only debate is it a clinical endpoint, feels function, survives, or is it a surrogate? In our opinion, and that is obviously a regulatory framework, but in our opinion, it is very much a clinical endpoint. Some of the others are more distant from the disease, for example, premature ventricular contractions, and are more subject to outside influences. If you have a lot of coffee one day, you can impact your PVCs, for example. We think NSVT is more central to the disease, less sensitive to outside factors. It is measurable in a clinical trial context. I do not know if there is anything else.
Yeah, so I would just add that the thing about it, as Nolan mentioned, the focus is really on NSVT. That is probably the most clinically meaningful. That is the arrhythmia starter, so to speak, that leads to sustained ventricular arrhythmias and then can lead to unfortunate events like sudden cardiac arrest or sudden cardiac death or for that matter, the firing of the defibrillators that these patients have. So they are always kind of living in this world of like, if I start to feel something, when is that defibrillator going to go off? It is a big impingement on their quality of life. The question is, well, how do you define the NSVT and what is really the meaningful definition? As we talk to thought leaders and we look at, there is a guideline-directed definition of what that is, and the clinicians certainly feel very comfortable with that definition.
That's really looking at the three beats or greater that string themselves together at a very fast heart rate of more than 100 beats per minute. That's really where we're going to be aligning on from a definition and backing perspective.
Any time you're working in a rare disease with no real optimal treatment, you're typically pioneering in, certainly with the novel modality, you're pioneering in novel endpoints. Sometimes you have to design a surrogate around the disease and look for the correlation. I think this one is far clearer than many other rare diseases from the perspective of the relevance of this endpoint to the disease. It's almost undebatable, its relevance. The questions will be, how do you calculate it? So what's the right way to look at NSVT in its most clinically meaningful manner? I think Nani pointed to some of the guideline-directed approaches that are the way to consider that. Then the other question is what's the clinically meaningful effect size? We know the antiarrhythmics existing standard of care is in the mid-20% improvement.
Anything at or greater than that, we think it would make a compelling therapy. I think those are a couple of the things we'll hash out with regulators. But whether it's NSVT or not probably isn't the debate. It's some of these other more nuanced features that I just described.
Anything you'd leave us with as to how we should be thinking about the bar for the additional data that can come later this year and in the background, also thinking about designing a registrational trial here?
Yeah, I think some of what I just mentioned, we have existing standard of care antiarrhythmics. These are in about a roughly 20%-25% improvement in non-sustained VT. I think we'd be looking for a therapy that meets or exceeds that threshold of improvement in NSVT. I think we'd want to see some consistency across the patients in that endpoint. We want to have a similar safety profile as we have today. From a future study, I think it's reasonable to assume that study would have a control group associated with it. The size of the study, we're not sure of yet. I think that we'd be looking at a study with an endpoint that's focused on NSVT across a certain number of patients, likely with the control group, and that's the likely direction of travel. I don't know if there's anything else you would add?
No, I think those are the major points.
Just in the last few minutes here, I wanted to take a step back to view the company as a platform. The commercial is potentially in the near future for you. So how do you think about COGS and different things as you really emphasize your manufacturing platform and strategy and differentiation in particular, especially since PKP2 -ACM is not exactly a super rare disease?
Yeah. At the outset of the company, we focused on designing a manufacturing process that was commercially scalable, that could allow us to treat diseases of the size of arrhythmogenic cardiomyopathy. I mentioned 60,000 patients. It's systemically administered at a, call it mid-E13 vg/kg dose. I mean, you could do the math and understand the vector demand associated with that. Also, early on in the company, we had a focus on APOE4 Alzheimer's disease. That's obviously not even a rare disease. It's 900,000 APOE4. So we had to design a manufacturing process that could allow us to address these very large markets. That led us to focusing on Sf9 baculovirus suspension as a manufacturing process. We've achieved a yield profile in that process that can yield cost of goods that are, in some cases, close to biologics, and at very compelling yields.
I think four or five batches may be able to supply the entire FA market with the process that we've developed. I think that this is a process that's fit for purpose for indications like PKP2 arrhythmogenic cardiomyopathy, and will yield substantial COGS advantages, but also can allow us to supply large indications like PKP2.
Okay, great. Well, thank you all so much. Really appreciate the support and for coming to our conference.
Yeah, thanks for having us.
Wish you all the best.
Great questions. Thank you so much.
Thank you.