Good morning and welcome to Lexeo Therapeutics' webcast presentation. At this time, all participants are in a listen-only mode. A brief question and answer session will follow the formal presentation. As a reminder, this call is being recorded. I would now like to turn the conference over to Ashley Kaplowitz, Head of Capital Markets for Lexeo Therapeutics. Ashley, please go ahead, ma'am.
Thank you. Before we begin, I would like to remind you that this call will contain forward-looking statements regarding Lexeo's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. With that, I would like to turn the call over to our CEO, Nolan.
Thank you, Ashley, and thank you to everyone joining us today. We are excited about the potential of LX2020 and the opportunity ahead of us in PKP2 ACM. We believe this is an underappreciated area within cardiovascular rare disease. PKP2 ACM is a serious, progressive genetic disease with no approved treatment designed to modify its course, and the affected population is larger than those associated with many traditional rare disease gene therapy indications. With additional data expected this quarter, today's discussion will provide important context on why we believe this is a compelling opportunity, including the clinical disease burden, the scientific rationale for LX2020, and the framework we will use to evaluate clinical treatment response. Later on, Dr. Gasperetti will provide an important clinical perspective on the assessment of ventricular arrhythmia burden in patients with PKP2 ACM.
To begin with the disease and significant unmet need, I'll turn the presentation over to our CMO, Nani Bhalla.
Thank you, Nolan. PKP2 is a serious, progressive, and potentially fatal genetic heart disease. It represents a larger rare disease with a meaningful global commercial potential, including 60,000 affected in the U.S. The disease has both electrical and structural manifestations, with patients experiencing premature ventricular contractions, non-sustained and sustained ventricular tachycardia, progressive ventricular dysfunction, and in the most serious cases, sudden cardiac death. Presentation often occurs in adolescence or early adulthood, creating a lifetime of uncertainty, monitoring, exercise restriction, and treatment burden. The impact is not limited to measurable cardiac events. Patients frequently live with anxiety about whether a symptom may signal an arrhythmia, a looming ICD shock, or disease progression. That is especially difficult for younger patients who may be asked to substantially limit physical activity.
Despite the severity and lifelong nature of PKP2 arrhythmogenic cardiomyopathy, there are currently no approved therapies designed to slow, prevent, or reverse the underlying disease. Current management is individualized and may include exercise restriction, beta blockers, and off-label use of antiarrhythmic drugs, catheter ablation, ICD implantation, and in advanced cases, transplantation. These interventions can be important and sometimes life-saving, but each has limitations. Arrhythmias frequently recur after ablation and lifelong risk for ventricular tachycardia remains high. Antiarrhythmic therapies may produce partial reductions in arrhythmic activity, but efficacy may be mixed, and chronic use can have negative long-term impact. ICDs can terminate life-threatening rhythms, but they do not prevent the underlying disease from progressing. Many patients continue to progress to advanced heart failure, with some ultimately requiring heart transplantation. Devices also carry procedural and lead-related risks, as well as the ongoing burden associated with the possibility of a painful shock.
The unmet need, therefore, extends beyond symptom control. Patients need a therapy that targets the genetic root cause and has the potential to improve the electrical and mechanical consequences of PKP2 deficiency. LX2020 is an AAVrh10-based gene therapy designed to deliver a full-length functional PKP2 gene to cardiomyocytes. PKP2 is a key component of the desmosome, which helps maintain the connections between heart cells. When PKP2 is deficient, those connections are disrupted, contributing to electrical instability, mechanical dysfunction, and progressive cardiac injury. By restoring PKP2 expression, LX2020 is designed to potentially address the biology underlying both the electrical and structural manifestations of the disease. PKP2 is not a one-dimensional disease, and no single measure captures its full biological and clinical burden. We think about treatment response across three complementary domains. The first is arrhythmic activity, including PVC burden, NSVT, and sustained ventricular arrhythmias.
The second is myocardial structure and function, including strain, contractility, ventricular size, and ejection fraction. The third is the patient and clinical burden, including symptoms, treatment escalation, hospitalization, ablation, ICD shocks, and other consequential patient-related outcomes. These measures may evolve on different timelines with electrical changes potentially emerging before structural remodeling. For today's discussion, I'll focus primarily on the arrhythmic domain. Ventricular arrhythmic activity can present in several forms. Premature ventricular contractions, or PVCs, are premature beats arising from the ventricles. They can occur frequently and provide a quantifiable measure of ventricular ectopic activity. NSVT represents a different pattern. Rather than isolated or separated ectopic beats, NSVT, as defined in the cardiovascular clinical guidelines, consists of at least three consecutive ventricular beats at a rate greater than 100 beats per minute, terminating spontaneously in less than 30 seconds.
Sustained ventricular tachycardia persists for at least 30 seconds or requires earlier intervention because of clinical instability. Other clinically consequential outcomes include ICD therapy and sudden cardiac death. These events are related, but they're not interchangeable. Not every PVC progresses to NSVT. Each provides different information about ventricular electrical instability. Both PVC burden and NSVT provide relevant information about ventricular electrical substrate in ACM. However, they measure different features. PVCs are prevalent, and PVC burden measures how frequently ventricular ectopic beats are occurring. Because most patients with PKP2 ACM have high PVC burden, it is an an important measure and a target to measure potential treatment response. PVCs, however, may be influenced by external factors such as exercise, stress, caffeine intake, and can fluctuate significantly over time. Furthermore, a large change in the PVC burden may not always trigger a meaningful change in treatment.
NSVT is made of ventricular beats which occur consecutively as a burst lasting less than 30 seconds. This reflects greater arrhythmic complexity and has a stronger established relationship with clinically consequential outcomes such as sustained ventricular tachycardia or ICD discharge. For this reason, NSVT is a major factor in ACM risk assessment, whereas PVC burden is a minor factor. Any incidence of NSVT is considered clinically meaningful and increases the risk of future ventricular tachycardia. As we evaluate the therapeutic impact of LX2020 across endpoints, we've developed a framework for how to best interpret PVC burden and NSVT, particularly when the measures do not move in the same direction. This matrix provides a framework for that interpretation. Rather than assigning significance to either measure in isolation, we consider the pattern across both measures, the magnitude and durability of the changes, and the broader patient-level data set.
This consistent framework informs our interpretation of the data presented to date and will guide our assessment as the data set matures. Importantly, the reason NSVT carries particular weight within this framework is its established relationship with clinically meaningful outcomes. Ultimately, we would hope to see both measures decreasing over time in the majority of the patients. But given the regular fluctuations in PVCs observed in PKP2 ACM and the susceptibility of this measure to external factors like exercise, we might interpret reduced NSVT as a more meaningful reduction in clinically significant arrhythmias despite a lingering PVC burden. The clinical relevance of NSVT is supported by evidence across multiple studies. NSVT is not simply a more complex rhythm observed on monitoring.
Its presence is associated with meaningful downstream clinical risk, where patients with NSVT had approximately 2.5 times the risk of subsequent sustained or life-threatening ventricular arrhythmic events. NSVT also informs clinical practice. Its detection may prompt additional monitoring and risk assessment and can contribute to decisions involving medication, ablation, surveillance, and primary prevention ICD therapy. PVC burden alone is unlikely to prompt ICD implantation or surgical ablation, for example, but NSVT almost always triggers a clinical intervention. Finally, NSVT can be assessed objectively through ambulatory monitoring using defined beat count, rate, and duration criteria. This provides a clinically grounded and consistently measurable framework for evaluating NSVT in our clinical program. Having established why NSVT is clinically important, I want to explain how we are defining and assessing this measure in the LX2020 clinical program.
In our January 2026 data cut, we evaluated and presented NSVT as total ventricular runs defined as three or more consecutive ventricular beats at any rate. That approach allowed us to capture the full spectrum of consecutive ventricular activity observed on ambulatory monitoring. As we progress discussions with regulators and work towards establishing an endpoint with the highest clinical relevance in ACM for the purposes of a future registrational trial, we have focused on guideline-defined NSVT. At least three consecutive ventricular beats at a rate greater than 100 beats per minute, terminating spontaneously within 30 seconds. This is a definition used in the clinical guidelines in ACM literature and in established risk frameworks. As the most common clinically significant manner in which to measure NSVT, it will be the basis of our assessment going forward. The distinction is illustrated by the examples on the slide.
The four-beat run at approximately 85 beats per minute is included in total ventricular runs, and it reflects a clinical abnormality, but it does not meet the rate threshold for guideline-defined NSVT. The five-beat run at approximately 150 beats per minute is included in both the prior and current measure since it qualifies as guideline-defined NSVT. Importantly, this does not change the underlying ECG recording or the ventricular activity that occurred. It provides a more clinically meaningful way to classify that activity and evaluate change over time. Turning to the patient-level baseline, this slide shows the guideline-defined NSVT data that will anchor our evaluation of LX2020 going forward. The event counts are lower than total ventricular run counts because slower runs that do not meet the greater than 100 beats per minute threshold are not classified as guideline-defined NSVT.
Every participant, however, had at least one qualifying NSVT event at baseline. That matters because established ACM risk frameworks recognize a history or presence of NSVT as a clinical risk marker. Any presence of qualifying NSVT is therefore clinically relevant even before considering the total number of events. Importantly, we do not expect the effect size to be diluted because of the updated baselines. In practice, I looked at PVC burden and NSVT differently. A modest change in the PVC burden may not by itself materially change my assessment of a patient's arrhythmic risk. The detection of NSVT, however, did change that assessment and prompted consideration of closer monitoring, a change in treatment, or, depending on the patient's overall risk profile, an ICD implant or a change in the settings of a previously implanted ICD. At the same time, presence and burden provide different information.
One qualifying event establishes that NSVT occurred, while the number of events provides additional information about the patient's overall arrhythmic burden and risk. For that reason, we will evaluate both the presence of NSVT and changes in the burden over time alongside PVC burden and other outcomes. This provides a clinically grounded and consistent framework for evaluating treatment responses as the LX2020 data set matures. Now, putting this into context as we think about the upcoming readout, our first consideration will be whether LX2020 produces a meaningful reduction in clinically relevant arrhythmic activity. NSVT will be an important clinical lens with PVC burden, safety, and the broader patient-level data set providing essential context.
If the current care results in 20%-30% relative reduction in the risk of NSVT, a benefit beyond that in the 35%-40% range with a favorable safety profile should be extremely meaningful for patients and physicians, particularly since currently used treatments such as flecainide and amiodarone may have significant side effects and do not address the progression of heart disease. This benefit can be measured in a number of different ways. For example, it can be looking at a change from baseline, or it can be understanding the number of patients that fall below a particular threshold with a treatment at a given time point. Seeing a sustained or deepening effect is also important, and we want to see an effect size materially better than current care with the guideline-defined NSVT baselines.
Because it may take time for the biological effects of gene therapy to translate into clinical benefit, we would want to see the effect maintained and potentially deepened over time. Finally, safety will remain central to the benefit risk profile of LX2020. The patients we are targeting may be earlier in the disease journey and are considering a one-time genetic therapy. A favorable safety profile, together with meaningful and durable arrhythmic improvement, would support the potential of LX2020 to change the treatment paradigm. The upcoming readout should offer insight not only into the clinical profile of LX2020 but also provide greater clarity on the path forward for the program. We remain on track to provide a regulatory update concurrently with the readout this quarter. To help put this framework into clinical context, I'm pleased to welcome Dr. Alessio Gasperetti of Cleveland Clinic.
Dr. Gasperetti is a clinical electrophysiologist whose clinical and research work focuses on inherited arrhythmia syndromes and arrhythmogenic cardiomyopathy, ventricular arrhythmias, and sudden cardiac death risk stratification. Dr. Gasperetti, thank you for joining us.
Oh, absolutely. Thank you for having me today. My journey into management of ACM patients has been quite long. I have the privilege of working with those patient population across Europe and the U.S. over the last decade, give or take. I started taking care of those patients in Europe, in Milan, Italy, one of the largest EP centers under the guidance of Professor Tondo. I did one of my post-docs at the University of Zurich, which has a very large registry for patients with arrhythmogenic cardiomyopathy. Then I came to the U.S., where for seven years I was in a joint tutelage under Dr. Calkins at The Johns Hopkins University, where they have the largest arrhythmogenic cardiomyopathy center in the world. And I was working also with team in Utrecht.
I really got a good exposure during my training and during my early years to high volume centers taking care of a large array of patients with arrhythmogenic cardiomyopathy, right-sided, left-sided, biventricular. It's been very exciting. Now I'm at the Cleveland Clinic, and we're doing good work here too. It's been a long journey, but I've certainly learned a lot, and it's been very, very exciting to see all the new changes and improvements that have entered the field.
Great. Hey, thanks for that. Then, as we think about ACM and arrhythmogenic cardiomyopathy, particularly PKP2 associated, can you give us a little bit of a sense as from your perspective, how do you see the unmet need and what are you thinking about when you see a patient who has PKP2-associated ACM? How are you trying to understand where they are in their disease journey, and how are you assessing them initially?
Oh, this is a fantastic question. Anytime you see a patient with arrhythmogenic cardiomyopathy, I think you got two questions to answer in front of you. Where is that patient in their journey right now, and where are they going to be in five years? And the reason for that is that this is a progressive disease. My role as a clinician is to make sure that this patient is safe today, right now, but that I'm also trying to steer the disease progression away from bad outcomes down the line. And this is a sort of a story of two clinical outcomes in this patient. This patient suffers from pretty gnarly arrhythmias. We know that sudden cardiac death from ventricular arrhythmias is really the main cause of death in the early stages of this disease.
But down the line, this is also progressive disease that can cause pretty advanced heart failure, and if untreated, this patient can progress to Stage D heart failure and require heart transplantation. It's always the first thing is to get a sense where they are right now. Are they in a more arrhythmogenic phase of the disease, or are we already seeing signs and symptoms of heart failure? And very often, the first question that we need to answer is, does my patient need a defibrillator right now? Risk stratification and specifically arrhythmia risk stratification plays a crucial role in our first interaction with the patient. It's a lot of data gathering, getting a sense of where they are mentally, clinically, and physically, and trying to see what I can offer them at the get-go.
Thanks. You talked about the risk assessment, you talked about the arrhythmia risk and trying to understand that risk a little bit better within the assessments that you do initially. Can you tell us a little bit about how you look at the various arrhythmias such as PVCs, NSVT, and the risk of ventricular tachycardia, and a bit about how do you interpret these different measures more clinically regarding clinical importance and overall burden, et cetera?
Absolutely. We have always tried to use a multimodality assessment of those patients. Whenever we get a Zio patch or a Holter, we always pay a lot of attention to the PVC burden. Most centers tend to use an average burden over 24 hours. We also pay a lot of attention of non-sustained ventricular tachycardia. Historically, the field has used non-sustained ventricular tachycardia as a binary outcome. A patient either has it or does not have it at a specific time and place. But over the last few years, there has been a lot of interest in trying to see what is the value of the burden of non-sustained ventricular tachycardia as well. Those two metrics give us very different signals and very different information about the patient.
Most of the current risk stratification strategies, both at a European and an American level, combine those two parameters, so they are both important. But if we look at, for example, the ARVC risk calculator implements both of those metrics, it is very clear that the relative weight of those two is somewhat different. If we look at the PVC burden, which is generally measured as a logarithmic association with risk, and the NSVT, the presence of non-sustained ventricular tachycardia as somewhat two-fold the magnitude of prognostic value that the PVC burden has. So really both are important metrics, but I think that whenever it comes down to what is a more predominant marker of arrhythmic risk, probably the presence of non-sustained ventricular tachycardia seems to be more important.
Thanks. Yeah, I think that is an interesting point about just the different weight that you would look at from the standpoint of NSVT versus PVC burden. One of the things that I wanted to ask you a little bit about is, albeit may seem simple and straightforward, but defining NSVT. How do you as clinicians and then also looking at what the guidelines say, how are you defining NSVT when you are reading a Holter monitor or looking at a Zio patch, et cetera?
Well, that's such a good question because we all need to speak the same language in order to pool our data. I think that the ARVC community and the arrhythmogenic cardiomyopathy community as a whole, starting at least in 2018, 2019, has somewhat come to an agreement that our definition of non-sustained ventricular tachycardia, and this is what has been reported across probably the last decade of scientific studies, has been three or more ventricular beats in a row, total episodes lasting less than 30 seconds with a heart rate of around 100 beats per minute or more. It's a fairly standardized definition with pros and cons, but it has served us well and has really helped us risk stratifying those patients.
Thanks. I think that's important only because, and you just said that also when you look at the literature and how the published literature is defining this is with that format. So I think it's important to make sure that we're all singing from the same hymn sheet, so I appreciate that. Thank you.
Of course.
So just keeping that lens a little bit more, how do you manage these differentially, let's say, in the terms of disease management when you see a patient who has both the PVC burden and also having episodes of NSVT? As you're talking about that a little bit, can you also talk a little bit about, you talked about this binary feeling of NSVT. But talking a little bit about what is a low burden of NSVT? What is the meaningfulness of that versus a higher burden? Because there's this sense that maybe a low burden of NSVT is not as clinically meaningful. So just trying to get a sense of how you see that and how do you assess and manage these arrhythmias differentially in patients?
Absolutely. It's a wonderful question, and I'll probably start from the back end of it, just because around 50%, 60% of all patients, whether it's arrhythmogenic cardiomyopathy, will come through a clinic or will get admitted with a combination of PVC and NSVT. If those two are present, we manage both, and we use both as a good marker of risk stratification. But there is probably around a quarter of patients, whether it's arrhythmogenic cardiomyopathy, that will be evaluated, will be found having a very low PVC burden, and yet they do have non-sustained ventricular tachycardia. Just because the burden of non-sustained ventricular tachycardia is low, the number is low, like one or two episodes on a Holter, it doesn't mean that we can ignore that data point. If anything, that data point is actually very important because that's the main marker of arrhythmic disease of a specific patient.
Just to give an idea, most of the current risk stratification strategies use NSVT, as I mentioned, as a binary outcome. The presence of one or two runs of NSVT at a Holter put patients into a completely different bin of arrhythmic risk, to the point that the presence of non-sustained ventricular tachycardia can easily trigger at least the consideration for an ICD implantation in a patient in an independent way from the PVC burden. Just because the number is low doesn't mean that the effect size is low. Clearly, a much higher number means a much higher risk. But just a low number doesn't automatically correlate with an absolute low risk of arrhythmias.
Now, when we try to get a sense of what's a meaningful change and how do we like to see those numbers change over time, well, in an ideal world, if a patient has non-sustained ventricular tachycardia, couple of runs, few runs over a Holter or Zio patch recording, ideally, I would like those to go away. I think that if we have a normalization of non-sustained VT burden to the point that they completely disappear, I think that we are really stabilizing the arrhythmic risk of this patient. I will also acknowledge that sometimes patients come in with a much higher non-sustained VTach burden, and it may be impossible to reach zero over a small period of time or with a single intervention. Right now, we do have few data out there from few of the interventions that have been attempted in this patient population.
Probably thinking about data from flecainide showing very good clinical response in these patients. We have seen around a 30% drop in NSVT burden, specifically around 25%- 30% of patients that had non-sustained ventricular tachycardia before the pharmacological intervention really become non-sustained ventricular tachycardia-free during follow-up. I think this is a reasonable drop to aim for in a therapeutic intervention, acknowledging that not all my patients will have non-sustained VTach, but those that have, if I get around a third of them NSVT-free or 40% of them NSVT-free, and we have a good 30% drop in their burden in those that are not NSVT-free, I think that's a reasonable clinical outcome to aim for.
As you think about that, when you think of those numbers that you talked about from the standpoint of reduction and what would be clinically meaningful from a reduction perspective, when you then bring gene therapy into the mix and LX2020, which is our program, how do you start to think about what would be a good bar for gene therapy to strike that would be clinically meaningful, not just for you as a clinician, but also for your patients, that would make sense for you to say, "Hey, you know what? This is a treatment that's met the bar that would be set"?
Oh, that is a phenomenal question, and I think it truly goes down to how are therapeutics affecting the natural course of disease in arrhythmogenic cardiomyopathy? The real answer is that none of the medication that we're currently using, none of the intervention that we're currently applying to those patients is really changing the natural history of disease. The gene therapy, both your program for sure, has the potential of changing the long-term trajectory of disease. Whenever I prescribe medication and I'm achieving a reduction in PVC burden, a reduction in non-sustained VTach burden, I'm somewhat stabilizing my patient. But I'm not doing anything for their overall risk of structural disease progression over the decade. And I'm not significantly impacting their risk of heart failure down the line. Probably exercise reduction is the only thing that plays a significant role in that alley.
But certainly, I don't think we have convincing data from any of the medications. Therefore, I think, gene therapy strategies have the unique opportunity or the unique feature of being potentially able of changing the whole natural history of disease. And that's why I think they're so appealing to clinicians, but also to patients, because the idea is that we are changing their structural components, and potentially we're altering the progression of disease. So probably, if we are achieving a similar bar of arrhythmia reduction that we have achieved with medications, we are in a very good spot because if we are tying, in terms of effect size, with flecainide or with beta blockers with exercise reduction, and on top of that, we also have the potential for reducing heart failure down the line. Well, I think that's a very reasonable clinical expectation from this sort of novel therapeutic.
Fully acknowledging that in most trials we won't be able, even probably in a phase III trial, we will not be able to see a meaningful heart failure or heart transplant reduction down the line just because this is a progressive disease that progresses over a timeline that is measured in multiple years. We're looking at maybe 5- 10 years to see really the heart failure kicking in from the vast majority of diagnosis. But I think the potential of preventing that is there, and that will be incredibly valuable for patients and clinicians alike.
Thanks. As we kind of come to a close on this, any last thoughts that you want to leave the audience with when it comes to PKP2 related arrhythmogenic cardiomyopathy management, NSVT? How do you think about gene therapy, et cetera? I know we've talked a lot about it, but anything that you want to add to the discussion we've just had?
Yeah, I think gene therapy in this patient population is a very exciting tool that is coming into our tool set. I don't think that every patient will automatically qualify for this kind of intervention, but I think that there is certainly a significant niche, and not even niche at all, but a significant portion of patients that, down the line, could really benefit from this. The arrhythmia components that we have discussed, I think that the most important point that I would really like to reiterate, because we discuss among colleagues about this all the time, non-sustained ventricular tachycardias are important, and over the years we've kind of forgot about the concept of burden. Arrhythmogenic cardiomyopathy has used this binary outcome from probably too long. I think our colleagues in hypertrophic cardiomyopathy have implemented a burden analysis much earlier than we did.
I think really taking into consideration all different points through multidisciplinary and multisystem assessment of this patient is important. Also reminding that we are managing the arrhythmic risk today with the hope of managing heart failure down the line with a single therapeutics is really important topic that I think should always be mentioned when we talk about pros and cons of this novel therapeutics.
Great. Dr. Gasperetti, thank you for sharing your perspective and for helping us place these measures in the context of clinical practice. That concludes our discussion. I'll now turn the call back to Nolan for closing remarks. Nolan?
Thank you, Nani, and thank you again, Dr. Gasperetti, for joining us today. I want to close by connecting the clinical discussion back to the broader opportunity for LX2020. Based on the addressable population and the potential value of a one-time disease-modifying therapy, we believe LX2020 represents a multi-billion dollar market opportunity. The program also benefits from practical development and commercial advantages. Patients are concentrated across a relatively small number of leading specialized heart failure treatment centers worldwide, creating a meaningful global opportunity, providing access to a substantial, identifiable patient population that can support rapid clinical trial recruitment and future commercial uptake. Our manufacturing platform at Lexeo is designed to support scalable and cost-efficient supply for a population that is one of the most prevalent disease area opportunities in gene therapy. Ultimately, the commercial opportunity depends on delivering a therapy that meaningfully changes the course of disease.
That is why the clinical framework we have discussed today and the additional data expected this quarter are so important. We remain excited about the potential of LX2020 and look forward to sharing the additional clinical data. Thank you for joining us. I will now turn the call back to the operator for questions.
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. In fairness all, we ask that you please limit yourself to one question. One moment as we compile our Q&A roster. Our first question is going to come from the line of Roanna Ruiz with Leerink Partners. Your line is open. Please go ahead.
Hey, everyone. A couple from me. I appreciate your comments about NSVT being the more clinically meaningful endpoint. As a follow-up, could you just walk us through what supports your confidence in being able to enroll patients with sufficient an NSVT burden? Could that be a hurdle for a pivotal, or if not, could you walk us through why?
Thanks, Roanna, for the question. I would say first off, you can see the patients in our study, the vast majority had an NSVT burden at baseline. So even in this study of 10 patients, we were able to find a meaningful number of patients with an NSVT burden. I do not know, Nani, if there is anything else you would want to add to that.
No, and I think as Dr. Gasperetti was talking, recognize that almost 85%-90% of patients, if you total up those who have PVCs and NSVT and then those who have low burden of PVCs but also have pretty much primarily only NSVT, I think you are looking at a very large majority of the population that has enough burden of NSVT to enroll into a trial.
Also remember, the presence of NSVT is a factor that leads to the implantation of an ICD. So many of the patients that we are enrolling in our trial have existing ICDs, almost by definition would have an NSVT burden. So we do not believe this would be an impediment to enrolling a registrational study around an endpoint of this profile.
Okay. Super helpful. If you could put your regulatory hat on for a sec, could you help share what you think the pushes and pulls are of what possible measures of disease activity might be incorporated into a future pivotal? Is composite score on the table? How should we think about the different scenarios, given that you are talking to the FDA soon?
I think it's premature to talk about the structure of the endpoint. That will be, I think, in part what we'll share as part of our future update. I think at this moment, what we can say is NSVT will be an important part of that picture. PVCs will also be there. But as we've discussed today, we believe NSVT is the more clinically meaningful endpoint, tracks closer to the disease. I think that's what we're able to share today, and I think we'll be able to address the question you asked in more detail with the update we'll give in the not too distant future.
Okay, great. I'll hop back in the queue.
Thank you. Our next question will come from the line of Kristen Kluska with Cantor Fitzgerald. Your line is open. Please go ahead.
Hey, everyone. Thanks so much for hosting this webinar for us. Dr. Gasperetti, I wanted to get your sense as a clinician when thinking about patients that present with this condition and level of interest or uptake for potential gene therapy. Do you think that's going to be driven by the baseline characteristics in NSVTs? Or in particular, if patients experience any of these at all, this is something that you think they'd be very interested in?
Well, thanks, Kristen, for the question. Maybe Dr. Gasperetti, if you'd like to provide a response.
Absolutely. I think all in all, there is quite some interest. I think that the baseline characteristics will not play a huge role. Certainly, a patient that has a higher arrhythmic activity at the time of screening will certainly be more interested in therapeutics such as this. So I don't think they're going to play a huge impact, but including a more non-sustained ventricular tachycardia-driven focus or lens on an inclusion criteria will certainly increase the stakes for the patient. So could be pretty good for enrollment as well.
Thank you.
Thank you. One moment for our next question. Our next question will come from the line of Paul Matteis with Stifel. Your line is open. Please go ahead.
Hey, this is Julian, on for Paul. Thanks so much for hosting this event and taking our questions. For the Lexeo team, can you just clarify for the guideline-defined NSVTs which you'll be using moving forward? I guess for the data that has been disclosed so far in the phase I/II for the high dose, is the magnitude of efficacy any different with this new sort of reporting format versus how you've disclosed it before? One other question as well for Dr. Gasperetti. I guess, would you expect to see a deepening of effect over time, either on NSVT or PVCs based on the mechanism of this gene therapy approach? Any thoughts on that would be very helpful. Thanks very much.
Just on the first question, when we present the data this quarter, we would intend to show the data on a time course basis with some form of spaghetti plot. So you'll have a picture of how the NSVTs evolve over time in that context. So we'll be able to address that very directly with the data set that we intend to present a bit later in the quarter. To the second question on deepening over time, Julian, as you're aware, I think we already saw signs of deepening in the data set that we presented in January with the patients at nine months with a more significant response than the 6-month patients. But maybe Dr. Gasperetti, if you'd like to give your perspective on that as well.
No, absolutely, happy to. I think this goes down for most of the intervention that we place, not just for gene therapy. Our timeline is always 6- 12, sometimes 6- 18 months. I think the biggest intervention that we have as a comparator is exercise reduction, where we have seen a progressive improvement in function and reduction in arrhythmias over up to 18 months. So I think it's absolutely reasonable to have sort of an extended observational phase to see over maybe 12 months could be a good timeline for a full taking up of the effect of such a therapy.
Terrific. Thank you.
Thank you. One moment for our next question. Our next question will come from the line of Christopher Raymond with Raymond James. Your line is open. Please go ahead.
Hey, this is Sam Leach on for Chris Raymond. Thanks for taking our question. This one's for the Lexeo team and Dr. Gasperetti. In some of our own tail work that we've done, something that came up was the potential to see maybe structural changes in the heart over a longer time course. What do you think right now is the potential to see that, whether that be at 12 months or even longer? How much weight should we put on eventually seeing structural changes in the heart alongside arrhythmia response?
Thank you for the question. I think the first, when we think about structural changes, I think we're referring to ejection fraction primarily. We are evaluating ejection fraction as one of the endpoints in this phase I/II study. We had ejection fraction data for all of the patients that was presented earlier in the year. What I would note there is the patients need to start with reduced ejection fraction at the outset in order to show an improvement. We did have at least one patient in that earlier data set that had low ejection fraction at the start of the study, and then that improved with the data that we showed. We may be able to have some lens into that, but I think the majority of patients have not presented with reduced ejection fraction at the outset.
Therefore, they're in somewhat of the earlier stages of the disease, not necessarily in the later stage heart failure component. Nani, I don't know if you want to add anything.
Yeah, I was just going to add that I would also suggest that if you think of the deepening effect that we've seen in the arrhythmia side as well, that we've shown before the two patients at a nine-month point, for example. We should be interpreting that as a structural change as well, because that whole milieu that causes those arrhythmias in the first place is this desmosomal architecture that's breaking down, that's in trouble. As a result, you get this electrical instability with the tissue that's laying down in between the cells as they start to isolate them, as the cardiomyocytes start to isolate themselves.
The fact that we're actually seeing this improvement in arrhythmias as well over time, I think is also a suggestion that there is a structural improvement because we're trying to repair and rescue some of those desmosomes and that architecture as we proceed. Dr. Gasperetti, I don't know if you want to add anything to that. In addition, happy to have your perspective.
No, I think it's a fair point, and I wouldn't necessarily expect big swings on what we measure in terms of structure. The ejection fraction that we've mentioned, the disease per se is from an ejection fraction perspective, as we said, most of the patients that have been enrolled and probably will be enrolled are patients that are more in their arrhythmic phase. So I wouldn't necessarily expect big changes in their ejection fraction in the immediate period of time following the dosing with therapeutics, just because probably they are nowhere close to being in an active heart failure phase. So it will probably be a more smoldering. I think I agree with what has been said.
Great. Thank you. I think we'll have time for one more question.
One moment. Our last question will come from the line of Brian Skorney from Baird. Your line is open. Please go ahead.
Yeah, thanks team. Thanks for taking my question and great call. I'm wanting to get some thoughts on evaluating beyond the simple binary nature of NSVT. Clearly the guideline-defined criteria has fallen a bit higher than what you're measuring NSVT for. But I think, correct me if I'm wrong, there's a number of studies that show that greater than 200 beats per minute or greater than seven beat runs are even more predictive of clinical events than sort of the area between the strict guideline criteria and those thresholds. I'm just wondering how important is getting a 200 plus to 120 or an eight beat to four beat in your view relative to just sort of the binary guideline NSVT? For management, is that being taken into account at all in preparation for a pivotal study?
Will there be secondary endpoints looking at reduction in high beat per minute, seven beat long NSVTs and eliminating or drastically reducing those? It just seems like from a regulatory perspective, that'd be even more compelling as sort of a clinically meaningful endpoint. Thanks.
Yeah. Brian, thanks for the question. It sounds like you've done a lot of work on this, as our team has. I think where we're landing from a regulatory perspective is in the definition of NSVT that we've discussed today. We believe this is the most broadly applicable and yet clinically meaningful way to evaluate NSVT. That is the direction of travel from a regulatory perspective that we think also fits well with current clinical treatment practice. The two need to meet in the same place. Obviously, if we utilize an endpoint for registrational study that's acceptable to the FDA, it also has to be an endpoint that cardiologists recognize when they're treating the disease and achieving a meaningful effect size against that is what we'd be seeking to do here. I don't know, Nani, if you want to add anything else to what-
No, I think you are spot on, Nolan. I think the points you are making are certainly interesting. I think they make clinical sense, and certainly those can be things that we can look at. There is work that is being done to look at that from exploratory perspective and what that looks like clinically. But as far as registrational endpoints and definitions are concerned, I think we need to reconcile to the ones that are guideline defined and then accepted in the literature. That is everybody's kind of singing from the same hymn sheet, as I said earlier in the webcast.
Also, if you continue to narrow into the definitions as you were just describing, you obviously run into issues of how frequent will you observe that event and in what number of patients and so on. You begin to maybe consider operational challenges, whereas with the endpoint as we have discussed today, it is clinically meaningful. It is recognized by physicians that treat this disease. But also, as you can see in our own study today, we have been able to find a sufficient number of those patients, even in a 10-patient study. I think it kind of threads the needle on all of the factors, clinical meaningfulness, frequency of those events, the instance of those occurring across a sufficient number of patients. Obviously, it is part of regular treatment course for most cardiologists today already. Okay. I think we are over time here, as I can see.
Thank you for joining today. We appreciated the questions and hopefully this was a helpful review of the background of the disease and some of the relevant endpoints. Also want to thank Dr. Gasperetti for joining us today for the call. Thanks everyone for joining and we appreciate you spending the time to discuss this disease today.
This concludes today's conference call. Thank you for participating and you may now disconnect. Everyone have a great day.