Lexeo Therapeutics, Inc. Common Stock Investor update

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 and a half 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.