Lexeo Therapeutics (NASDAQ:LXEO) executives outlined the company’s focus on precision medicines for inherited cardiac diseases during a presentation at Oppenheimer’s 36th Annual Healthcare Life Sciences Conference, highlighting progress across two lead gene therapy programs targeting Friedreich’s ataxia (FA) cardiomyopathy and PKP2-associated arrhythmogenic cardiomyopathy (PKP2-ACM).
Cardiac gene therapy thesis and vector strategy
CEO Nolan Townsend said Lexeo’s core thesis is that precision medicine will play an increasingly important role in cardiovascular care, noting there are currently “fewer than 10” precision medicines approved in cardiovascular disease. He argued that adeno-associated virus (AAV) vectors are currently the most efficient way to deliver genetic payloads to cardiomyocytes, compared with other delivery systems.
Friedreich’s ataxia cardiomyopathy: clinical signals and pivotal planning
Management framed Friedreich’s ataxia as a global rare disease affecting about 15,000 patients, concentrated in the U.S. and Europe, with some prevalence in Latin America. Townsend said approximately 70% of patients die from cardiac disease, arguing that mortality can only be addressed by treating the cardiac component.
The company’s FA gene therapy candidate, LX2006, is designed to deliver a functional frataxin (FXN) gene to the heart. In discussing interim data, Lexeo executives focused on reductions in left ventricular mass index (LVMI) and cardiac troponin. A company representative said LV mass is the “best biomarker for death” in FA cardiomyopathy and that the company has observed a “consistent and large reduction” in LV mass across dose cohorts in a dose-responsive manner. The team also described “striking reductions” in troponin, which they characterized as another biomarker associated with worse outcomes in cardiomyopathies.
Townsend added that patients with abnormal LVMI at baseline “all returned into the normal range,” describing this as reversal of a hallmark of the disease. The company also discussed biopsy findings, noting meaningful increases in cardiac frataxin expression. Executives said they found FA cardiomyopathy patients in general had extremely low frataxin levels—around 2% or less of normal—and pointed to animal model data suggesting even 5% of normal frataxin can be associated with normal cardiac function. They also said the FDA agreed that “any increase” in frataxin could be sufficient for the biopsy endpoint in their discussions, while emphasizing that the registrational study would be powered on LVMI.
On trial design, Lexeo said it is working toward final alignment with the FDA on an accelerated approval pathway. Townsend said the company knows the relevant endpoints and that the FDA is open to an LVMI assessment time point earlier than 12 months. He reiterated a target effect size of greater than 10% improvement in LVMI. The company said it is also working with regulators to better define the link between the LVMI surrogate endpoint and confirmatory endpoints, and to address potential sources of bias in the pivotal study’s design and statistical plan. Lexeo guided that it remains on track to report results in early 2026.
Natural history study and label considerations
Lexeo said it is running a natural history study in parallel, with identical inclusion criteria to the treatment study. Executives said this effort helps identify eligible patients and accelerate enrollment by allowing patients to cross over, while also characterizing the untreated course of disease. Management said LV mass would typically be expected to increase slightly over time, and that the natural history data could help demonstrate there is no spontaneous improvement in LVMI outside of treatment.
Executives also addressed potential label breadth, noting secondary endpoints such as troponin, wall thickness, and the neurologic scale mFARS. Townsend said it is typical in rare diseases for pivotal inclusion criteria not to precisely match the eventual label, and the company’s perspective is that labeling would not necessarily be restricted only to patients with abnormal LVMI at baseline, based on supportive data.
SKYCLARYS use in trial and combined cardiac/neurologic framing
Lexeo discussed the presence of patients in its study who have also been treated with SKYCLARYS. Management said it expects data both from SKYCLARYS-naïve patients and those treated with SKYCLARYS through the duration of Lexeo’s study. Townsend said the company has observed mFARS benefit across both groups, and described a 1- to 2-point improvement on mFARS, which he characterized as roughly similar to the benefit SKYCLARYS showed in its registrational study. He argued that combining neurologic benefit with regression of cardiac disease could represent a “step change” in standard of care.
PKP2-ACM: early efficacy signal and upcoming update
In PKP2-ACM, Lexeo is developing LX2020 to deliver a functional PKP2 gene and restore plakophilin-2. Executives described PKP2-ACM as among the more common inherited cardiomyopathies seen in practice and associated with potentially fatal arrhythmias, high patient anxiety, and long-term progression to heart failure and, in some cases, transplant. They also described limitations of current management approaches, including adverse effects of antiarrhythmic drugs and the painful nature of defibrillator shocks, which prevent death but do not prevent disease progression.
Lexeo said it observed a dose-dependent increase in plakophilin-2 expression in early clinical cohorts. The company highlighted reductions in nonsustained ventricular tachycardia (VT), describing a 22% reduction at the earliest time point and, in a smaller number of patients, closer to a 60% reduction. Executives contrasted this with natural history observations in which VT risk increased over time, and said the two high-dose patients were at an average improvement of about 65% at nine months. Lexeo said it will provide a clinical update in the fourth quarter of the year, with most or all patients expected to have 12 months of follow-up to assess durability and other endpoints, including structural measures and right ventricular ejection fraction.
On enrollment and competition, Townsend said Lexeo does not anticipate enrollment challenges, describing PKP2-ACM as a roughly 60,000-patient rare disease with high motivation among patients to seek treatment.
Lexeo also provided a financial update, stating it completed a financing in October that left the company with cash in the “mid $200s” and a quarterly burn rate in the “mid $20s,” which management said provides runway into 2028. The company said this runway is intended to cover activities through an FA BLA filing, including manufacturing and initial commercial readiness, and to fund the PKP2 program through completion of its phase 1/2 study.
About Lexeo Therapeutics (NASDAQ:LXEO)
Lexeo Therapeutics, Inc is a clinical‐stage biotechnology company dedicated to developing novel, precision‐designed therapies for central nervous system disorders. The company’s research platform leverages advanced medicinal chemistry to create next‐generation psychedelic-inspired compounds aimed at treating a range of mental health conditions, including anxiety, depression and substance use disorders.
The company’s pipeline features proprietary synthetic molecules engineered to target specific neural pathways while improving safety and tolerability profiles over traditional treatments.
