Lexeo Therapeutics (LXEO) investor relations material

PKP2 ACM and unmet need

• PKP2 ACM affects an estimated 60,000 people in the U.S.; progressive electrical and structural disease can lead to ventricular arrhythmias, heart failure and sudden cardiac death.

• No approved therapy is designed to slow, prevent or reverse the underlying disease; current care includes exercise restriction, drugs, ablation, ICDs and, in advanced cases, transplantation.

• Current interventions can manage symptoms or risk but have limitations, including recurrent arrhythmias after ablation, ongoing disease progression with ICDs and treatment-related burdens.

LX2020 and clinical response framework

• LX2020 is an AAVrh10 gene therapy designed to deliver full-length functional PKP2 to cardiomyocytes and potentially address electrical and structural consequences of PKP2 deficiency.

• Response assessment spans arrhythmic activity, myocardial structure and function, and patient and clinical burden; electrical changes may emerge before structural remodeling.

• PVC burden can fluctuate with exercise, stress and caffeine; NSVT carries greater clinical weight and was associated with ~2.5x risk of subsequent sustained or life-threatening ventricular arrhythmias.

• Guideline-defined NSVT is at least 3 consecutive ventricular beats above 100 bpm, ending spontaneously within 30 seconds; future assessments will use this definition rather than the January 2026 total-run measure.

• Evaluation will consider NSVT presence and burden, PVC changes, durability and broader patient-level outcomes; each participant had qualifying NSVT at baseline.

Clinical perspective and development expectations

• Cleveland Clinic electrophysiologist Alessio Gasperetti emphasized that even 1–2 NSVT episodes can affect risk assessment; he cited flecainide data showing ~30% lower NSVT burden and 25%-30% of patients becoming NSVT-free.

• Management views NSVT and PVC burden as complementary, while NSVT presence is generally the stronger arrhythmic risk marker; gene therapy could potentially affect disease progression beyond symptom control.

• A 35%-40% NSVT risk reduction with favorable safety was described as highly meaningful versus a cited 20%-30% reduction with current care; sustained or deepening benefit is important.

• A majority of the 10-patient study had baseline NSVT; management estimated 85%-90% of the broader population could have sufficient NSVT burden for trial enrollment.