Lexeo Therapeutics (LXEO) investor relations material

Disease overview and clinical management

• Arrhythmogenic cardiomyopathy (ACM) is a severe, inherited heart disease with high risk of arrhythmias and sudden cardiac arrest, affecting about 125,000 people in the U.S.

• PKP2 gene mutations are the most common cause, especially in right ventricular ACM, accounting for over 50% of cases in this subset.

• Diagnosis relies on a combination of structural and electrical criteria, including MRI, ECG, and genetic testing, with non-sustained VT and high PVC counts as key indicators.

• Management focuses on arrhythmia control with beta blockers, antiarrhythmics, ICDs, and ablation, but there are no effective therapies to halt or reverse heart failure progression.

• Family screening and genetic testing are critical for early detection and risk stratification, allowing for targeted monitoring and intervention.

Unmet needs and gene therapy potential

• Current treatments do not address the underlying genetic defect or prevent progression to heart failure, highlighting a significant unmet need.

• Gene therapy is seen as a promising approach, especially for patients with early symptomatic arrhythmias or after their first major arrhythmic event.

• Most patients presenting with symptomatic PKP2 ACM are considered good candidates for gene therapy, with estimated eligibility rates of 70-80%.

• Uptake among eligible patients is expected to be high due to the severity and life-threatening nature of initial symptoms.

• Introduction of gene therapy is anticipated to increase referrals to expert centers and require education for community physicians.

Efficacy measures and disease progression

• Key efficacy endpoints for gene therapy include reduction in non-sustained VT, fewer arrhythmias, and stabilization or improvement in right ventricular function.

• Electrical changes (ECG abnormalities, arrhythmias) typically precede structural deterioration, with rapid progression from arrhythmia onset to need for ablation within 1-2 years.

• Variability in arrhythmic measures is high, but consistent reduction in arrhythmia burden and fewer spikes are considered meaningful.

• Both right ventricular and biventricular disease may benefit from gene therapy, and disease severity at presentation does not preclude eligibility unless advanced heart failure is present.

• Endurance athleticism may accelerate disease progression, but management and eligibility for gene therapy remain consistent regardless of athletic history.