Key Points:
- PKP2-arrhythmogenic cardiomyopathy (PKP2-ACM) is a rare, inherited cardiac disease affecting approximately 60,000 individuals in the United States. It signifncalt increases the risk of fatal ventricular arrhythmias. No existing therapy halts or reverses disease progression.
- The HEROIC-PKP2 trial enrolled 10 adults with confirmed PKP2-ACM and frequent premature ventricular contractions, administering a single intravenous infusion of LX2020 — a gene therapy designed to deliver full-length PKP2 to cardiomyocytes.
- LX2020 was safe and well tolerated, with robust cardiac transduction and dose-dependent increases in PKP2 protein expression observed in cardiac biopsies. PVC burden was reduced or stable and symptoms improved in most patients.
Arrhythmogenic cardiomyopathy (ACM) is a rare inherited cardiac disorder characterized by progressive fibro-fatty replacement of the myocardium, ventricular arrhythmias, and an elevated risk of sudden cardiac death. Variants in the plakophilin-2 gene (PKP2) represent the most common genetic cause of ACM, accounting for the majority of identified mutations. Loss-of-function PKP2 variants disrupt desmosomal integrity, leading to slow conduction, arrhythmogenesis, and progressive structural deterioration. Approximately 60,000 individuals in the United States are estimated to carry pathogenic PKP2 variants, and around 23% first present with sudden cardiac arrest. Despite the availability of implantable cardioverter-defibrillators and anti-arrhythmic medications to manage arrhythmia burden, no approved therapy modifies the underlying disease process or prevents progression to end-stage arrhythmia or heart failure. LX2020 is gene therapy that delivers a full-length PKP2 complementary DNA under a cardiac-specific promoter, with the goal of restoring PKP2 protein at the desmosome level.
The HEROIC-PKP2 trial is an open-label Phase 1/2 study with a 52-week primary follow-up period and 4-year long-term extension, conducted across 6 U.S. academic medical centers. Adults aged 18–65 years with a confirmed diagnosis of ACM, documented PKP2 mutation, and a minimum threshold of premature ventricular contractions per 24 hours were eligible. Participants received a single intravenous infusion of LX2020 at one of two dose levels: a low dose of 2.0×10¹³ vg/kg (Cohort 1, n=3) or a high dose of 6.0×10¹³ vg/kg (n=7). All participants received prophylactic immunosuppression with prednisone and sirolimus. Key measurements included ventricular arrhythmia burden (PVCs per 24 hours, NSVT episodes per 7 days), cardiac structure and function (RV ejection fraction by cardiac MRI), symptom status (NYHA class and Patient Global Impression of Change), and vector transduction and expression in cardiac biopsy tissue (vector copy number, PKP2 mRNA, and PKP2 protein by quantitative western blot).
High-dose participants had more advanced disease at baseline, with a high mean PVC and NSVT burden as well as longer disease duration (9 years compared to 3 years). LX2020 was generally well tolerated across both dose levels. Liver function test elevations were observed in 7 of 7 high-dose participants, all of which resolved with modified immunosuppression. No participants discontinued from the study. Cardiac biopsy analysis confirmed robust LX2020 payload delivery in all evaluated participants. Vector copy number was higher in the high-dose cohort, as was PKP2 mRNA expression. PKP2 protein expression increased in a dose-dependent fashion, with a mean increase of 93% in the low-dose cohort and 162% in the high-dose cohort. Immunofluorescence microscopy confirmed appropriate localization of newly expressed PKP2 protein to the desmosome. Early clinical signals in the high-dose cohort were encouraging: NSVT was reduced or stable in the majority of participants, and 4 of 5 evaluable high-dose patients reported improvement in symptoms.
Presenting at the American College of Cardiology Scientific Sessions on March 30, 2026, lead investigator Dr. Victoria N. Parikh concluded that LX2020 demonstrated a favorable safety profile alongside robust, dose-dependent PKP2 protein restoration in cardiac tissue — the first demonstration of successful gene therapy delivery in human PKP2-ACM.