Phase I gene therapy clinical trial design of RP-A601 in adult patients with PKP2-arrhythmogenic cardiomyopathy (PKP2-ACM)

Abstract Background Arrhythmogenic cardiomyopathy (ACM) is a rare, progressive, autosomal dominant disorder characterized by increased risk of ventricular arrhythmias and sudden cardiac death. Up to 45% of all ACM cases are caused by pathogenic variants in the PKP2 gene, which encodes for the desmosomal protein Plakophilin-2. This genetic cardiomyopathy is referred to as PKP2-ACM. AAVrh.74-PKP2a is a recombinant adeno-associated viral (AAV) vector containing the coding sequence of human PKP2 isoform A (PKP2a) and delivers the functional PKP2 gene to cardiomyocytes. Preclinical testing conducted in a clinically relevant mouse model of PKP2-ACM (with survival ≤50 days post disease onset) demonstrated that administration of a single AAVrh.74-PKP2a dose after disease onset extended survival through 5 months with improved right ventricular (RV) function, and decreased cardiac dilation, myocardial fibrosis, and arrhythmias. Additional studies in rodents and nonhuman primates demonstrated AAVrh.74-PKP2a safety. These preclinical findings support clinical initiation. Purpose We describe the design of a phase I trial to assess safety and preliminary efficacy of AAVrh.74-PKP2a (RP-A601) in high-risk adult patients with PKP2-ACM. Methods This study (NCT05885412) is a multi-center, open-label, dose escalation trial evaluating the safety and preliminary efficacy of a single intravenous infusion of RP-A601 in adult patients (age ≥18 yrs) with clinical and genetic PKP2-ACM diagnosis and an implanted ICD. Patients with severe right ventricular dysfunction, LV ejection fraction ≤50% (echocardiogram or cardiac MRI) and/or NYHA Class IV heart failure are excluded. Preliminary efficacy will be assessed at 12 months after RP-A601 infusion and includes evaluation of change in PKP2 myocardial tissue expression and clinical markers of arrhythmia burden. Conclusions PKP2-ACM is a devastating disease associated with high morbidity and mortality. This Phase I trial will evaluate the safety and preliminary efficacy of RP-A601 and was initiated based on robust preclinical efficacy and safety data.