P2.B022: AAV Gene Therapies for Serious Inherited Cardiomyopathies

Background: Inherited cardiomyopathies can present across a range of phenotypes and result in significant morbidity and mortality, with examples including Danon disease, arrhythmogenic cardiomyopathy caused by PKP2 mutations (PKP2-ACM). The Pediatric Cardiomyopathy Registry Study Group (1) concluded that despite available guidelines, genetic testing for definitive diagnoses should be performed more routinely and consistently. Furthermore, there is a critical need for cause-specific therapies in children for the prevention and attenuation of their cardiomyopathy in addition to symptomatic treatments (2). These needs may be served by the successful development of targeted gene therapies. Certain serotypes of adeno-associated viral vectors (AAV) have demonstrated myocardial tropism and high transduction efficiency in non-dividing terminally differentiated cardiomyocytes. The goal of gene therapy is to rescue disease phenotype by introducing a functional copy of the mutated gene to obtain long-term protein expression necessary for normal structure and function.

Methods: Preclinical and Phase 1 clinical data have demonstrated robust safety and preliminary efficacy of RP-A501 (AAV9.LAMP2B) to address and improve cardiac manifestations of Danon disease including LAMP2B protein expression, ventricular wall thickness, and survival. Preclinical studies have shown that RP-A601 (AAV serotype rh.74 vector containing the human plakophilin-2a transgene, AAVrh.74-PKP2a) has enabled expression of PKP2 protein, reduction of arrhythmia, improvement in cardiac histology and structure, and survival in a PKP2-deficient animal model of ACM.

Results: The development of RP-A501 has successfully progressed to a global multi-center Phase 2 trial that is currently enrolling male patients age ≥ 8 years with pathologic or likely pathologic genetic variants of Danon disease. This single arm study involves a single intravenous infusion of RP-A501 with a primary endpoint including improvement in LAMP2 protein expression and reduction in ventricular hypertrophy. RP-A601 is being evaluated in a multi-center, open-label, dose escalation trial as a single intravenous infusion in adult patients (age ≥18 years) with clinical (2010 revised Task Force Criteria) and genetic diagnosis of PKP2-ACM and an implanted ICD. The primary endpoint for this study is safety and tolerability with secondary endpoints to capture preliminary efficacy. Efforts to minimize and address potential risks of systemic AAV infusions include the use of an immunomodulating regimen and active monitoring.

Conclusion: Scientific advances in AAV-based gene therapies offer potential to deliver unprecedented clinical benefit in patients with Danon disease and PKP2-ACM. Timely and comprehensive use of genetic testing is vital for definitive diagnosis and directing targeted treatment developments.