119 - AAV Gene Therapies For Serious Inherited Cardiomyopathies

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Author Block: Catherine Datto¹, Matthew Coggins², Paul Yarabe³, Gopal Parthasarathy³, Carole Wishneski³, Sydney Reilly³, Christopher Herzog³, David Ricks³, Bitha Narayanan³, Latika Hickey³, Raj Prabhakar³, Kinnari Patel³, Barry Greenberg⁴. ¹Rocket Pharmaceuticals, Inc., Glen Mills, PA; ²Rocket Pharmaceuticals, Inc., Cambridge, MA; ³Rocket Pharmaceuticals, Inc., Cranbury, NJ; ⁴The University of California - San Diego Health, La Jolla, CA
Disclosure Block: C.Datto: Employee; Pharmaceutical Company/Distributors; Rocket Pharmaceuticals. L.Hickey: n/a. R.Prabhakar: n/a. K.Patel: n/a. B.Greenberg: Consultant; Device Manufacturer/Distributor; Impulse Dynamics, Consultant; Diagnostic Lab; ACI Clinical, Consultant; Pharmaceutical Company/Distributors; AstraZeneca, Bayer AG, Boehringer Ingelheim, Cytokinetics, Merck, Ionis Pharmaceuticals, Relypsa, Windtree Therapeutics, Vifor Pharma, Tenaya Therapeutics, Bristol-Myers Squibb, Lexicon Pharmaceuticals, Other Relationship; Pharmaceutical Company/Distributors; Rocket Pharmaceuticals, Speaker's Bureau; Pharmaceutical Company/Distributors; Novartis. M.Coggins: Employee; Bio-Medical Startup; Rocket Pharmaceuticals. P.Yarabe: n/a. G.Parthasarathy: n/a. C.Wishneski: n/a. S.Reilly: n/a. C.Herzog: n/a. D.Ricks: Employee; Bio-Medical Startup; Rocket Pharmaceuticals. B.Narayanan: n/a.

Introduction: 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), and dilated cardiomyopathy (DCM) caused by BAG3 mutations. Currently, there are no treatment options that target the underlying causes of these inherited cardiomyopathies. 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 cellular structure and function. Certain serotypes of adeno-associated viral vectors (AAV) have demonstrated myocardial tropism and high transduction efficiency in non-dividing terminally differentiated cardiomyocytes.
Hypothesis: AAV-mediated gene therapies can restore expression of essential proteins which are impaired in inherited disorders, leading to improvement in cardiac structure, function, and survival.
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. An AAV-based gene therapy is currently under pre-clinical development to address BAG3-associated DCM, in which the BAG3 protein plays a critical role in cardiomyocytes including excitation-contraction coupling, facilitation of autophagy, inhibition of apoptosis, and structural support of sarcomeres.
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.
Conclusions: Scientific advances in AAV-based gene therapies offer potential to deliver unprecedented clinical benefit in patients with Danon disease, PKP2-ACM, and BAG3-DCM. Timely and comprehensive use of genetic testing is vital for definitive diagnosis and directing targeted treatment developments.