A Phase 1, Dose Escalation Trial of RP-A601 in Subjects With PKP2 Variant-Mediated Arrhythmogenic Cardiomyopathy (PKP2-ACM)

Study Overview
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Brief Summary
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This Phase 1 dose escalation trial will assess the safety and preliminary efficacy of a single dose intravenous infusion of RP-A601 in high-risk adult patients with PKP2-ACM.

Official Title
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A Phase 1 Dose Escalation Trial Evaluating an Intravenously Administered Recombinant Adeno-Associated Virus Serotype rh.74 (AAVrh.74) Vector Containing the Human Plakophilin-2a (PKP2a) Coding Sequence (RP-A601; AAVrh.74-PKP2a) in Subjects With Arrhythmogenic Cardiomyopathy Arising From Pathogenic PKP2 Variants (PKP2-ACM)

Conditions
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PKP2 Arrhythmogenic Cardiomyopathy (PKP2-ACM)

Intervention / Treatment
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* Genetic: RP-A601


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female ≥18 years at the time of signing the informed consent Capable and willing to provide signed informed consent Clinical diagnosis of ACM as defined by the 2010 revised Task Force Criteria (TFC) Documentation of a pathogenic or likely pathogenic truncating variant in PKP2 Anti-AAVrh.74 capsid neutralizing antibody assay ≤1:40 History of Implantable Cardioverter-Defibrillator (ICD) implantation ≥6 months prior to enrollment Key Exclusion Criteria: Cardiomyopathy related to a genetic etiology other than PKP2 truncating variant Previous participation in a study of gene transfer or gene editing Severe Right ventricular (RV) dysfunction Left ventricular ejection fraction by echocardiogram ≤50% New York Heart Association (NYHA) Class IV heart failure.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RP-A601<br>Single ascending dose of RP-A601 in 2 consecutive cohorts | Genetic: RP-A601<br>* RP-A601 is a recombinant viral vector composed of an AAV serotype rh.74 (AAVrh.74) capsid encapsulating the transgene, human plakophilin 2 (PKP2), transcript variant 2a (PKP2a)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment emergent adverse events (TEAEs) | Evaluation of safety associated with RP-A601 | 12 months post-infusion | 
| Incidence of Serious Adverse Events (SAEs) | Evaluation of safety associated with RP-A601 | 12 months post-infusion | 
| Identification of Dose Limiting Toxicities (DLTs) | Evaluation of safety associated with RP-A601 | 12 months post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in PKP2 myocardial tissue expression | Preliminary Efficacy: Extent of RP-A601 transduction through assessment of protein expression | 12 months post-infusion | 
| Change in the frequency of clinical markers of life threatening arrhythmias | Preliminary Efficacy: Clinical impact of RP-A601 | 12 months post-infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Arrhythmogenic cardiomyopathy, Arrhythmogenic Right Ventricular Cardiomyopathy, Arrhythmogenic Right Ventricular Dysplasia, Sudden Cardiac Death, Genetic cardiomyopathy, Gene therapy, PKP2, ARVC, ARVD, ACM, Cardiac Arrest, Ventricular Arrythmia