Challenges in Cardiomyopathy Gene Therapy Clinical Trial Design

Gene therapy has emerged as a possible treatment for progressive, debilitating Mendelian cardiomyopathies with limited therapeutic options. This paper arises from discussions at the 2023 Cardiovascular Clinical Trialists Forum and highlights several challenges relevant to gene therapy clinical trials, including low prevalence and high phenotypic heterogeneity of Mendelian cardiomyopathies, outcome selection complexities and resulting regulatory uncertainty, and immune responses to the adeno-associated viral vectors that are being used in ongoing studies. Avenues to address these challenges such as natural history studies, external controls, novel regulatory pathways, and immunosuppression are discussed. Relevant cases of recent therapy approvals are highlighted. Ultimately, this work aims to broadly frame discussions on and provide potential future avenues for clinical trial design for rare cardiomyopathy gene therapies.