A Phase 2B Multicenter Study of the Comparative Efficacy and Safety of Transendocardial Injection of MSC in Patients with Nonischemic Dilated Cardiomyopathy
Abstract
This proposal addresses the Topic Area of Cardiomyopathy. Non-ischemic dilated cardiomyopathy (NIDCM) is one of the more common causes of heart failure in young adults, a leading cause of disability and death and accounts for approximately 50% of heart transplants performed. As such, this disorder is a lead candidate for cell-based therapy. Patients with NIDCM have an enlarged, structurally damaged heart muscle with reduced function. Our group and others have shown that cell-based therapy using mesenchymal stem cells (MSCs) holds great promise as a new approach to produce durable and sustainable improvements in heart function and structure in patients with heart failure due to NIDCM. If these effects can be clinically established and optimized, there is enormous potential for improving clinical outcomes for the many patients suffering from NIDCM. Our group has extensive experience with catheter delivery of bone marrow-derived MSCs in patients with heart failure due to heart attack as well as NIDCM. There is substantial scientific and public interest for cardiac regenerative cell therapy strategies, based on preclinical, translational, and early Phase I/II clinical studies. In the POSEIDON-DCM (PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesis in Dilated CardioMyopathy) clinical trial, we identified a meaningful increase in cardiac function in a cohort of patients with NIDCM who received MSCs. One-third of the patients transitioned from heart failure with reduced cardiac function to heart failure with recovered function, which is associated with reductions in disease-related symptoms and complications as well as death. Since NIDCM is associated with genetic mutations in a significant proportion of patients, we hypothesized that NIDCM genotype influences patient responsiveness to MSC therapy. Accordingly, we conducted a sub-study in the POSEIDON-DCM patients by performing a detailed genotyping using a comprehensive cardiomyopathy gene panel. Our novel preliminary findings show a benefit of MSC therapy, namely improvement in cardiac function, quality of life, major adverse cardiac events, and survival, in patients that lack a known pathogenic mutation, suggesting that patients devoid of pathogenic mutations represent a “super-responder” group compared to those that have a pathogenic mutation. This Phase IIB clinical trial proposal will test whether MSC therapy is effective in improving cardiac function, as compared to placebo, in patients with NIDCM. Patients will be genotyped and the efficacy of MSC therapy will be compared to placebo in patients that lack a known disease-causing mutation (genotype A), patients with mutations of unknown significance (genotype B), and in those that have a known disease-causing mutation in NIDCM associated genes (genotype C). We expect that patients without a disease-causing mutation will respond better to MSC therapy than those with known mutations or mutations of unknown significance. The primary outcome will be assessed using cardiac magnetic resonance imaging (MRI) to measure cardiac function at 12 months. This study is clinically important because it will help physicians determine which patients are more likely to respond to specific therapies and will help us develop more individualized therapies for patients with heart failure due to NIDCM. The proposed trial is currently approved by the U.S. Food and Drug Administration under IND BB-14419.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010272
Entities
People
- Joshua M Hare
Organizations
- United States Army
- University of Miami