High-dose AAV1/SERCA2a gene transfer reduced the risk of recurrent cardiovascular events by 82% compared to placebo over 3 years in patients with advanced heart failure (P=0.048).
RCT (n=39)
Effect estimate: 82% risk reduction
p-value: p=0.048
RATIONALE: The Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID 1) study was a phase 1/phase 2 first-in-human clinical gene therapy trial using an adeno-associated virus serotype 1 (AAV1) vector carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a) in patients with advanced heart failure. The study explored potential benefits of the therapy at 12 months, and results were previously reported. OBJECTIVE: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1. METHODS AND RESULTS: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6×10(11) DNase-resistant particles; mid-dose, 3×10(12) DNase-resistant particles; and high-dose, 1×10(13) DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low- and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up. CONCLUSIONS: After a single intracoronary infusion of AAV1/SERCA2a in patients with advanced heart failure, positive signals of cardiovascular events persist for years.
Zsebo et al. (Wed,) conducted a rct in advanced heart failure (n=39). AAV1/SERCA2a vs. placebo was evaluated on recurrent cardiovascular and terminal events (myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death) (82% risk reduction, p=0.048). High-dose AAV1/SERCA2a gene transfer reduced the risk of recurrent cardiovascular events by 82% compared to placebo over 3 years in patients with advanced heart failure (P=0.048).