A single intracoronary infusion of an adeno-associated virus (AAV) vector/ sarcoplasmic reticulum CA2+ ATPase (SERCA2a) enzyme, known as AAV1/SERCA2a, in addition to optimal heart failure (HF) therapy, did not reduce the rate of HF-associated recurrent events in patients with moderate to advanced systolic HF, according to results from the CUPID 2 Trial presented at ESC Congress 2015 in London.

The study was based on 250 patients between the ages of 18 and 80 years with NYHA class II-IV chronic HF of either ischemic or non-ischemic etiology and a left ventricular ejection fraction of ≤35 percent, and who were at high risk for HF hospitalizations. Patients with circulating neutralizing adeno-associated virus antibodies (≥1.2) were excluded. Patients were randomized to receive a single intracoronary infusion of either AAV1/SERCA2a or placebo. The primary endpoint was time from treatment to HF-associated recurrent events in the modified intent-to-treat population (n=243). The secondary efficacy endpoint was time to first terminal event (all-cause death, heart transplant, or implantation of a mechanical circulatory support device).

Results found that treatment with AAV1/SERCA2a did not result in an improvement in the primary endpoint of recurrent HF events compared to placebo (HR = 0.93, 95 percent confidence interval 0.53-1.65; p=0.81). Comparison of AAV1/SERCA2a to placebo of the secondary endpoint of all-cause death, need for a mechanical circulatory support device, or heart transplant, also did no show a significant treatment effect. Study investigators said no safety issues were noted.

"Why infusion of AAV1/SERCA2a did not improve outcomes in CUPID 2 is not certain and review of the data is underway to try to understand this," said lead investigator Barry Greenberg, MD, FACC, from University of California San Diego Sulpizio Cardiovascular Center in La Jolla, CA. "Although preliminary results in experimental models and in pilot studies of HF patients showed favourable results, it is possible that AAV1/SERCA2a may not be an appropriate target for treating HF in human patients and that the positive pilot study results could just be a chance finding."

He added, however, that while CUPID 2 failed to meet its endpoints, the results should help inform future efforts to use gene therapy to treat HF.

Keywords: ESC Congress, Heart Failure, Antibodies, Neutralizing, Dependovirus, Genetic Therapy, Heart Failure, Systolic, Heart Transplantation, Stroke Volume

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