SAN DIEGO – In a phase II study of patients with advanced heart failure, gene therapy with MYDICAR was found to be safe and was associated with benefit in clinical outcomes, symptoms, functional status, and cardiac structure.
Deficiency of the protein SERCA2a is central to the progression of heart failure, resulting in abnormal calcium transfer and impairing myocardial relaxation and contraction, Dr. Barry H. Greenberg said at the annual meeting of the Heart Failure Society of America.
MYDICAR, manufactured by Celladon Corp., is an enzyme replacement therapy that is designed to restore levels of SERCA2a. A recombinant adeno-associated viral vector is used to deliver the SERCA2a gene.
The objectives of the phase II study, known as CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease), were to evaluate safety and feasibility and to explore the activity and efficacy of MYDICAR in patients with advanced heart failure, said Dr. Greenberg, professor of medicine and director of the Advance Heart Failure Treatment Program at the University of California, San Diego.
To be eligible for the trial, patients had to be 18-75 years old, have New York State Heart Association class III or IV heart failure caused by an ischemic or nonischemic etiology, have a maximal oxygen consumption of 20 mL/kg per minute or less, have a left ventricular fraction of 35% or less, and be on a stable, optimized heart failure regimen for 30 days.
Dr. Greenberg and his associates randomized 39 patients to one of three doses of MYDICAR or to placebo, and all were treated via single intracoronary infusion. All patients were observed for 12 months, with a primary analysis after 6 months of therapy.
The mean age of patients was 61 years, 87% were male, 87% were white, half had heart failure resulting from ischemic cardiomyopathy, and all had NYHA class III heart failure.
Safety measurements included physical examination, electrocardiogram, adverse events, complete blood count, serum chemistries, urinalysis, creatine kinase myocardial band, troponin T, and enzyme-linked immunospot testing for cellular immune response against viral proteins.
Efficacy domains included symptomatic changes in NYHA class and the MLHF (Minnesota Living With Heart Failure) questionnaire; functional changes based on 6-minute walk test and maximal oxygen consumption; changes in N-terminal prohormone brain natriuretic peptide; and evidence of remodeling based on ejection fraction scores and end systolic volume.
CUPID’s primary efficacy end point was defined as evidence of success in one of four areas: group-level analysis, individual analysis, time-to-event analysis, and duration of cardiovascular-related hospitalization analysis. All were deemed statistically significant (P less than .2).
CUPID met the primary efficacy end point for high-dose MYDICAR treatment group vs. placebo in three of the four areas. In the group-level analysis, significant improvements were seen in the treatment group, compared with the placebo group, in improvements in the 6-minute walk test and end systolic volume, with no clinically significant worsening in any end point and numerical superiority to placebo in all other end points.
In the individual analysis, the mean efficacy “score” for the treatment was significantly greater than that of the placebo group.
In the time-to-death analysis, the treatment group scored numerically better than the placebo group, but this difference did not reach statistical significance.
In the duration of cardiovascular-related hospitalization analysis, the duration of stay was significantly shorter for patients in the treatment group, compared with the placebo group (mean, 2 fewer days).
Dr. Greenberg reported that there were no statistically significant differences between the treatment groups and the placebo groups in the proportion of adverse events or serious events.
“These encouraging results support further studies to determine the value of genetically targeted enzyme replacement of SERCA2a in advanced heart failure,” Dr. Greenberg concluded.
The meeting’s invited discussant, Dr. Michael R. Bristow, president and CEO of ARCA Biopharma Inc., described it as “a big deal to have done gene therapy on this number of patients who are this sick and see absolutely no evidence of safety concern. I believe there’s definite evidence of an efficacy signal ... [and] that CUPID will serve as a catalyst for the development of other gene therapies for heart failure.”
Disclosures: Celladon Corp. funded the trial. Dr. Greenberg said that he had no relevant financial disclosures to make.