Phase 2 of the CUPID trial, which is assessing a gene therapy for heart failure (HF) patients, has met the safety and efficacy endpoints, and has shown to improve heart function, according to a late-breaking trial presentation at Heart Failure Congress 2010 (HFC), the annual meeting of the Heart Failure Association of the European Society of Cardiology in Berlin.
In HF patients, the SERCA2a gene, which regulates calcium, important for contractile function, is down regulated. In the CUPID trial (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease), researchers used a recombinant adeno-associated viral vector, a naturally occurring virus that is not associated with any disease in humans, to implant the SERCA2a genes in 39 patients, divided into four groups, three of which received a different dose (low—8, mid—8 and high—9), while one group of 14 received placebo.
The gene (Mydicar, Celladone) is delivered one time via a catheter through the coronary arteries into the myocardium. It takes two to three weeks for the gene to be expressed, but the expression theoretically lasts for years, giving class III and IV HF patients a longer lease on life, as well as improved quality of life. Patients cannot receive a second injection of the gene because the body builds up immunity to the viral vector.
The primary outcomes of the trial were safety, as measured by the incidence and severity of adverse events; all-cause mortality; and progression of HF leading to hospitalization and/or IV inotrope, vasodilator, and/or diuretic administration. The secondary outcomes were efficacy based on changes from baseline to three, six, nine and 12 months in maximum oxygen consumption, six-minute walk test, echocardiographic assessments, levels of the serum biomarker NT-pro-BNP, HF classification and quality of life assessed by Minnesota Living with Heart Failure Questionnaire.
Barry Greenberg, MD, a professor of medicine at the University of California, San Diego, on behalf of the CUPID investigators, reported the six-month results at the conference.
Overall, patients treated with the gene therapy fared better than the placebo group. However, high-dose gene therapy fared better than low- and mid-dose.
Patients treated with the high-dose gene therapy had a statistically significant reduction in cardiovascular events as defined by death, the need for left ventricular assist device or cardiac transplant, and worsening of HF or HF related hospitalizations, which translated into a of 50 percent risk-reduction in favor of high-dose therapy (hazard ratio 50 percent vs. placebo), Greenberg reported.
In addition, the mean duration of hospitalization in the gene therapy high-dose group during the six-month period was 0.2 days per patient, compared with 2.1 days per patient in the placebo-treated group.
Researchers also found that patients treated with high-dose gene therapy improved significantly in their HF symptoms, exercise tolerance, serum biomarkers and cardiac function.
Specifically, the quality of life worsened by +3.4 points for placebo-treated patients, but improved by -10.3 points for gene therapy-treated patients; exercise tolerance, measured with the six-minute walk test, decreased (worsened) in the placebo group by 87 meters but increased by one meter in the therapy group.
Levels of NT-pro-BNP worsened by +5540 pg/mL in placebo-treated patients, and improved by -13.5 pg/mL in therapy-treated patients; cardiac function worsened (heart further enlarged) by 18.2 mL (left ventricular end-systolic volume) in the placebo group, but improved by -9.6 mL in the therapy group, indicating a reverse remodeling of the damaged heart, Greenberg reported.
"Throughout the study for all of the effects, there appears to be greater benefit for patients taking the higher dose of the gene therapy than the lower doses," he said. "These findings provide strong support for moving forward to Phase III studies using larger numbers of patients conducted over longer periods of time."