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Injecting a gene into patients with advanced heart failure may substantially improve clinical outcomes, according to phase II results of the multicenter CUPID (Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease) trial presented today at the 2010 American Heart Association Scientific Sessions in Chicago.

Study results are being presented at 11:30 a.m. CT in Room N227, McCormick Place, by Dr. Donna Mancini, the study's principal investigator at NewYork-Presbyterian Hospital/Columbia University Medical Center, where she is medical director of the Center for Advanced Cardiac Care.

"This is the first time gene therapy has been tested and shown to improve outcomes for patients with advanced heart failure," says Dr. Mancini, who is professor of medicine and the Sudhir Choudhrie Professor of Cardiology at Columbia University College of Physicians and Surgeons. "The therapy works by replenishing levels of an enzyme necessary for the heart to pump more efficiently by introducing the gene for SERCA2a, which is depressed in these patients. If these results are confirmed in future trials, this approach could be an alternative to heart transplant for patients without any other options."

The Phase II randomized, double-blind, placebo-controlled clinical trial compared the gene therapy at two- or three-dose levels with placebo at 16 medical centers nationally. A total of 39 enrolled patients underwent a cardiac catheterization that introduced a specially engineered gene that stimulates production of an enzyme necessary for the heart to pump more efficiently directly into the coronary arteries.

The investigators found that the gene therapy had an excellent safety profile and substantially improved clinical outcomes compared with optimal medical therapy at one-year post-dosing. In addition, study participants receiving a higher dose of the therapy showed an 88 percent risk reduction in cardiovascular-related death, need for LVAD (left ventricular assist device) or cardiac transplant, worsening of heart failure or heart-failure-related hospitalizations vs. placebo.

Gene therapy is a technique for correcting defective genes responsible for disease development by inserting genes into a patient's cells and tissues. In most gene therapy studies, a "normal" gene is inserted into the genome to replace an "abnormal" disease-causing gene. A carrier molecule called a vector must be used to deliver the therapeutic gene to the patient's target cells. Currently, one of the most common vectors is a non-pathogenic virus that carries the gene.

More than 5 million people in the U.S. have heart failure. Patients with severe form of the disease have trouble breathing because the heart muscle is not strong enough to pump fluid out of their lungs. Approximately 70 percent die of the disease within 10 years, and the five-year survival rate is less than 50 percent. Heart failure is the only cardiovascular disease whose incidence has been increasing rather than decreasing in recent years.

The multicenter national trial was funded and administered by the Celladon Corporation of La Jolla, Calif.

Phase I CUPID results were presented at the American Heart Association Scientific Sessions in November 2008, reporting on safety, dosage and side effects.

The CUPID Trial

The CUPID trial (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) is a randomized, double-blind, placebo-controlled study to assess the efficacy and safety of MYDICAR®, a genetically targeted enzyme-replacement therapy for advanced heart failure. Enrolled patients had severe forms of the disease defined by New York Heart Association Class III or IV heart failure, significantly impaired pumping function of their hearts (ejection fraction ≤ 35 percent), and less than half the normal ability to transport and utilize oxygen during exercise testing (VO2max ≤20 mL/kg/min). The CUPID trial ClinicalTrials.gov Identifier is NCT00454818. Primary outcome measures included safety, worsening of heart failure leading to hospitalization, frequency of and time to cardiac transplantation or LVAD implantation, changes in patients' ability to exercise, echocardiographic assessments, a blood test for NT-proBNP, and symptoms of heart failure.

Heart Failure

Chronic heart failure is a leading cause of hospitalization and is expected to result in direct and indirect costs of $39.2 billion to the U.S. healthcare system in 2010. Nearly 6 million people in the U.S. have heart failure, and at least 670,000 new cases will be diagnosed this year. Heart failure leads to about 280,000 deaths annually. The most common symptoms of heart failure are shortness of breath, feeling tired and swelling in the ankles, feet, legs and sometimes the abdomen. There is no cure.

NewYork-Presbyterian Hospital

NewYork-Presbyterian Hospital, based in New York City, is the nation's largest not-for-profit, non-sectarian hospital, with 2,353 beds. The Hospital has nearly 2 million inpatient and outpatient visits in a year, including more than 220,000 visits to its emergency departments — more than any other area hospital. NewYork-Presbyterian provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, NewYork-Presbyterian/Morgan Stanley Children's Hospital, NewYork-Presbyterian/The Allen Hospital and NewYork-Presbyterian Hospital/Westchester Division. One of the most comprehensive health care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report. The Hospital has academic affiliations with two of the nation's leading medical colleges: Weill Cornell Medical College and Columbia University College of Physicians and Surgeons. For more information, visit www.nyp.org.

Columbia University Medical Center

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians and Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia's College of Physicians and Surgeons was the first institution in the country to grant the M.D. degree and is now among the most selective medical schools in the country. Columbia University Medical Center is home to the most comprehensive medical research enterprise in New York City and State and one of the largest in the United States. Columbia University Medical Center is affiliated with NewYork-Presbyterian Hospital, the nation's largest not-for-profit, non-sectarian hospital provider. For more information, please visit www.cumc.columbia.edu.