New Drug Application 21-628, Certican (Everolimus), for the Proposed Indication of Prophylaxis of Rejection in Heart Transplantation

The Cardiovascular and Renal Drugs Advisory Committee (Committee) of the Food and Drug Administration (FDA), Center for Drug Evaluation and Research, met on November 16, 2005, to discuss the new drug application (NDA) 21-628 by Novartis Pharmaceuticals Corporation for Certican (everolimus), for the proposed indication of prophylaxis of rejection in heart transplantation. The Committee reviewed 1 primary trial in heart failure and additional background information, as well as 2 studies of everolimus in renal transplantation. The meeting consisted of presentations by the sponsor and the FDA regarding an overview of heart transplantation; a summary of the efficacy and safety of everolimus, including the intravascular ultrasound (IVUS) results and renal toxicity; and an overall assessment of risk and benefit.The primary causes of heart failure in patients undergoing transplantation are coronary artery disease and noncoronary cardiomyopathy.1 After transplant, there is an initially high mortality rate due to acute postsurgical complications. Survivors have a subsequent average mortality of 3.4% per year.1 Risk factors for mortality at 5 years include need for repeat transplant, cerebrovascular disease, and the development of coronary artery vasculopathy. IVUS identification of rapidly progressive vasculopathy is an independent predictor of adverse outcomes and mortality in heart transplant recipients.2 Morbidity rates are also high in heart transplantation patients, with more than 30% developing renal dysfunction within 1 year, 1.5% requiring dialysis, and 0.3% requiring renal transplantation. After 3 years, more than 16% will develop chronic renal failure, of whom &29% will require maintenance dialysis or renal transplantation.3 The development of chronic renal failure is also an independent predictor of mortality.There are 2 FDA-approved drugs to prevent cardiac rejection. The first is the calcineurin inhibitor cyclosporin A (CsA), and the other is mycophenolate mofetil (MMF), which is used …