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| |  FDA Approves Rapamune To Prevent Kidney Transplant Rejection MADISON, N.J. -- September 16, 1999 -- Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Products Corporation, has received marketing approval from the U.S. Food and Drug Administration (FDA) for Rapamune® (sirolimus), the first in a new class of immunosuppressant agents developed for the prevention of organ rejection following renal transplantation. Discovered more than 25 years ago from the soil of Easter Island, Rapamune is recommended to be used in combination with cyclosporine and corticosteroids for the prevention of acute organ rejection in kidney transplant patients. Results from clinical trials demonstrate that Rapamune, when used in this combination, reduces acute rejection rates by up to 60 percent compared to control regimens. The control regimens contained cyclosporine and corticosteriods in combination with either azathioprine or placebo. Graft loss and patient survival rates at six and 12 months were similar in the Rapamune- and comparator-treated patients. Studies also show that patients treated with Rapamune experienced a reduction in the incidence of all grades of acute rejection episodes. "Rapamune represents a new alternative in immunosuppression. It will provide an important new treatment option for renal transplant patients, which is especially significant since there aren’t many therapeutic choices," says Barry D. Kahan, Ph.D., M.D., Professor of Surgery, Director, Division of Immunology and Organ Transplantation at The University of Texas-Houston Health Science Center. Kidney transplantation is the most common type of transplant procedure in the United States. To help reduce the risk of organ rejection, transplant patients are given a life-long regimen of immunosuppressant agents. These drugs are intended to lower the body’s normal immune response, allowing the transplanted organ to remain functional.
Improving Organ Transplant Survival Immunosuppressant drugs are necessary after organ transplants because the human body is designed to reject cells that are foreign and perceived to be potentially dangerous, such as a transplanted organ. Thus, the very system that provides protection against intruding organisms is the system that poses a substantial threat to the transplant recipient. Reducing the potential for organ rejection has become increasingly important due to a global shortage of donor organs available for human transplantation. For instance, there are currently more than 40,000 patients in the United States awaiting kidney transplants, and approximately 12,000 kidneys were transplanted in 1998. "This shortage increases the importance that each organ transplant is successful, and that the medications to help support a successful outcome are optimal. Therefore, this new therapy holds particular promise in meeting this global challenge," noted Dr. Kahan.
A Novel Mechanism of Action In mechanistic terms, Rapamune differs considerably from cyclosporine and tacrolimus, which are calcineurin inhibitors. Rapamune is the first of a distinctive class of immunosuppressants; Rapamune inhibits the activation of TOR (target of rapamycin), a key regulatory kinase involved in cell cycle progression. "Since Rapamune works by a novel mechanism, it will expand the therapeutic options available to transplant physicians and patients," says Joseph S. Camardo, M.D., Senior Vice President, Clinical Research and Development, Wyeth-Ayerst.
Clinical Trial Overview In its application, Wyeth-Ayerst presented clinical data from two prospective, Phase III, double-blind, comparative studies that demonstrated the efficacy and safety of Rapamune. In one of the largest transplant studies ever conducted in the United States involving 700 kidney transplant patients, researchers compared the efficacy of Rapamune (2 mg/day and 5 mg/day) versus azathioprine. These groups also received cyclosporine and prednisone as a triple therapy regimen. A second trial conducted among 550 patients in nine countries compared the efficacy of Rapamune (2 mg/day and 5 mg/day) plus cyclosporine and prednisone, versus cyclosporine and prednisone plus placebo. Safety Information Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in imunosuppressive therapy and management of renal transplant patients should use Rapamune. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Increased serum cholesterol and triglycerides that may require treatment occurred more frequently in patients treated with Rapamune compared to azathioprine or placebo controls. Mean serum creatinine was increased and mean glomerular filtration rate was decreased in patients treated with Rapamune and cyclosporine compared to those treated with cyclosporine and placebo or azathioprine controls. Renal function should be monitored during the administration of maintenance immunosupression regimens including Rapamune in combination with cyclosporine, and appropriate adjustment of the immunosupression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when using agents which are known to impair renal function. Specific adverse reactions associated with Rapamune administration occurring at a significantly higher frequency vs. controls were for both 2 and 5 mg/day: hypercholesterolemia, hyperlipemia, hypertension, and rash; for 5 mg/day: anemia, arthralgia, diarrhea, hypokalemia, and thrombocytopenia; and for 2 mg/day: acne. Elevations of triglycerides and cholesterol, and decreases in platelets and hemoglobin occurred in dose-related manner.
Related Links: Wyeth-Ayerst.
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