Brand Name: Rapamune
Active Ingredient: sirolimus
Indication: The prevention of acute kidney rejection following transplantation
Company Name: Wyeth-Ayerst Laboratories
Availability: By prescription only
The U.S. Food and Drug Administration’s (FDA) Subcommittee of the Antiviral Drugs Advisory Committee on Immunosuppressive Drugs voted unanimously 27 July 1999 that Rapamune® (sirolimus) is safe and effective for the prevention of acute kidney rejection following transplantation. If final approval is ultimately given by the FDA, Rapamune would be the first of a new class of immunosuppressive agents developed to treat transplant patients. Rapamune is a product of Wyeth-Ayerst Laboratories, the pharmaceutical division of American Home Products Corporation.
Kidney transplantation is the most common type of transplant procedure in the U.S., with over 12,000 transplants occurring in 1998. To help minimize the risk of organ rejection, transplant patients are given a life-long regimen of immunosuppressive agents. These drugs are intended to lower the body’s normal immune response allowing the transplanted organ to remain functional.
Many patients require retransplants in part because of organ failure due to toxicities; this need for repeat organ transplants only compounds the organ shortage. For example, there are more than 40,000 patients in the U.S. awaiting kidney transplants. However, only about 12,000 kidneys were available for use in 1998. These organ shortages have increased the importance of organ transplants being successful and the need for new therapies that can help decrease the incidence of rejection episodes.
Rapamune (sirolimus) was first developed as a potential antifungal agent, called rapamycin. When testing the antifungal properties of rapamycin in the 1970′s, researchers discovered that it caused suppression of the immune system and abandoned it as an antifungal agent. The drug then demonstrated the ability to halt the growth of cancerous tumors, but attempts to develop an intravenous formula of rapamycin proved futile. In the 1980′s, researchers focused their attention on rapamycin’s immunosuppressive properties. Subsequent clinical trials demonstrated that rapamycin could more effectively and safely lower the risk of chronic rejection of kidney transplants.
How it Works
When an organ is transplanted, the recipient’s immune system recognizes the new organ as foreign and attacks it. The attack causes a build-up of scar tissue, associated with chronic rejection, on the transplanted organ. Rapamune (sirolimus) reduces the risk of chronic rejection by suppressing the immune system, hence weakening its attack.
Rapamune (sirolimus): Clinical Study Results
Two clinical trials, one conducted in the United States and one involving patients from nine countries, demonstrated Rapamune’s efficacy versus standard treatment and versus placebo.
The U.S. study was randomized, double-blinded, comparative, and race-stratified. It involved 38 centers and included 719 kidney transplant patients. Patients were randomized to receive a combination of cyclosporin, a steroid, and Rapamune 2 mg or 5 mg or the standard treatment of cyclosporin, a steriod, and azathioprine. The primary endpoint was efficacy failure. 18.7% and 16.8% of the patients receiving 2 mg and 5 mg of Rapamune, respectively, reached endpoint; whereas, 32.3% of the patients receiving standard therapy experienced endpoint.
The second study included 576 patients and compared Rapamune (sirolimus) to placebo. Except for the control group that received cyclosporin, a steroid, and placebo, patients in the international trial received the same drug treatments as the patients in the above-mentioned trial. 30%, 25.6%, and 47.7% of patients who were administered Rapamune 2 mg, Rapamune 5 mg, and placebo, respectively, experienced endpoint. The large differences in the results of the U.S. trial and the international trial could be attributable to the differing methodologies of the studies. The U.S. study eliminated high-risk patients that may have been included in the international trial.
What the Patient Should Know
Rapamune (sirolimus) is administered orally (2 mg or 5 mg) in combination with cyclosporin and a steriod to avoid transplant rejection. Patients receiving this treatment are under strict medical supervision.