Wyeth Pharmaceuticals, a division of Wyeth (NYSE: WYE), today announced that the U.S. Food and Drug Administration (FDA) has approved new dosing recommendations for its immunosuppressant drug RAPAMUNE(R) (sirolimus).

RAPAMUNE is the first and only kidney transplant therapeutic with dosing recommendations specifically for the treatment of high immunologic risk renal transplant recipients. In high immunologic risk patients, it is recommended that a RAPAMUNE-based regimen be used in combination with cyclosporine (CsA) and corticosteroids for the first year following transplantation. The new dosing recommendations for RAPAMUNE also allow for use in combination with antibody induction therapy in this population. High immunologic risk patients have a greater likelihood of developing acute rejection than low to moderate risk kidney transplant recipients.

High immunologic risk patients are defined as transplant recipients who are Black; and/or repeat renal transplant recipients who lost a previous kidney transplant for immunologic reasons; and/or patients with high-panel reactive antibodies (PRA). For patients with high PRA, it is more difficult to find a compatible organ donor.

"Preventing acute rejection is the highest priority for both physicians and their patients during the first year following kidney transplantation. The new labeling for RAPAMUNE is significant because it provides a needed treatment option for high immunologic risk renal transplant recipients," says John F. Neylan, M.D., Vice President, Clinical Research and Development, Transplant Immunology/Internal Medicine of Wyeth Pharmaceuticals. "Wyeth remains committed to improving outcomes in renal transplant patients."

In the clinical trial of high immunologic risk patients, patient survival at 12 months was 94.6 percent. The incidence of biopsy-confirmed acute rejection (BCAR) was 17.4 percent during the first 12 months post-transplant, and the majority of the episodes of acute rejection were mild in severity. Of those receiving RAPAMUNE plus CsA in the trial, 88.4 percent also received antibody induction therapy. The safety and efficacy of this combination in high risk patients has not been studied beyond one year. After the first year following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient.

High Immunologic Risk Population

Black kidney transplant recipients represent the largest segment of the high immunologic risk population. According to the Organ Procurement and Transplant Network (OPTN), approximately 91 percent of white kidney transplant recipients have a fully functioning kidney one year post-transplant versus approximately 89 percent of Black recipients. This gap grows steadily over time. By five years post-transplant, only 60 percent of Black kidney transplant recipients have a fully functioning kidney, versus 72 percent of white recipients. Black kidney transplant recipients are more likely than white kidney transplant recipients to experience acute rejection.

"There are many barriers to successful kidney transplantation for Black and repeat recipients," says Joe Vassalotti, M.D., the National Kidney Foundation's Chief Medical Officer. "The Foundation believes that it is extremely important to have options in preventing and treating acute rejection for these high risk patients."

Pivotal Study Description

The new labeling was based on clinical data indicating that a RAPAMUNE-based regimen, when initiated post-transplant in combination with CsA, is efficacious in preventing acute rejection in high immunologic risk renal transplant recipients.

The study was conducted at 35 centers in the United States. A total of 224 patients received a transplant and at least one dose of RAPAMUNE (sirolimus) and cyclosporine and was comprised of 77.2 percent Black patients, 24.1 percent repeat renal transplant recipients, and 13.5 percent patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function.

About RAPAMUNE(R)

RAPAMUNE(R) (sirolimus) is in a novel class of immunosuppressant agents called mammalian target of rapamycin (mTOR) inhibitors, a key regulatory enzyme involved in cell growth and survival. RAPAMUNE(R) works by arresting T cell development early in the cell cycle, resulting in inhibition of lymphocyte proliferation. RAPAMUNE(R) inhibits the mTOR pathway and avoids the calcineurin pathway. It is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants.

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Safety Information

RAPAMUNE is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any component of the drug product. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of sirolimus.

WARNING:

Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. Only physicians experienced in immunosuppressive 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.

Oversuppression of the immune system can also increase susceptibility to infection including opportunistic infections, fatal infections and sepsis.

Relative to patients treated with cyclosporine and azathioprine or placebo controls, patients treated with RAPAMUNE and cyclosporine more frequently experienced impaired renal function as well as hyperlipidemia requiring treatment.

Renal function should be closely monitored during the administration of RAPAMUNE in combination with cyclosporine since long-term administration can be associated with deterioration of renal function. Appropriate adjustment of the immunosuppressive regimen including discontinuation of RAPAMUNE and/or cyclosporine should be considered in patients with elevated serum creatinine levels. In patients at low to moderate immunologic risk continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when benefits outweigh the risks of this combination for the individual patients.

Liver Transplantation -- Excess Mortality, Graft Loss, and Hepatic Artery Thrombosis (HAT): The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death.

In this and another study in de novo liver transplant recipients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT; most cases of HAT occurred within 30 days post-transplantation and most led to graft loss or death.

Lung Transplantation -- Bronchial Anastomotic Dehiscence: Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

The safety and efficacy of RAPAMUNE as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.

Conversion from a calcineurin inhibitor (CNI) to RAPAMUNE in a study of maintenance renal transplant recipients with a baseline glomerular filtration rate