• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Kidney Transplant Patients Who Took Rapamune(R) Achieved Superior Graft Survival at 4 Years After Early Cyclosporine Withdrawal

Posted on: Monday, 23 May 2005, 12:01 CDT

SEATTLE, May 23 /PRNewswire-FirstCall/ -- Data from a large comparative study presented today at the American Transplant Congress showed that kidney transplant patients on an immunosuppressive regimen of RAPAMUNE(R) (sirolimus) plus cyclosporine who had cyclosporine withdrawn at an early stage (2-4 months post-transplantation) had significantly better graft survival than those patients who remained on a cyclosporine regimen. This benefit, noted in four- year data from the RAPAMUNE Maintenance Regimen (RMR) study, appeared to be related to the significantly improved kidney function these patients experienced.

Poor kidney function is the most accurate predictor of a transplant patient losing their transplanted kidney(1). Calcineurin inhibitors, such as cyclosporine, while protecting the transplanted kidney from rejection are also toxic to the kidney(2). In another study of kidney-pancreas transplant recipients who received a calcineurin inhibitor, this toxicity was associated with deteriorating kidney function and was almost universal after 10 years post-transplantation(3).

"For many years, cyclosporine has been a mainstay of transplant therapy," said Professor Graeme Russ, of the Queen Elizabeth Hospital, Woodville, South Australia. "This study confirms that 2-4 months post-transplantation, sirolimus can be used without cyclosporine and can improve long-term graft survival in kidney transplant recipients."

In this, the largest cyclosporine withdrawal trial, 430 eligible patients were randomized to remain on cyclosporine, sirolimus and steroids (n=215) or to have the cyclosporine withdrawn, remaining on a maintenance regimen of sirolimus and steroids (n=215). The study looked at the long-term impact of baseline renal function (calculated by glomerular filtration rate - [GFR]) when withdrawing cyclosporine.

Patient Survival

At 4 years post-transplantation, excellent patient survival was observed in both groups (92.1% in patients maintained on cyclosporine vs. 95.3% in patients in whom cyclosporine had been withdrawn). The difference between these groups was not statistically significant.

Graft survival

Overall, at 4 years, graft survival was significantly better in those patients who had cyclosporine withdrawn and remained on a maintenance regimen of sirolimus and steroids compared with those patients maintained on cyclosporine. (91.5% vs. 84.2%; P=0.024).

Renal function as calculated by GFR

In all groups over the 4 years of the study, GFR continued to be significantly better in patients who had cyclosporine withdrawn compared with those maintained on cyclosporine (58.3 vs. 43.8 mL/min; P<0.001).

Side effect profile

The side effect profile was generally the same across groups.

Acute rejection

Overall, at 4 years, the difference in rates of biopsy-proven acute rejection was not significant between those patients maintained on cyclosporine and those patients in whom cyclosporine had been withdrawn (15.8% vs. 20.5%; P=0.260).

Product Indication

RAPAMUNE(R) (sirolimus) is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. It is recommended that RAPAMUNE be used initially in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunologic risk cyclosporine should be withdrawn 2 to 4 months after transplantation and RAPAMUNE dose should be increased to reach recommended blood concentrations.

The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, or with serum creatinine >4.5 mg/dL, black patients, re-transplants, multi-organ transplants, patients with high panel of reactive antibodies.

Important Safety Information - RAPAMUNE(R) (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. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of sirolimus.

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(R) (sirolimus) as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended.

In general, adverse events related to the administration of RAPAMUNE were dependent on dose/concentration. Adverse reactions associated with RAPAMUNE administration include hypercholesterolemia, hypertriglyceridemia, lymphocele, hypertension, abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), elevated lactate dehydrogenase, thrombocytopenia, abnormal healing, anemia, arthralgia, diarrhea, edema, hypokalemia, tachycardia, rash, ileus, rectal disorder, and acne.

About Wyeth Pharmaceuticals

Wyeth Pharmaceuticals, a division of Wyeth, has leading products in the areas of women's health care, cardiovascular disease, central nervous system, inflammation, transplantation, hemophilia, oncology, vaccines and nutritional products. Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products and nonprescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health.

The statements in this press release that are not historical facts are forward-looking statements based on current expectations of future events that involve risks and uncertainties including, without limitation, risks associated with the inherent uncertainty of the timing and success of pharmaceutical research, product development, manufacturing, commercialization, economic conditions including interest and currency exchange rate fluctuations, changes in generally accepted accounting principles, the impact of competitive or generic products, trade buying patterns, wars or terrorist acts, product liability and other types of lawsuits, the impact of legislation and regulatory compliance and obtaining reimbursement, favorable drug pricing, access and other approvals, environmental liabilities, and patent, and other risks and uncertainties, including those detailed from time to time in the Company's periodic reports, including current reports on Form 8-K, quarterly reports on Form 10-Q and the annual report on Form 10-K, filed with the Securities and Exchange Commission. Actual results may vary materially from the forward-looking statements. The Company assumes no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise.

References

(1) Hariharan S, McBride MA, Cherikh WS, et al. Post-transplant renal function in the first year predicts long-term kidney transplant survival. Kidney Int. 2002;62:311-318.

(2) Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a non-renal organ. N Engl J Med. 2003;349:931-940.

(3) Nankivell BJ, Borrows RJ, Fung CL-S, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326-2333.

Wyeth

CONTACT: Glenn Silver of Wyeth Pharmaceuticals, +(001) 646 437 4851

Source: PRNewswire-FirstCall

More News in this Category