Sirolimus-based therapy following early cyclosporine withdrawal improves transplanted kidney structure and function

Main Category: Transplants / Organ Donations
Article Date: 12 Jun 2004 - 10:00 PDT

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Wyeth Pharmaceuticals, the pharmaceutical division of Wyeth, announced today important new study findings for RAPAMUNE® (sirolimus). Kidney histology and function three years after transplantation are better in kidney-transplant patients who remain on sirolimus-based therapy following early withdrawal of cyclosporine than in patients who continue on this calcineurin inhibitor, according to a new study published in the American Journal of Transplantation.

Dr. Alfredo Mota, from Hospitais da Universidade de Coimbra, Portugal, lead author of the study commented, "Graft function and histology are seen as predictive of renal transplant survival. Despite their efficacy, calcineurin inhibitors are known to contribute to suboptimal renal graft half-life because they increase blood pressure, decrease glomerular filtration rates (GFR), and contribute to chronic allograft nephropathy."

He continued, "From the RAPAMUNE Maintenance Regimen study we already know that early cyclosporine elimination significantly improved renal function and blood pressure. Now in the three-year biopsy results of the same study we see an improvement in glomerular filtration rates, and, in the biopsies, a significant decrease in tubular atrophy. This reinforces the advantages of a sirolimus-based immunosuppressive regimen with early cyclosporine withdrawal over continuous combined sirolimus-cyclosporine maintenance therapy for management of renal transplant patients."

The RAPAMUNE Maintenance Regimen (RMR) study involved 525 patients from 57 centers in Europe, Canada, and Australia. All patients were started on a combination of RAPAMUNE, cyclosporine, and steroids. After three months, 430 patients were randomized either to have cyclosporine withdrawn and remain on a once-a-day regimen of RAPAMUNE and steroids, or to continue with their original treatment.

Protocol biopsies were performed at the time of transplant, and at 12 and 36 months post-transplant. Two pathologists, blinded to treatment and clinical outcome, evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. This scoring system can be used to detect subtle chronic changes in the structure of the transplanted kidney. They rated each of the six components of the CADI score (diffuse or focal inflammation, tubular atrophy, intimal proliferation, glomerular sclerosis, mesangial matrix increase, and interstitial fibrosis).

Results

The 63 patients in whom all three serial biopsies were performed were representative of patients completing 36 months of treatment.

The mean CADI scores were comparable between the two treatment groups both at baseline and 12 months. However, the mean CADI scores diverged thereafter, becoming significantly lower at 36 months in the group of patients who had cyclosporine withdrawn than in those who continued on cyclosporine (3.20vs4.70; P = 0.003).

When the investigators looked at the six component parts of the CADI score separately at 36 months, they found that all were lower in the patients who had cyclosporine withdrawn, and the mean tubular atrophy score was significantly lower in the patients who had cyclosporine withdrawn than in the group continuing on cyclosporine (0.32 vs. 0.77; P < 0.001).

The results of the RMR trial have demonstrated excellent graft and patient survival. The results reported by Mota are consistent with the other clinical findings of the RMR trial: improved renal function and lower blood pressure in favor of early cyclosporine withdrawal. At 36 months, the renal function as judged by calculated glomerular filtration rate was significantly better in the patients who had cyclosporine withdrawn than in the group continuing on cyclosporine (68.2 vs. 54.8 mL/min; P = 0.009).

Conclusions

Commenting on tubular atrophy, Dr. Mota said, "Tubular changes are hallmarks of cyclosporine nephrotoxicity. Thus, these data suggest that sirolimus-based, cyclosporine-free therapy will reduce the incidence of tubular atrophy if cyclosporine is withdrawn early in the post-transplantation period."

Overall, the investigators concluded that withdrawing cyclosporine from the sirolimus-cyclosporine-steroid regimen resulted in improved renal histology and function.

"These findings from the RMR study are important to physicians, patients, and the renal transplant community," says Joseph Camardo, M.D., Senior Vice President, Global Medical Affairs, Wyeth Pharmaceuticals. "Current immunosuppressive regimens involving the use of calcineurin inhibitors, such as cyclosporine, have long been associated with nephrotoxic effects. This new histology data strengthens evidence that RAPAMUNE can be used to avoid the toxic effects of calcineurin inhibitors."

RAPAMUNE is the first of a distinctive class of immunosuppressants known as mTOR inhibitors. mTOR stands for mammalian target of rapamycin, a key regulatory kinase involved in cell cycle progression.

RAPAMUNE is available in both 1 mg and 2 mg tablet formulations, as well as a 1 mg/mL oral solution.

Product Information

RAPAMUNE® (sirolimus) is indicated for the prophylaxis of organ rejection in patients 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 two to four 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.

The following is important safety information for RAPAMUNE:

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 the 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.

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

Wyeth Pharmaceuticals, a division of Wyeth (NYSE:WYE), has leading products in the areas of women's health care, cardiovascular disease, central nervous system, inflammation, hemophilia, oncology and vaccines. 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 non-prescription 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, and 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.

Media
Douglas Petkus
Wyeth Pharmaceuticals
484-865-5140

Jenifer Antonacci
Wyeth Pharmaceuticals
484-865-5220

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