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

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 After three months, 430 patients were randomized either to have cyclosporine withdrawn and remain on a once-a-day regimen of RAPAMUNE and steroids, or to continue with their original treatment.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.