Belatacept may be better than calcineurin inhibitors (CNIs) at improving renal function in kidney transplant recipients, according to a new study.
Initial results of a study conducted at 100 centers worldwide suggest that this new agent may provide similar patient and graft survival to cyclosporine but with fewer adverse effects and superior kidney function after 12 months.
“Our findings show that this will be a novel and more specific way of suppressing the immune system with less toxicity,” said lead researcher Flavio Vincenti, MD, Professor of Nephrology at the University of California in San Francisco. “It will target the specific responses that cause rejection of transplanted organs with less damage to other systems in the body.”
The study, which appears the American Journal of Transplantation (2010;10: 535-546), provides the first findings from BENEFIT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial). Although advances in transplantation have reduced rates of organ rejec- tion and improved outcomes after one year, corresponding improvements in long-term survival rates have not been observed. During the first year, the kidney allograft survival rate is 95% for living donor transplants and 89% for deceased donor transplants.
BENEFIT is a three-year, randomized, active-controlled, parallel-group, study that is evaluating the efficacy of belatacept for post-transplant maintenance immunosuppressive management. This agent is different from CNIs such as cyclosporine because it does not cause CNI-associated toxicities, including nephrotoxicity, and it does not aggravate cardiovascular risk factors. Belatacept selectively blocks T-cell activation. BENEFIT results suggest that this selectivity allows for effective immunosuppression, better preservation of renal function, and an improved cardiovascular and metabolic risk profile.
For this study, the investigators randomly assigned 686 patients who received a kidney transplant from a standard criteria donor into one of three groups: 1) those who received a more intensive regimen of belatacept (MI); 2) patients who receinved a less intensive (LI) regimen, or 3) those who received cyclosporine. The mean age of the patients was 43 years and approximately 72% were male. The primary end points for the study were patient/graft survival, a composite renal impairment end point (percentage with a measured glomerular filtration rate [mGFR] below 60 mL/min/1.73m2 at 12 months post-transplant or a decrease in mGFR of 10 mL/min/1.73 m2 or greater from month 3 through month 12), and the incidence of acute rejection.
At 12 months, both belatacept regimens had similar patient/graft survival rates versus cyclosporine (95% for MI, 97% for LI, and 93% for cyclosporine), but were associated with superior renal function as measured by the composite renal impairment end point (55% for MI, 54% for LI and 78% for cyclosporine).
However, the researchers found that belatacept-treated patients experienced a higher inci- dence and grade of acute rejection episodes (22% for MI, 17% for LI and 7% for cyclosporine).
Safety was generally similar among all three groups, but post-transplant lymphoproliferative disorder (PTLD) was more common in the belatacept groups. PTLD occurred in recipients with known risk factors, particularly EBV negative status, administration of T-cell depleting therapy, and in those who developed cytomegalovirus disease.
The researchers reported that the incidence of PTLD with belatacept may be reduced by minimizing its use in patients with EBV negative serology, selectively using T-cell depletion therapy and utilizing prophylaxis for cytomegalovirus infections.
“Although belatacept was associated with a higher early rejection rate than patients treated with cyclosporine, it was also associated with better kidney function and thus has the potential of extending the life of the renal graft,” Dr. Vincenti said.
“This is a whole new class of medications that represents a paradigm shift in immunosuppression, eliminating some of the drugs we have had to rely on for the past two decades,” Dr. Vincenti told Renal & Urology News.
“Belatacept is much more pa-tient friendly. It doesn’t have any nephrotoxicity or scarring of the kidney. It has the potential to finally extend the life of the graft like none of the other medicines we have used in the past,” he added.n