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A Phase III Study of Belatacept Versus Cyclosporine in Kidney Transplants from Extended Criteria Don
Abstract and Introduction
Abstract
Recipients of extended criteria donor (ECD) kidneys are at increased risk for graft dysfunction/loss, and may benefit from immunosuppression that avoids calcineurin inhibitor (CNI) nephrotoxicity. Belatacept, a selective costimulation blocker, may preserve renal function and improve long-term outcomes versus CNIs. BENEFIT-EXT (Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial—EXTended criteria donors) is a 3-year, Phase III study that assessed a more (MI) or less intensive (LI) regimen of belatacept versus cyclosporine in adult ECD kidney transplant recipients. The coprimary endpoints at 12 months were composite patient/graft survival and a composite renal impairment endpoint. Patient/graft survival with belatacept was similar to cyclosporine (86% MI, 89% LI, 85% cyclosporine) at 12 months. Fewer belatacept patients reached the composite renal impairment endpoint versus cyclosporine (71% MI, 77% LI, 85% cyclosporine; p = 0.002 MI vs. cyclosporine; p = 0.06 LI vs. cyclosporine). The mean measured glomerular filtration rate was 4–7 mL/min higher on belatacept versus cyclosporine (p = 0.008 MI vs. cyclosporine; p = 0.1039 LI vs. cyclosporine), and the overall cardiovascular/metabolic profile was better on belatacept versus cyclosporine. The incidence of acute rejection was similar across groups (18% MI; 18% LI; 14% cyclosporine). Overall rates of infection and malignancy were similar between groups; however, more cases of posttransplant lymphoproliferative disorder (PTLD) occurred in the CNS on belatacept. ECD kidney transplant recipients treated with belatacept-based immunosuppression achieved similar patient/graft survival, better renal function, had an increased incidence of PTLD, and exhibited improvement in the cardiovascular/metabolic risk profile versus cyclosporine-treated patients.
Introduction
Kidney transplantation is the treatment of choice for selected patients with ESRD and is associated with improved patient survival and quality of life compared with dialysis, but the waiting list for renal transplantation is larger than the availability of organs. Because of the growing discrepancy between kidney supply and demand, there is tremendous pressure to utilize all available kidneys for transplantation, many of which come from extended criteria donors. The definition of extended criteria donor varies by country, but usually includes older donors and donors with health issues that increase risk of graft loss or dysfunction. This is reflected in lower 1-year allograft survival rates for extended criteria donor kidneys versus nonextended criteria donors deceased donor kidney transplants, and allograft survival declines even further over time, primarily due to chronic allograft injury.
In addition, extended criteria donor transplant recipients are challenging to immunosuppress, as they tend to be older and are at increased risk for cardiovascular events and mortality compared with nonextended criteria donor recipients. Although calcineurin inhibitors remain a cornerstone of immunosuppression, they are nephrotoxic and exacerbate cardiovascular and metabolic risk factors that can limit graft and patient survival. Furthermore, kidneys from extended criteria donors are more susceptible to the adverse effects of calcineurin inhibitors. Impaired kidney function at 1 year is associated with reduced long-term graft survival and is an independent cardiovascular risk factor. Immunosuppressive regimens that avoid the renal and nonrenal toxicities of calcineurin inhibitors may make extended criteria donor transplants more attractive, might improve long-term patient and graft survival and could enable more patients to benefit from transplantation.
Belatacept is a first-in-class costimulation blocker that selectively blocks T-cell activation. A Phase II study demonstrated that belatacept-based regimens were associated with a similar incidence of acute rejection and better renal function and structure compared with a cyclosporine-based regimen.
The Phase II study results suggested that belatacept-based regimens could provide adequate immunosuppressive efficacy while avoiding the renal toxicity associated with calcineurin inhibitors and the chronic nonrenal effects of calcineurin inhibitors that can negatively impact patient/graft survival. Thus, the objective of this global Phase III study, the largest conducted to date in an extended criteria donor patient population, was to assess whether treatment with belatacept would result in similar patient/graft survival and superior renal function versus cyclosporine in patients receiving an extended criteria donor kidney transplant. The study endpoints also included cardiovascular/metabolic assessments, and the incidence of chronic allograft nephropathy and of acute rejection episodes. The study was prospectively designed to continue beyond the 12-month primary endpoint reported here, to a total of 3 years, to assess longer-term efficacy and safety of the belatacept-based regimens.
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