Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Abstract

Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

CTLA4-Ig in combination with FTY720 promotes allograft survival in sensitized recipients

“…However, the majority of those studies focused on tolerance induction that used a short treatment course of costimulation blockade, whereas in this study we treated continuously with CTLA4-Ig, which is similar to its clinical use (1,2,34). Furthermore, most of those studies were based on the adoptive transfer of donor-reactive memory T cells that drove the costimulation blockade-resistant rejection process (11,28,35,36).…”

“…Indeed, we observed that the efficacy of CTLA4-Ig was inferior in recipients that were more recently sensitized and harbored higher levels of DSA. In initial trials with belatacept that involved nonsensitized recipients and current clinical use involving patients that do not meet this stringent criteria, higher rates of acute rejection have been reported (2,34,(57)(58)(59). Thus, we consider the more stringent model with low levels of circulating DSA an excellent model to investigate CTLA4-Ig efficacy.…”

“…The relatively high incidence of early aggressive T cell-mediated acute rejection is a significant impediment to the widespread use of belatacept in clinical transplantation, despite recent reports of improved long-term outcomes (1)(2)(3). High frequencies of alloreactive memory T cells have emerged as the major hypothesis to explain this emergence of belatacept-resistant cellular rejection.…”

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly

“…The comparable rates of acute rejection for belatacept‐based vs CsA‐based immunosuppression were preserved over 10 years: acute rejection rates in the belatacept treatment arms (6%‐7%) were noninferior to that observed in the CsA treatment arm (8%) at 6 months posttransplant in IM103‐100 10. Most acute rejection events in belatacept‐treated patients occur within 6 months of treatment initiation 10, 12, 13. In IM103‐100, most BPAR events in the population at first randomization were reported by month 6 (28 of 41, 68.3%).…”

New targets for immunosuppression in kidney transplantation: Focus on recent clinical trials

“…Recently, the results of the Phase 2 long-term extension trial have been published. 31 Continued follow-up of 128 of the original 218 patients demonstrated that no patients who were treated with belatacept and 1 patient who was treated with cyclosporine developed PTLD during the extension follow-up period. Additionally, renal function was superior in belatacept-treated patients.…”