Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial

Grinyó, Josep M.; Rial, María del Carmen; Alberú, Josefina; Steinberg, Steven M.; Manfro, Roberto Ceratti; Nainan, Georgy; Vincenti, Flavio; Jones-Burton, Charlotte; Kamar, Nassim

doi:10.1053/j.ajkd.2016.09.021

Cited by 85 publications

(92 citation statements)

References 30 publications

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“…We observed 2 cases of rejection, of which one recovered completely after treatment, allowing belatacept continuation. As in previous studies, the acute rejection occurred soon after initiating belatacept . The rate of AR in the phase II study was 7.1% after 1 year (all cases resolved with treatment) and less than 10% after 3 years .…”

Section: Discussionsupporting

confidence: 73%

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Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study

Bertrand¹,

Cheddani²,

Étienne³

et al. 2017

American Journal of Transplantation

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Immunosuppression in kidney transplant recipients with decreased graft function and severe histological vascular changes can be particularly challenging. Belatacept could be a valuable option, as a rescue therapy in this context. We report a retrospective case control study comparing a CNI to belatacept switch in 17 patients with vascular damage and low eGFR to a control group of 18 matched patients with CNI continuation. Belatacept switch was performed on average 51.5 months after kidney transplantation (6.2-198 months). There was no difference between the two groups regarding eGFR at inclusion, and 3 months before inclusion. In the "CNI to belatacept switch group," mean eGFR increased significantly from 23.5 ± 6.7 mL/min/1.73m on day 0, to 30.4 ± 9.1 mL/min/1.73 m on month 6 (p < 0.001) compared to the control group, in which no improvement was observed. These results were still significant on month 12. Two patients experienced biopsy-proven acute rejection. One was effectively treated without belatacept discontinuation. Two patients needed belatacept discontinuation for infection. In conclusion, the remplacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in eGFR.

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Section: Discussionsupporting

confidence: 73%

“…In the phase II study published in 2011 by Rostaing et al, CNI switch to belatacept was also associated with eGFR improvement . This improvement was also found at 3 years, as was recently reported by Grinyo et al . Nevertheless, the switch was performed in patients with stable renal function and not as a rescue therapy.…”

Section: Discussionmentioning

confidence: 60%

Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study

Bertrand¹,

Cheddani²,

Étienne³

et al. 2017

American Journal of Transplantation

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“…Because belatacept had not been previously studied in adolescents, initial dose selection for this age group was based on simulations that extrapolated data from an adult population pharmacokinetic model to adolescents . The dose selected for use in adolescents was that necessary to achieve steady‐state trough ( C min ) concentrations comparable to those observed in stable adult renal transplant recipients participating in a phase II study . Based on the assumption that belatacept exposure at C min is highly correlated with receptor occupancy, which then drives pharmacologic activity, and because it was expected that belatacept clearance would increase with decreasing age (due to generally higher metabolic rates in children), we reasoned that a higher belatacept dose was likely needed for adolescents to achieve C min similar to that observed in adults.…”

Section: Methodsmentioning

confidence: 99%

Phase I study of single-dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients

Moudgil

Dharnidharka

Feig

et al. 2019

American Journal of Transplantation

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Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12‐17 years receiving a stable calcineurin inhibitor–based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein‐Barr virus were enrolled; all completed the 6‐month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [Cmax] and area under the serum concentration‐time curve from time zero extrapolated to infinity [AUC0‐INF] were 20% and 25%, respectively). Mean half‐life (T1/2) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady‐state (Vss) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.

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“…There was no difference in patient or graft survival between groups. A trend in improvement of renal function may have been blunted by the addition of 16 patients who were switched from a CNI-based immunosuppression regimen to belatacept after 24 months post-randomization (32). …”

Section: Aims and Methodsmentioning

confidence: 99%

Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants

Kumar¹,

LeCorchick²,

Gupta³

2017

Front. Med.

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The goal of immunosuppression in transplantation has shifted to improving long-term outcomes, reducing drug-induced toxicities while preserving the already excellent short-term outcomes. Long-term gains in solid organ transplantation have been limited at least partly due to the nephrotoxicity and metabolic side effects of calcineurin inhibitors (CNIs). The alloimmune response requires activation of the costimulatory pathway for T cell proliferation and amplification. Belatacept is a molecule that selectively blocks T cell costimulation. In June 2011, the U.S. Food and Drug Administration approved it for maintenance immunosuppression in kidney transplantation based on two open-label, randomized, phase III trials. Since its introduction, belatacept has shown promise in both short- and long-term renal transplant outcomes in several other trials. It exhibits a superior side effect profile compared to CNIs with a comparable efficacy. Across all solid organ transplants, the burden of chronic kidney disease, its associated cardiovascular morbidity, mortality, and inferior patient/allograft survival is a well-documented problem. In this review, we aim to discuss the evidence behind the use of belatacept in solid organ transplants as an effective alternative to CNIs for renal rescue in patients with acute and/or chronic kidney injury.

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Safety and Efficacy Outcomes 3 Years After Switching to Belatacept From a Calcineurin Inhibitor in Kidney Transplant Recipients: Results From a Phase 2 Randomized Trial

Abstract: Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Cited by 85 publications

References 30 publications

Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study

Belatacept Rescue Therapy in Kidney Transplant Recipients With Vascular Lesions: A Case Control Study

Phase I study of single-dose pharmacokinetics and pharmacodynamics of belatacept in adolescent kidney transplant recipients

Belatacept As an Alternative to Calcineurin Inhibitors in Patients with Solid Organ Transplants

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