A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation

Abstract

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUC_inf , C_max , and AUC_last . The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUC_inf and AUC_last demonstrated a more than dose-proportional increase in the range of 50-500 mg, and C_max increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment-emergent anti-bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose-dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).

Keywords: antibody biology; clinical research/practice; kidney transplantation/nephrology; kidney transplantation: living donor.

Figure 1

Study design. *Day 0

Figure 2

Patient disposition. *Four randomized patients withdrew before receiving study drug due to one AE during screening, one patient no longer fulfilled inclusion/exclusion criteria, two were never dispensed study drug. ^†one patient excluded from table summaries owing to evidence of not taking study drug. ^‡The one patient who received their treatment but did not complete the study in the bleselumab 50 mg group discontinued the study owing to not returning for their final visit. AE, adverse event; FAS, full analysis set; PDAS, pharmacodynamic analysis set; PKAS, pharmacokinetic analysis set; SAF, safety analysis set

Figure 3

Mean serum concentration of bleselumab, from predose to (A) 144 hours and (B) 90 days

Figure 4

Median B cell CD40 receptor occupancy. Note that median data are shown because interpatient variability was such that mean values were not informative