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

Am J Transplant. 2020 Jan;20(1):172-180 doi: 10.1111/ajt.15560.
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 AUCinf , Cmax , and AUClast . 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]). AUCinf and AUClast demonstrated a more than dose-proportional increase in the range of 50-500 mg, and Cmax 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).

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Conclusion: This phase Ib study investigates the safety and pharmacokinetics of a novel anti-CD40 monoclonal antibody in renal transplant recipients. Participants received standard baseline immunosuppression, and were randomised to either placebo or a single infusion of the monoclonal antibody at one of 4 doses. The drug appeared well tolerated at all doses, and pharmacokinetic data including AUCs and receptor occupancy over time are presented. These results are encouraging, and the drug has now moved on to phase II investigation. It is not yet clear how this will sit within our current immunosuppressive armoury, but it may ultimately provide an alternative agent to facilitate CNI minimisation.
Methodological quality
Jadad score 3
Allocation concealment NO
Data analysis PER PROTOCOL
Study Details
Aims: This study aimed to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of four dose levels of bleselumab administered with standard immunosuppressants to de novo kidney transplant recipients.
Interventions: Kidney transplant recipients were randomized to receive bleselumab, 50mg, 100mg, 200mg, or 500mg, or placebo with standard immunosuppression.
Participants: 50 Adult (18-65 years of age) de novo kidney transplant recipients who received their kidney from either a living or deceased donors.
Outcomes: The primary pharmacokinetic endpoints were AUCinf, Cmax, and AUClast. The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time.
Follow Up: 90 days
Metadata
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Organ: Kidney
Language: Engish
MeSH terms: Adult; Antibodies, Monoclonal, Humanized; CD40 Antigens; Double-Blind Method; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Risk Factors; Tissue Distribution; Transplant Recipients; 0 (Antibodies, Monoclonal, Humanized); 0 (CD40 Antigens); 0 (Immunosuppressive Agents); AS3AZ5R46K (Bleselumab)