Objective was to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ASKP1240, a fully human anti-CD40 monoclonal antibody, administered following a de novo kidney transplant (tx).
Subjects were >18 but <65 years,receiving first/repeat tx from living or deceased donor in the US. Subjects received a single IV dose of 1 of 4 ASKP1240 dose levels (50 mg, 100 mg, 200 mg, 500 mg) or placebo. Subjects were followed to Study Day 90. Antibody induction therapy was prohibited. Patients received standard (by center) maintenance immunosuppression post-tx.
Forty-six subjects received study drug between 24-48 hours after tx. One subject in 50 mg group did not complete last study visit. Baseline characteristics were similar in groups except there were no females in the 50 mg group.
Cmax increased linearly with increasing dose;AUC showed more than dose proportional increase from 50 mg to 500 mg. Maximal receptor occupancy (MaxRO) for B cell CD40 was reached at all dose levels. Duration of MaxRO tended to increase as dose increased.
There were no deaths, graft losses or malignancies in the study. Other key outcomes at Day 90 are below.
|Parameter||Placebo [N=8]||ASKP1240 50 mg [N=10]||ASKP1240 100 mg [N=9]||ASKP1240 200 mg [N=10]||ASKP1240 500 mg [N=9]|
|Acute Rejection (AR) (n)||1||3||0||0||3|
|Onset AR (study day)||3||6/19/90||NA||NA||7/8/10|
|Treatment Given for AR (n,steroids/n,ATG)||1/1||3/1||NA||NA||3/1|
|Serum creatinine @time of AR (mg/dL)||3.15||3.65/2.4/2.1||NA||NA||1.9/2.9/2.6|
|Serum Creatinine Day 90 (mg/dL)||1.68||1.86/1.6/unknown||NA||NA||1.4/1.6/1.1|
|Serious AEs (%)||37.5||60.0||11.1||0.0||33.3|
|BK Infection (%)||12.5||40.0||0.0||10.0||22.2|
|CMV Infection (%)||12.5||0.0||11.1||0.0||11.1|
|Cardiac Events (%)||12.5||0.0||0.0||10.0||11.1|
Conclusions: ASKP1240 was well tolerated at all doses. Acute rejection (AR) occurred early post-tx and responded to steroids in 5/7 cases. Renal function improved following treatment of AR in 6 cases for whom data was available. Incidence of infection was not dose dependent. ASKP1240 showed non-linear pharmacokinetics. The MaxRO tended to be prolonged as dose increased.
To cite this abstract in AMA style:Vincenti F, Yang H, Klintmalm G, Steinberg S, Wang L, Zhang W, Conkle A, Blahunka P, First R, Holman J. Clinical Outcomes in a Phase 1b, Randomized, Double-Blind, Parallel Group, Placebo-Controlled, Single-Dose Study of ASKP1240 in De Novo Kidney Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/clinical-outcomes-in-a-phase-1b-randomized-double-blind-parallel-group-placebo-controlled-single-dose-study-of-askp1240-in-de-novo-kidney-transplantation/. Accessed July 24, 2021.
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