Recombinant ADAMTS-13: first-in-human pharmacokinetics and safety in congenital thrombotic thrombocytopenic purpura

Abstract

Safety, tolerability, and pharmacokinetics of recombinant ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; BAX 930; SHP655) were investigated in 15 patients diagnosed with severe congenital ADAMTS-13 deficiency (plasma ADAMTS-13 activity <6%) in a prospective phase 1, first-in-human, multicenter dose escalation study. BAX 930 was well tolerated, no serious adverse events occurred, and no anti-ADAMTS-13 antibodies were observed. After single-dose administration of BAX 930 at 5, 20, or 40 U/kg body weight to adolescents and adults, there was approximate dose proportionality with respect to maximum plasma concentration (Cmax [U/mL]) and area under the concentration-time curve (AUC [h∙U/mL]). Dose-related increases of individual ADAMTS-13:Ag and activity were observed and reached a maximum within 1 hour. With escalating BAX 930 doses administered, a dose-dependent persistence of ADAMTS-13-mediated von Willebrand factor (VWF) cleavage products and reduced VWF multimeric size were observed. This study demonstrated that pharmacokinetic parameters of BAX 930 were comparable to those estimated in previous plasma infusion studies and provided evidence of pharmacodynamic activity. This study was registered at www.clinicaltrials.gov as #NCT02216084.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Study population disposition.

Figure 2.

Observed ADAMTS-13 activity over time. ADAMTS-13 activity in plasma was measured at baseline and at times up to 288 hours, using the FRETS-VWF73 assay after a 40 U/kg administration of BAX 930.

Figure 3.

VWF structural analyses pre- and postinfusion of BAX 930. (A) Representative sodium dodecyl sulfate-agarose gel pattern of pretreatment TTP plasma depicting UL, large, intermediate, and small VWF multimers. (B) The proportions of intermediate and large/UL multimers of plasma VWF were estimated from sodium dodecyl sulfate-agarose gels at various times before and after infusion of 40 U/kg BAX 930. The observed concentration of large and UL multimers tended to decrease in all treated patients in the first 12 hours before gradually returning to preinfusion levels. (C) Time course of the 176-kDa ADAMTS-13 VWF cleavage product after administration of 5, 20, and 40 U/kg BAX 930. High levels of detectable VWF cleavage products are apparent just after dosing, which gradually return to preinfusion levels in a dose-related manner.

Figure 4.

Changes in platelet counts after BAX 930 administration. Changes in mean platelet counts over time are depicted after administration of 5, 20, and 40 U/kg of BAX 930. An increasing trend in platelet levels was observed in all dosing cohorts.

Figure 5.

Predicted PK estimates from two-compartment model. Predicted FRETS-VWF73 activity time profiles are depicted based on a 2-compartmental model according to linear and log concentrations. Both display approximate dose proportionality. The use of the 2-compartment (n = 9) and the noncompartmental (NCA; n = 7) models yield comparable results.