Pharmacodynamic Activity of Recombinant ADAMTS13 Versus Plasma-Based Therapies in Congenital Thrombotic Thrombocytopenic Purpura: Interim Results of a Phase 3 Randomized, Controlled, Open-Label Study

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombotic microangiopathy caused by an inherited deficiency of the ADAMTS13 enzyme. ADAMTS13 regulates von Willebrand factor (VWF) activity by cleaving the highly active ultra-large multimers of VWF into smaller multimers. Recombinant ADAMTS13 (rADAMTS13; Takeda Pharmaceuticals U.S.A., Inc.) is being studied in a phase 3, open-label, crossover trial in patients with cTTP (NCT03393975). Planned interim results from the study demonstrated substantial improvement in ADAMTS13 activity exposure with rADAMTS13 compared with standard plasma-based therapies; however, the pharmacodynamic effects of rADAMTS13 on VWF total protein antigen and activity have not been previously reported. Aims: Exploratory pharmacodynamic biomarkers were evaluated in this phase 3 study to understand the effects of rADAMTS13 treatment versus plasma-based therapies (PBT) on its substrate, VWF. Methods: The trial included two crossover pharmacokinetic (PK) assessments (PK-I and PK-II). Pharmacodynamic biomarkers were assessed at baseline and following intravenous (IV) infusion of rADAMTS13 (40 IU/kg) treatment or PBT (determined by the investigator) during PK-I and PK-II assessments. Ristocetin cofactor activity of total VWF was measured via a platelet agglutination method. Total VWF protein concentration was measured by an enzyme linked immunosorbent assay. ADAMTS13-mediated VWF cleavage products were visualized by Western blot analysis. Within-patient paired change from baseline was calculated at serial post-dose time points. Results: Evaluable data from 36 patients with cTTP of all ages were analyzed. Overall, rADAMTS13 and PBT had little effect on total protein levels of VWF. The mean VWF baseline activity in both rADAMTS13 (PK-I and PK-II) and PBT treatment arms (PK-I period) were ~140−150% of average normal activity. A mean reduction from baseline of ~15−25% in VWF activity was observed for timepoints up to 1 to 2 days post-infusion following administration of rADAMTS13 (PK-I and PK-II) or PBT (PK-I). The results suggested a longer pharmacodynamic action of rADAMTS13 versus PBT (mean change from baseline in VWF activity [95% confidence interval (CI)]): 24h postinfusion: rADAMTS13, -15.9% [95% CI: -29.5- -2.4]; PBT, -4.9% [95% CI: -13.3-3.5]. 72h postinfusion: rADAMTS13, -11.9% [95% CI: -26.9-3.2]; PBT, -1.2% [95% CI: -15.9-13.4]). More patients receiving rADAMTS13 showed detectable ADAMTS13-mediated VWF cleavage products than with PBT at early timepoints, peaking immediately following PK-I treatment (1h postinfusion: rADAMTS13, 97% [34/35], PBT, 61% [22/36]; 24h: rADAMTS13, 69% [24/35], PBT, 47% [17/36]). Conclusions: These pharmacodynamic findings suggest that treatment with rADAMTS13, when compared with PBT, may provide a greater and more sustained reduction in VWF activity, further supporting the pharmacodynamic benefit of treatment with rADAMTS13 in patients with cTTP.