Safety and Pharmacokinetics of Recombinant ADAMTS13 in Patients with Sickle Cell Disease: A Phase 1 Randomized, Double-Blind, Placebo-Controlled Study
Authors: Kanter Julie , Patwari Parth , Desai Payal , Ataga Kenneth I. , Crary Shelley E. , Lanzkron Sophie , Field Joshua , Chung Yu-Che , Wang Linda T. , Mellgård Björn , Nguyen Van Anh (Vika) , Gordeuk Victor R. 
Published: December 2023

Background
Sickle cell disease (SCD) is an autosomal recessive hemoglobinopathy associated with chronic hemolysis and vaso-occlusive crises (VOCs). Despite the use of treatments such as hydroxyurea, many patients continue to experience VOCs. There is emerging evidence implicating the dysregulation of the von Willebrand factor (VWF)-ADAMTS13 axis in the pathophysiology of VOCs. The size and platelet-binding activity of ultra-large VWF multimers is regulated by the VWF-cleaving metalloprotease ADAMTS13; therefore, the administration of recombinant ADAMTS13 (rADAMTS13), particularly during VOCs, may be therapeutically beneficial in patients with SCD. Here, we present findings from a phase 1 study (NCT03997760) investigating the safety and pharmacokinetics (PK) of three doses of rADAMTS13 (TAK-755; Takeda Development Center Americas, Inc., Lexington, MA, USA) in patients with SCD.
Aims
To assess the safety, tolerability, and PK of 40 IU/kg, 80 IU/kg, and 160 IU/kg rADAMTS13 in patients with SCD at baseline health.
Methods
This phase 1, randomized, double-blind, placebo-controlled, multicenter, ascending single dose study (NCT03997760) enrolled patients aged between 18 and 65 years with a documented history of HbSS or HbSβ o thalassemia. Concurrent treatment with a stable dose of hydroxyurea was permitted. Patients were at baseline health: those diagnosed with acute VOC in the 21 days prior to dose administration were excluded. Patients who had received a blood transfusion within 30 days of screening were also excluded. Patients were randomized 3:1 to receive a single intravenous infusion of either rADAMTS13 or placebo in three sequential dose cohorts: cohort 1, 40 IU/kg; cohort 2, 80 IU/kg; cohort 3, 160 IU/kg. Patients were followed for 28 days post-infusion. Each dose cohort was opened sequentially following a review of safety data by a dose escalation committee. Primary safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs, and the incidence of neutralizing antibodies against ADAMTS13. Secondary endpoints included an assessment of PK, comprising the maximum concentration (C max) and the area under the concentration-time curve (AUC) from zero (pre-dose) to 72 hours post-dose (AUC 0-72) estimated from ADAMTS13 antigen and activity levels, among other parameters.
Results
Five patients received placebo and 14 patients received a single dose of rADAMTS13 (cohort 1, n=4; cohort 2, n=6; cohort 3, n=4). The median age (range) of patients who received placebo was 36.0 (20-43) years and 2 (40.0%) were male. Median age (range) of patients who received rADAMTS13 was 38.5 (23-50) years and 9 (64.3%) were male. TEAEs were reported in 2 (40.0%) patients who received placebo and 8 (57.1%) patients who received rADAMTS13. TEAEs considered related to rADAMTS13 were reported in 4 patients (28.6%; Table). One serious TEAE (sickle cell anemia with crisis) not considered related to rADAMTS13 was reported in a patient who received 40 IU/kg rADAMTS13. No bleeding-related TEAEs were reported during the study and no TEAEs led to study discontinuation or death. No anti-ADAMTS13 neutralizing antibodies were detected within 28 days following rADAMTS13 administration. For the PK assessment, mean (standard deviation [SD]) baseline ADAMTS13 antigen was 0.68 (0.16) μg/mL, and rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen level ( Figure). For cohorts 1, 2, and 3, respectively, baseline-adjusted ADAMTS13 antigen mean C max was 0.51 μg/mL (n=4), 1.07 μg/mL (n=5), and 2.08 μg/mL (n=4), and mean AUC 0-72 was 18.21 h*μg/mL (n=3), 43.01 h*μg/mL (n=5), and 74.51 h*μg/mL (n=4). Mean (SD) baseline ADAMTS13 activity was 1.06 (0.31) IU/mL. For cohorts 1, 2 and 3, respectively, mean C max for baseline-adjusted ADAMTS13 activity was 0.94 IU/mL (n=4), 2.09 IU/mL (n=5), and 3.08 IU/mL (n=4).
Conclusions
No safety signals or dose-limiting toxicities, such as bleeding events, were observed for the three evaluated doses of rADAMTS13 up to 160 IU/kg, and no rADAMTS13-related serious TEAEs were reported. No anti-ADAMTS13 neutralizing antibodies were detected during the study. rADAMTS13 demonstrated a dose-proportional increase in ADAMTS13 antigen levels, which is consistent with linear PK. Findings from this study support the further investigation of rADAMTS13 as a potential therapeutic option for patients with SCD.