Phase I Study Reports No Dose-Limiting Toxicities for Recombinant ADAMTS13 in Patients with SCD

For patients with sickle cell disease (SCD), the administration of recombinant ADAMTS13 (rADAMTS13) up 160 IU/kg did not result in safety concerns or dose-limiting toxicities, according to a phase I, randomized, double-blind, placebo-controlled study presented at the 65th ASH Annual Meeting & Exposition.

The study assessed “safety, tolerability, and PK [pharmacokinetics] of 40 IU/kg, 80 IU/kg, and 160 IU/kg rADAMTS13 in patients with SCD at baseline health.” Five patients received placebo and 14 received a single dose of rADAMTS13. Of the patients who received rADAMTS13, four received 40 IU/kg (cohort 1), six received 80 IU/kg (cohort 2), and six received 160 IU/kg (cohort 3).

The primary safety endpoints included treatment-emergent adverse events (TEAEs), serious TEAEs, and the occurrence of neutralizing antibodies against ADAMTS13. Secondary endpoints involved evaluating PK, which included parameters such as the maximum concentration (C_max) and the area under the concentration-time curve (AUC) from zero (pre-dose) to 72 hours post-dose (AUC0–72).

Two patients in the placebo cohort and eight patients who received rADAMTS13 experienced TEAEs; TEAEs considered related to rADAMTS13 were reported in four patients. There were no TEAEs related to bleeding or that led to study discontinuation or death.

The investigators noted that no anti-ADAMTS13 neutralizing antibodies were identified within 28 days after the administration of rADAMTS13, and the baseline ADAMTS13 antigen exhibited a standard deviation (SD) of 0.68 μg/mL, and rADAMTS13 displayed a dose-proportional escalation in the ADAMTS13 antigen level.

In cohorts one, two, and three, the baseline-adjusted mean C_max for ADAMTS13 antigen was 0.51 μg/mL, 1.07 μg/mL, and 2.08 μg/mL, respectively, while the mean AUC0–72 was 18.21 hμg/mL, 43.01 hμg/mL, and 74.51 h*μg/mL, respectively. The baseline ADAMTS13 activity had a SD of 1.06 IU/mL. In cohorts one, two, and three, the mean C_max for baseline-adjusted ADAMTS13 activity was 0.94 IU/mL, 2.09 IU/mL, and 3.08 IU/mL, respectively.

The investigators concluded that the results provide support for additional exploration of rADAMTS13 as a potential therapeutic choice for patients with SCD.

Reference

Kanter J, Patwari P, Desai P, et al. Safety and pharmacokinetics of recombinant ADAMTS13 in patients with sickle cell disease: a phase 1 randomized, double-blind, placebo-controlled study. Abstract #149. Presented at the 65th American Society of Hematology Annual Meeting; December 9-12, 2023; San Diego, California.