Abstract
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, potentially life-threatening condition caused by a deficiency of the blood enzyme ADAMTS13. Until now, ADAMTS13 replacement has been achieved with infusions of plasma or plasma-based therapies (PBT). However, the quantitative relationship between ADAMTS13 plasma activity and clinical manifestations is poorly understood. We therefore conducted integrated population pharmacokinetics (PopPK) analysis and exposure-response modeling based on three clinical trials of recombinant ADAMTS13 (rADAMTS13, Takeda Pharmaceuticals U.S.A., Inc.) in patients with cTTP. These aim to assess the clinical benefit of rADAMTS13, which at the proposed dose of 40 IU/kg provides ADAMTS13 peak levels of approximately 100% of normal levels. The PK model indicated that, besides body weight-based dosing, no further dose adjustment was required based on age or race. The only extrinsic covariates with a significant impact on ADAMTS13 plasma activity levels were dosing interval and treatment type (rADAMTS13 vs. PBT). The correlation between ADAMTS13 plasma activity levels and cTTP manifestations was investigated with three different exposure-response models. Increasing exposure to ADAMTS13, as measured by average activity over a one-to-two-week period, predicted the probability of disease manifestations, primarily assessed as thrombocytopenia. Model simulations predicted that >90% of patients treated with 40 IU/kg rADAMTS13 achieve an average ADAMTS13 plasma activity >13% of normal, which was shown to be highly protective against thrombocytopenia (>70% lower hazard). Similar results were observed for protection against elevation of lactate dehydrogenase, a marker of microangiopathic hemolytic anemia. Overall, these results support the use of rADAMTS13 treatment for patients with cTTP.