Quantitative Systems Pharmacology Modeling of Platelet Responses to Recombinant ADAMTS13 in Patients With Congenital Thrombotic Thrombocytopenic Purpura.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare, life-threatening thrombotic microangiopathy caused by a severe inherited deficiency of ADAMTS13, a von Willebrand factor (VWF) cleaving enzyme. Inadequate clinical endpoint data often make it challenging to statistically power clinical trials in ultra-rare diseases. Therefore, utilizing in vitro, adamts13-knockout mouse, literature-based, and clinical data, a quantitative systems pharmacology (QSP) model was developed to describe the mechanistic relationship between ADAMTS13, VWF, and platelet count, and to supplement evidence from clinical trials of recombinant ADAMTS13 (rADAMTS13) for the treatment of cTTP. The effect of long-term prophylaxis with rADAMTS13 versus plasma-based therapies (PBT) on platelet count in patients with cTTP was investigated. One-year clinical trial simulations of thrombocytopenia occurrences in 1000 virtual patients, phenotype-matched to a cTTP Phase 3 study population (NCT03393975), were produced. Simulations suggested that once-weekly (Q1W) or once every 2 weeks (Q2W) rADAMTS13 administered over 1 year resulted in fewer patients experiencing thrombocytopenia versus patients treated with PBT (e.g., Q2W [rADAMTS13] relative to Q2W [PBT], HR = 0.47 [platelet count drop to < 150 × 10⁹/L], HR = 0.41 [< 100 × 10⁹/L]). These results provide confirmative evidence to support the use of rADAMTS13 in cTTP by integrating the current mechanistic understanding of interactions between ADAMTS13 and VWF multimers as its substrate, as well as key downstream parameters, primarily platelet count. Virtual patient clinical simulations from the QSP model supported the regulatory approval of rADAMTS13 in cTTP, highlighting the significant potential of QSP modeling to supplement clinical trial data in rare disease drug development.