Treatment Burden during a Phase 3 Randomized, Crossover Study of Recombinant ADAMTS13 Prophylaxis and Standard of Care in Patients with Congenital Thrombotic Thrombocytopenic Purpura

Introduction: Standard treatment for congenital thrombotic thrombocytopenic purpura (cTTP), an ultra-rare thrombotic microangiopathy caused by ADAMTS13 deficiency, focuses on ADAMTS13 replacement with plasma-based therapies (PBTs). These products, however, are associated with a high treatment burden including allergic reactions and large infusion volumes. An ongoing Phase 3 study (NCT03393975) is investigating the safety and efficacy of recombinant ADAMTS13 (rADAMTS13; Takeda Pharmaceuticals U.S.A., Inc.) prophylaxis compared with PBTs in patients with cTTP. Here we describe the treatment burden associated with rADAMTS13 and PBT prophylaxis in patients with cTTP.

Method: The Phase 3 prospective, randomized, controlled, open-label, multicenter, crossover study enrolled patients 0–70 years old with confirmed cTTP who could tolerate prophylaxis with PBTs. Patients were randomized 1:1 to receive either 40 IU/kg intravenous rADAMTS13 or PBT prophylaxis, administered weekly or every other week. PBTs, determined by the investigator, included fresh frozen plasma (FFP), pooled solvent/detergent-treated (S/D) plasma, or plasma-derived factor VIII/von Willebrand factor (pdFVIII/VWF) concentrates. Patients received rADAMTS13 or PBT for 6 months then crossed over to the alternate treatment for 6 months; all patients then received rADAMTS13 for 6 months. All patients provided written informed consent. Data are presented for all patients who received prophylaxis (cutoff: Aug 11, 2023). Events potentially consistent with hypersensitivity reactions were identified in a post-hoc analysis using a standardized MedDRA query for adverse events (AEs) that occurred on the same day as an infusion and were treated with glucocorticoid, anti-allergy, or antipyretic medication. Descriptive results of mean±SD are presented.

Results: At data cutoff, 48 patients had received prophylaxis. For PBTs, 33 patients received FFP, 8 received S/D plasma, 4 received FFP and S/D plasma, and 3 received pdFVIII/VWF concentrates. Mean infusion duration was 5.6±3.7 minutes for rADAMTS13 prophylaxis (n=47) vs 165±137 minutes for PBT (n=48). During rADAMTS13 prophylaxis, no AEs consistent with hypersensitivity reactions were identified; mean number of infusions administered were 34±13. During PBT prophylaxis, 17 patients experienced 26 AEs consistent with hypersensitivity reactions; mean number of infusions administered were 17±6. Twelve AEs occurred despite premedication with antihistamines, glucocorticoids, or antipyretics. No AEs led to the interruption/discontinuation of rADAMTS13 prophylaxis. During PBT prophylaxis, 9 AEs experienced by 8 patients led to treatment interruption, of which 7 AEs were consistent with hypersensitivity reactions.

Conclusion: In patients with cTTP, PBT prophylaxis was associated with long infusion durations and AEs consistent with hypersensitivity reactions despite a high burden of pre-infusion medication. During rADAMTS13 prophylaxis, no AEs consistent with hypersensitivity reactions were identified.

Publication History

Article published online:
13 February 2025