Recombinant ADAMTS13 in congenital thrombotic thrombocytopenic purpura: final analysis from a randomized phase 3 trial.

Recombinant ADAMTS13 (rADAMTS13) was approved for prophylactic or on-demand ADAMTS13 replacement therapy for congenital thrombotic thrombocytopenic purpura (TTP) based on data from a preplanned interim analysis of a phase 3, open-label, crossover trial (NCT03393975). Here, we report results from the final analysis with 48 participants (3-68 years old) randomized 1:1 to two 6-month periods of prophylaxis with rADAMTS13 (40 IU/kg) or plasma-based therapy (PBT), followed by the alternate treatment at the same frequency; thereafter, all participants received 6 months of rADAMTS13. The primary outcome was acute TTP events. No participants experienced an acute event during rADAMTS13 prophylaxis, whereas 1 experienced an acute event during PBT prophylaxis (mean annualized event rate [AER], 0.04). A lower model-based mean AER of subacute TTP events was observed during rADAMTS13 prophylaxis (0.04) versus PBT (0.26). Thrombocytopenia was the most frequent TTP manifestation (model-based mean AER, 0.91 with rADAMTS13 and 1.62 with PBT). Treatment-related adverse events (AEs) occurred in 4.3% of participants with rADAMTS13 and in 45.8% with PBT. No serious AEs were considered related to rADAMTS13, whereas 1 serious AE (pyrexia) was considered related to PBT. No ADAMTS13-neutralizing antibodies were detected. Greater treatment satisfaction was reported for rADAMTS13 prophylaxis versus PBT (assessed using the 9-item Treatment Satisfaction Questionnaire for Medication). A ~6-fold increase in ADAMTS13 activity and prolonged time with ADAMTS13 activity of ≥10% was noted in participants receiving rADAMTS13 versus PBT. Consistent with the interim analysis, results with a longer follow-up support the continued clinical benefit of rADAMTS13 prophylaxis in congenital TTP.