• Marie Scully, Ana Antun, Spero R Cataland, Paul Coppo, Claire Dossier, Nathalie Biebuyck, Wolf-Achim Hassenpflug, Karim Kentouche, Paul Knöbl, Johanna A Kremer Hovinga, M Fernanda López-Fernández, Masanori Matsumoto, Thomas L Ortel, Jerzy Windyga, Indranil Bhattacharya, Michael Cronin, Hong Li, Björn Mellgård, Munjal Patel, Parth Patwari, Shan Xiao, Pinghai Zhang, Linda T Wang, and cTTP Phase 3 Study Investigators.
• From the Department of Haematology, University College London Hospitals, London (M.S.); the Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta (A.A.); the Department of Internal Medicine, Ohio State University, Columbus (S.R.C.); the Department of Hematology and National Reference Center for Thrombotic Microangiopathies, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP) and Sorbonne Université (P.C.), the Department of Pediatric Nephrology, Robert Debré Hospital, AP-HP and University of Paris (C.D.), and the Department of Pediatric Nephrology, Hôpital Universitaire Necker-Enfants Malades, AP-HP (N.B.) - all in Paris; the Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg (W.-A.H.), and the Section of Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Universitätsklinikum Jena, Jena (K.K.) - both in Germany; the Department of Medicine 1, Division of Hematology and Hemostasis, Medical University of Vienna, Vienna (P.K.); the Department of Hematology and Central Hematologic Laboratory, Bern University Hospital, University of Bern, Bern, Switzerland (J.A.K.H.); the Hematology and Hemotherapy Service, Mother and Child Hospital, Biomedical Research Institute of A Coruña, University Hospital Complex of A Coruña, A Coruña, Spain (M.F.L.-F.); the Department of Blood Transfusion Medicine, Nara Medical University, Kashihara, Japan (M.M.); the Division of Hematology, Department of Medicine, and Department of Pathology, Duke University, Durham, NC (T.L.O.); the Department of Hemostasis Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); and Takeda Development Center Americas, Cambridge, MA (I.B., M.C., H.L., B.M., M.P., P.P, S.X., P.Z., L.T.W.).
• N. Engl. J. Med. 2024 May 2; 390 (17): 158415961584-1596.

BackgroundCongenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known.MethodsIn this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment.ResultsA total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy.ConclusionsDuring prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).Copyright © 2024 Massachusetts Medical Society.

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