先天性血栓性血小板减少性紫癜中的重组 ADAMTS13。
Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.
机构信息
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.).
出版信息
N Engl J Med. 2024 May 2;390(17):1584-1596. doi: 10.1056/NEJMoa2314793.
BACKGROUND
Congenital 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.
METHODS
In 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.
RESULTS
A 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.
CONCLUSIONS
During 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.).
背景
先天性血栓性血小板减少性紫癜（TTP）是由 ADAMTS13 严重遗传性缺乏引起的。重组 ADAMTS13 与标准疗法（血浆衍生产品）作为常规预防或按需治疗用于先天性 TTP 患者的疗效和安全性尚不清楚。
方法
在这项 3 期、开放标签、交叉试验中，我们按照 1:1 的比例将患者随机分配至两个为期 6 个月的预防治疗期，分别接受重组 ADAMTS13（40IU/千克体重，静脉注射）或标准疗法，然后进行交替治疗；此后，所有患者均接受重组 ADAMTS13 额外 6 个月的治疗。此次中期分析的触发因素是至少 30 名患者完成了试验。主要结局是急性 TTP 事件。评估了 TTP 的表现、安全性和药代动力学。发生急性 TTP 事件的患者可以接受按需治疗。
结果
共有 48 名患者接受了随机分组；32 名患者完成了试验。在接受重组 ADAMTS13 预防治疗期间，未发生急性 TTP 事件，而 1 名患者在接受标准疗法预防治疗期间发生了急性 TTP 事件（年化事件发生率分别为 0.05）。血小板减少是最常见的 TTP 表现（年化事件发生率分别为 0.74 与重组 ADAMTS13，1.73 与标准疗法）。接受重组 ADAMTS13 治疗的患者中有 71%发生了不良事件，接受标准疗法的患者中有 84%发生了不良事件。研究者认为与试验药物相关的不良事件发生在接受重组 ADAMTS13 治疗的患者中 9%，在接受标准疗法的患者中 48%。无患者因不良事件中断或停止使用重组 ADAMTS13 治疗，而 8 名患者因不良事件停止使用标准疗法。在接受重组 ADAMTS13 治疗期间，未产生中和抗体。与标准疗法相比，接受重组 ADAMTS13 治疗后 ADAMTS13 活性平均最高达到 101%。
结论
在先天性 TTP 患者中接受重组 ADAMTS13 预防治疗时，ADAMTS13 活性达到正常水平的 100%左右，不良事件通常为轻度或中度，TTP 事件和表现罕见。（由 Takeda Development Center Americas 和 Baxalta Innovations 资助；ClinicalTrials.gov 编号，NCT03393975）。
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