康西珠单抗治疗伴有抑制剂的血友病的 3 期临床试验。
Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.
机构信息
From the Department of Transfusion Medicine, Nagoya University Hospital, Nagoya (T.M.), and Nara Medical University, Kashiwara (K.N.) - both in Japan; Indiana Hemophilia and Thrombosis Center, Indianapolis (A.S.); the Department of Hematology, Christian Medical College, Vellore, India (A.A.); the Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy (P.A.); the Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (G.C.); Novo Nordisk, Søborg, Denmark (K.C., J.H., S.H.J., J.S.R.); the Reference Center for Hemophilia and Rare Congenital Bleeding Disorders, Bicêtre Hospital Assistance Publique-Hôpitaux de Paris, University of Paris-Saclay and UMR_S1176 INSERM, Le Kremlin-Bicêtre, France (R.O.); the Department of Pediatrics, University of Texas Health Long School of Medicine, San Antonio (M.F.-J.); the Department of Medicine, Hospital Pulau Pinang, Georgetown, Malaysia (A.-S.G.); the Department of Molecular Medicine and Haematology, University of the Witwatersrand, National Health Laboratory Service, Johannesburg (J.M.); Great Ormond Street Hospital for Children NHS Foundation Trust, London (M.M.); the Institute of Blood Pathology and Transfusion Medicine, Lviv (O.S.), and National Specialized Children's Hospital Okhmatdyt, Kyiv (K.V.) - both in Ukraine; the Ronald Sawers Haemophilia Centre,Alfred Hospital, and the Australian Centre for Blood Diseases, Monash University - both in Melbourne, VIC, Australia (H.T.); Dr. José Eleuterio González Monterrey University Hospital, Monterrey, México (L.V.M.); the Department of Hemostasis Disorders and Internal Medicine, Laboratory of Hemostasis and Metabolic Diseases, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (J.W.); the Department of Pediatrics, Daejeon Eulji Medical Center, Eulji University School of Medicine, Daejeon, South Korea (C.W.Y.); the National Research Center for Hematology of the Ministry of Health of the Russian Federation, Moscow (N.Z.); the Division of Pediatric Hematology-Oncology, Istanbul University Oncology Institute, Istanbul, Turkey (B.Z.); and the Hematology Department, La Paz University Hospital, Hospital La Paz Institute for Health Research, Universidad Autónoma Madrid, Madrid (V.J.-Y.).
出版信息
N Engl J Med. 2023 Aug 31;389(9):783-794. doi: 10.1056/NEJMoa2216455.
BACKGROUND
Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors.
METHODS
We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed.
RESULTS
Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time.
CONCLUSIONS
Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).
背景
康西珠单抗是一种抗组织因子途径抑制剂单克隆抗体，旨在通过皮下给药实现所有血友病类型的止血。先前的康西珠单抗（explorer4）试验在有抑制剂的血友病 A 或 B 患者中证实了其概念。
方法
我们进行了 explorer7 试验，以评估康西珠单抗在有抑制剂的血友病 A 或 B 患者中的安全性和疗效。患者以 1:2 的比例随机分配，至少 24 周不接受预防治疗（第 1 组）或至少 32 周接受康西珠单抗预防治疗（第 2 组），或非随机分配接受至少 24 周的康西珠单抗预防治疗（第 3 组和第 4 组）。在三名接受康西珠单抗治疗的患者（包括一名来自 explorer7 试验）发生非致命性血栓栓塞事件后暂停治疗后，康西珠单抗治疗重新开始，给予 1.0 毫克/千克体重的负荷剂量，随后每天 0.2 毫克/千克（根据第 4 周测量的康西珠单抗血浆浓度进行潜在调整）。主要终点分析比较了第 1 组和第 2 组接受治疗的自发性和创伤性出血发作。还评估了安全性、患者报告的结果以及药代动力学和药效学。
结果
在 133 名入组患者中，19 名被随机分配到第 1 组，33 名被分配到第 2 组；其余 81 名被分配到第 3 组和第 4 组。第 1 组的估计平均年化出血率为 11.8 次（95%置信区间[CI]，7.0 至 19.9），而第 2 组为 1.7 次（95%CI，1.0 至 2.9）（比率，0.14 [95%CI，0.07 至 0.29]；P<0.001）。接受康西珠单抗治疗（第 2 组、第 3 组和第 4 组）的患者的总体中位年化出血率为 0 次。在重新开始康西珠单抗治疗后，没有报告血栓栓塞事件。康西珠单抗的血浆浓度随时间保持稳定。
结论
在有抑制剂的血友病 A 或 B 患者中，与不预防治疗相比，康西珠单抗预防治疗的年化出血率较低。（由诺和诺德资助；explorer7 ClinicalTrials.gov 编号，NCT04083781）。
Zotero 插件