Results from the main parts (24 weeks) of two concizumab phase 2 trials are presented: explorer4 (NCT03196284) in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI); explorer5 (NCT03196297) in HA without inhibitors. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level); secondary objectives were safety and immunogenicity (assessed as number of adverse events [AEs] and anti-drug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if {greater than or equal to}3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic parameters were assessed. 36 HA, 9 HAwI and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15/17; 88.2%) did not escalate the dose, and all patients chose to continue to the extension phase of the trials. Clinical proof of concept for the prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs. HA: 3.0 (95% confidence interval [CI]: 1.7;5.3) and 5.9 (95% CI: 4.2;8.5) vs. 7.0 (95% CI: 4.6;10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin F1+2 and D-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very-low to medium-titer) ADA-positive tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients.

中文翻译：

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使用抑制剂对血友病 A 和血友病 A/B 进行皮下注射 concizumab 预防：2 期试验结果

展示了两项 concizumab 2 期试验主要部分（24 周）的结果： explorer4 (NCT03196284) 在血友病 A (HA) 或 B (HB) 中使用抑制剂 (HAwI/HBwI)；不含抑制剂的 HA 中的 explorer5 (NCT03196297)。这些试验旨在评估每日皮下注射 concizumab 预防的疗效（评估为末次剂量水平的年化出血率 [ABR]）；次要目标是安全性和免疫原性（根据不良事件 [AE] 和抗药物抗体 [ADA] 的数量进行评估）。患者接受 0.15 mg/kg concizumab，潜在剂量增加至 0.20 和 0.25 mg/kg（如果在 concizumab 治疗的 12 周内{大于或等于}3 次自发性出血事件）。评估了相关的药代动力学/药效学参数。36 名 HA、9 名 HAwI 和 8 名 HBwI 患者暴露于 concizumab。大多数抑制剂患者（15/17；88.2%）没有增加剂量，所有患者都选择继续试验的延长期。两项试验均证明了预防出血事件的临床证据。HAwI 和 HBwI 中的估计 ABR 低于 HA：3.0（95% 置信区间 [CI]：1.7；5.3）和 5.9（95% CI：4.2；8.5）与 7.0（95% CI：4.6；10.7），分别。PK/PD 结果如预期，在 concizumab 暴露、游离组织因子途径抑制剂、凝血酶生成、凝血酶原 F1+2 和 D-二聚体的血友病亚型之间没有差异。Concizumab 安全且耐受性良好（无严重 AE、AE 相关停药或血栓栓塞事件）。三名患者在每个试验中都有（非常低到中等滴度）ADA 阳性测试，没有观察到临床效果。