Division of Pediatric Hematology/Oncology, Central Michigan University School of Medicine, Detroit, MI.
Louis Pradel Cardiology Hospital, Lyon 1 University, Lyon, France.
Blood. 2021 Apr 22;137(16):2231-2242. doi: 10.1182/blood.2020009217.
Prophylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
依库珠单抗预防治疗，一种皮下注射的双特异性人源化单克隆抗体，可促进 A 型血友病患者（PwHA）的有效止血。依库珠单抗的主要疗效、安全性和药代动力学先前已有报道，但长期数据有限。在此，汇总了 3 项 3 期 HAVEN 1、HAVEN 2、HAVEN 3 和 HAVEN 4 研究（NCT02622321、NCT02795767、NCT02847637、NCT03020160）中 401 例有/无 FVIII（FVIII）抑制剂的儿科和成年 PwHA 的数据，以建立长期疗效、安全性和药代动力学概况。在中位疗效期 120.4 周（四分位距，89.0-164.4）（数据截止日期 2020 年 5 月 15 日）内，基于模型的治疗年化出血率（ABR）为 1.4（95%置信区间，1.1-1.7）。在 24 周治疗间隔的分析中，ABR 下降并稳定在<1；在第 121 周到 144 周（n=170），平均治疗 ABR 为 0.7（95%置信区间，0-5.0）。在第 121 周到 144 周期间，82.4%的参与者无治疗出血，97.6%的参与者有≤3 次治疗出血，94.1%的参与者报告无治疗靶关节出血。靶关节出血显著减少。依库珠单抗具有良好的耐受性，无参与者因不良事件而停药，这与之前报道的 5 起不良事件不同。此数据截止日期包括之前报道的 3 例血栓性微血管病（1 例发生在致命性直肠出血的 PwHA 中）和 2 例血栓栓塞事件，均与激活的凝血酶原复合物浓缩物的使用相关，还包括 1 例心肌梗死和 1 例静脉装置阻塞。在 970.3 患者年的暴露中，依库珠单抗预防治疗维持了所有年龄伴有/不伴有 FVIII 抑制剂的 PwHA 的低出血率，且耐受性良好，未发现新的安全性问题。
