Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with , . Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5–33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0–2·7]) than in the bypassing agents on-demand group (18·1 [10·6–30·8]), corresponding to a 90·8% (95% CI 80·8–95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. Sanofi.

中文翻译：

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Fitusiran 预防治疗 A 型血友病或 B 型血友病抑制剂 (ATLAS-INH) 患者的有效性和安全性：一项多中心、开放标签、随机 3 期试验

Fitusiran 是一种皮下研究的小干扰 RNA 治疗药物，以抗凝血酶为靶点，以重新平衡血友病 A 或血友病 B 患者的止血，无论抑制剂状态如何。我们评估了使用 Fitusiran 预防药物对 A 型血友病或 B 型血友病患者进行抑制剂预防的有效性和安全性。这项多中心、随机、开放标签的第 3 期研究在 12 个国家的 26 个地点（主要是二级或三级中心）进行。12 岁或以上患有严重血友病 A 或血友病 B 且先前接受过按需旁路药物治疗的抑制剂的男性、男孩和年轻人被随机分配 (2:1) 接受每月一次 80 mg 皮下 fitusiran 预防治疗。 fitusiran 预防组）或继续使用按需旁路药物（旁路药物按需组）9 个月。主要终点是通过负二项式模型估计的意向治疗人群在疗效期间的平均年化出血率。安全性被评估为安全人群的次要终点。该试验已完成并已在 , 注册。2018 年 2 月 14 日至 2021 年 6 月 23 日期间，对 85 名参与者进行了纳入筛选，其中 57 名（67%；57 [100%] 男性；中位年龄 27·0 岁 [IQR 19·5–33·5]）随机分配：19 名 (33%) 参与者被分配到按需绕过药物组，38 名 (67%) 参与者被分配到 fitusiran 预防组。基于负二项式模型的平均年化出血率在 fitusiran 预防组 (1·7 [95% CI 1·0–2·7]) 显着低于按需旁路药物组 (18·1 [10·7]) 6–30·8]），相当于年出血率降低 90·8%（95% CI 80·8–95·6），有利于 fitusiran 预防（p<0·0001）。Fitusiran 预防组中有 25 名 (66%) 参与者的治疗出血次数为零，而按需旁路药物组中有 1 名 (5%) 参与者的出血次数为零。Fitusiran 预防组中最常见的治疗中出现的不良事件是安全人群中 41 名参与者中的 13 名（32%）丙氨酸转氨酶升高；在按需绕过药物组中，丙氨酸转氨酶治疗引起的不良事件没有增加。Fitusiran 预防组中有两名 (5%) 参与者报告了疑似或确诊的血栓栓塞事件。没有死亡报告。皮下注射 Fitusiran 预防可使 A 型血友病或 B 型血友病抑制剂患者的年出血率显着降低，有统计学意义，其中三分之二的参与者出血量为零。Fitusiran 预防可能对 A 型血友病或 B 型血友病抑制剂患者显示出止血功效；因此，该疗法可能有潜力改善血友病患者的治疗。赛诺菲。