美国南加州大学洛杉矶分校Guy Young团队研究了fitusiran预防使用抑制剂的A型或B型血友病患者的有效性和安全性。相关论文于2023年3月29日发表在《柳叶刀》杂志上。

Fitusiran是一种皮下研究的小干扰RNA治疗药物，靶向抗凝血酶，以重新平衡A型或B型血友病患者的凝血，无论其抑制剂状态如何。研究组评估了fitusiran预防使用抑制剂的A型或B型血友病患者的疗效和安全性。

这项多中心、随机、开放标签的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。之前接受过按需旁路抑制剂的12岁或以上患有严重血友病A或血友病B的男性、男孩和年轻人被随机分配（2:1），每月接受一次80mg皮下fitusiran预防（fitusiran预防组）或继续按需旁路抑制剂（按需旁路抑制剂组）9个月。主要终点是通过负二项模型估计的意向治疗人群在疗效期内的平均年化出血率。安全性被评估为安全人群中的次要终点。

2018年2月14日至2021年6月23日，共筛选了85名参与者，其中57名（67%；57[100%]男性；平均年龄27.0岁）被随机分配：19名（33%）参与者被分配至按需旁路抑制剂组，38名（67%）参与者被分配到fitusiran预防组。基于负二项模型的平均年出血率在fitusiran预防组（1.7）显著低于按需旁路抑制剂组（18.1），相应的年出血率降低90.8%，有利于fitusiran预防组。

在fitusiran预防组中，25名（66%）参与者的治疗零出血，而在按需旁路抑制剂组中有1名（5%）。Fitusiran预防组最常见的治疗突发不良事件是安全人群41名参与者中有13人（32%）丙氨酸氨基转移酶升高；在按需旁路抑制剂组中，治疗后出现的丙氨酸氨基转移酶不良事件没有增加。在fitusiran预防组的两名（5%）参与者中报告了疑似或确诊的血栓栓塞事件。没有死亡报告。

研究结果表明，皮下fitusiran预防导致使用抑制剂的血友病A或血友病B参与者的年出血率在统计学上显著降低，三分之二的参与者零出血。Fitusiran预防可能在患有血友病A或血友病B使用抑制剂的参与者中显示出止血效果；因此，该疗法可能具有改善血友病患者管理的潜力。

附：英文原文

Title: Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial

Author: Guy Young, Alok Srivastava, Kaan Kavakli, Cecil Ross, Jameela Sathar, Chur-Woo You, Huyen Tran, Jing Sun, Runhui Wu, Stacey Poloskey, Zhiying Qiu, Salim Kichou, Shauna Andersson, Baisong Mei, Savita Rangarajan

Issue&Volume: 2023-03-29

Abstract:

Background

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.

Methods

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 ClinicalTrials.gov, NCT03417102.

Findings

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.

Interpretation

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.

DOI: 10.1016/S0140-6736(23)00284-2

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00284-2/fulltext