The National Hemophilia Centre, Amalia Biron Thrombosis Research Institute, Sheba Medical Centre, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel.
Department of Hematology, Children's Health Ireland at Crumlin, Dublin, Ireland.
Blood. 2024 May 30;143(22):2256-2269. doi: 10.1182/blood.2023021864.
Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.
菲替司他，一种皮下注射的小干扰 RNA 治疗药物，可靶向抗凝血酶以重新平衡血友病 A 或 B（PwHA/B）患者的止血平衡，无论是否存在抑制剂。这项 3 期、开放标签研究评估了菲替司他预防治疗在既往接受旁路物（BPA）/凝血因子浓缩物（CFC）预防治疗的伴或不伴抑制剂的 12 岁及以上血友病 A 或 B 男性中的疗效和安全性。参与者在开始接受每月一次 80mg 菲替司他预防治疗的 7 个月前，继续接受之前的 BPA/CFC 预防治疗 6 个月（BPA/CFC 预防治疗和菲替司他疗效期）。主要终点是 BPA/CFC 预防治疗和菲替司他疗效期的年化出血率（ABR）。次要终点包括自发性 ABR（AsBR）和关节 ABR（AjBR）。评估了安全性和耐受性。在 80 名入组的参与者中，有 65 名（抑制剂，n=19；非抑制剂，n=46）符合 ABR 分析的条件。接受 BPA/CFC 预防治疗的观察到的中位 ABR 分别为 6.5（四分位距 [IQR]，2.2-19.6）/4.4（IQR，2.2-8.7），而相应的菲替司他疗效期的中位 ABR 分别为 0.0（IQR，0.0-0.0）/0.0（IQR，0.0-2.7）。与 BPA/CFC 预防治疗相比，菲替司他的估计平均 ABR 分别显著降低了 79.7%（P=0.0021）和 46.4%（P=0.0598）。41 名参与者（63.1%）接受菲替司他治疗后无 1 例治疗性出血，而 11 名参与者（16.9%）接受 BPA/CFCs 治疗后无 1 例治疗性出血。接受 BPA/CFC 预防治疗的中位 AsBR 和 AjBR 均为 2.2，而菲替司他疗效期的中位 AsBR 和 AjBR 均为 0.0。2 名参与者（3.0%）接受菲替司他治疗后发生疑似或确诊的血栓栓塞事件。与 BPA/CFC 预防治疗相比，每月接受一次菲替司他预防治疗可显著降低血友病 A 或 B 患者（伴或不伴抑制剂）的出血事件，报告的不良事件通常与菲替司他先前确定的风险一致。该试验在 www.ClinicalTrials.gov 上注册，编号为 #NCT03549871。
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