From the Royal London Haemophilia Centre, Barts and the London School of Medicine and Dentistry (K.J.P.), National Institute for Health Research (NIHR) Biomedical Research Centre (T.M.), Guy's and St. Thomas' NHS Foundation Trust, King's College London (D.B.), St. George's Healthcare NHS Trust Haemophilia Centre (S.A.), and Royal Free Hospital London (P.C.), London, the Haemophilia, Haemostasis and Thrombosis Centre, Hampshire Hospitals NHS Foundation Trust, Basingstoke (S.R.), Quintiles IMS, Reading (T.M.), Royal Cornwall Hospitals NHS Trust, Truro (M.D.C.), Manchester Royal Infirmary, Manchester (C.R.H.), and University Hospital Southampton NHS Foundation Trust, Southampton (R.K.) - all in the United Kingdom; University Multiprofile Hospital for Active Treatment Sveti Georgi and Medical University Plovdiv, Plovdiv (P. Georgiev), University Hospital for Hematology, Sofia (T.L.), and the Department of Hematology, University Hospital of St. Marina, Varna (L.G.-K.) - all in Bulgaria; University Hospital of Zurich, Zurich, Switzerland (I.H.); National Research Center for Hematology, Moscow (V.M.), and Research Institution of Hematology and Blood Transfusion, Kirov (M.T.) - both in Russia; Alnylam Pharmaceuticals, Cambridge (C.-H.S., P. Garg, A.V., A.A., B.S.), and Codiak Biosciences, Woburn (B.S.) - both in Massachusetts; and the University of Pittsburgh and Hemophilia Center of Western Pennsylvania, Pittsburgh (M.V.R.).
N Engl J Med. 2017 Aug 31;377(9):819-828. doi: 10.1056/NEJMoa1616569. Epub 2017 Jul 10.
Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations.
In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran.
No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants.
Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
目前的血友病治疗涉及频繁的静脉输注凝血因子，这与可变的止血保护、高治疗负担和产生抑制性同种异体抗体的风险有关。Fitusiran 是一种正在开发的 RNA 干扰 (RNAi) 疗法，针对抗凝血酶 (由 SERPINC1 编码)，旨在解决这些和其他限制。
在这项 1 期剂量递增研究中，我们招募了 4 名健康志愿者和 25 名患有中度或重度血友病 A 或 B 且没有抑制性同种异体抗体的参与者。健康志愿者接受单次皮下注射 fitusiran（0.03 毫克/公斤体重）或安慰剂。血友病患者接受 fitusiran 三次注射，每周一次（剂量为 0.015、0.045 或 0.075 毫克/公斤）或每月一次（剂量为 0.225、0.45、0.9 或 1.8 毫克/公斤或固定剂量 80 毫克）。研究目的是评估 fitusiran 的药代动力学和药效学特征和安全性。
在研究期间未观察到血栓栓塞事件。最常见的不良事件是轻度注射部位反应。血浆 fitusiran 水平呈剂量依赖性增加，且重复给药无蓄积。每月方案诱导的抗凝血酶平均最大降低 70%至 89%基线。抗凝血酶水平降低超过基线的 75%，导致健康参与者观察到的范围内较低端的中位峰值凝血酶值。
在没有抑制性同种异体抗体的血友病 A 或 B 患者中，每月一次皮下给予 fitusiran 导致抗凝血酶水平呈剂量依赖性降低，并增加凝血酶生成。（由 Alnylam 制药公司资助；ClinicalTrials.gov 编号，NCT02035605）。
