• K John Pasi, Savita Rangarajan, Pencho Georgiev, Tim Mant, Michael D Creagh, Toshko Lissitchkov, David Bevan, Steve Austin, Charles R Hay, Inga Hegemann, Rashid Kazmi, Pratima Chowdary, Liana Gercheva-Kyuchukova, Vasily Mamonov, Margarita Timofeeva, Chang-Heok Soh, Pushkal Garg, Akshay Vaishnaw, Akin Akinc, Benny Sørensen, and Margaret V Ragni.
• 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.

BackgroundCurrent 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.MethodsIn 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.ResultsNo 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.ConclusionsOnce-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 .).

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