K John Pasi1, Savita Rangarajan1, Pencho Georgiev1, Tim Mant1, Michael D Creagh1, Toshko Lissitchkov1, David Bevan1, Steve Austin1, Charles R Hay1, Inga Hegemann1, Rashid Kazmi1, Pratima Chowdary1, Liana Gercheva-Kyuchukova1, Vasily Mamonov1, Margarita Timofeeva1, Chang-Heok Soh1, Pushkal Garg1, Akshay Vaishnaw1, Akin Akinc1, Benny Sørensen1, Margaret V Ragni1. 1. 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.).
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).
RCT Entities:
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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 .).
Authors: Cory D Sago; Melissa P Lokugamage; Fatima Z Islam; Brandon R Krupczak; Manaka Sato; James E Dahlman Journal: J Am Chem Soc Date: 2018-11-16 Impact factor: 15.419
Authors: Cory D Sago; Melissa P Lokugamage; Gwyneth N Lando; Naima Djeddar; Nirav N Shah; Chris Syed; Anton V Bryksin; James E Dahlman Journal: Nano Lett Date: 2018-09-20 Impact factor: 11.189
Authors: Armando Tripodi; Rita C Santoro; Sophie Testa; Angelo C Molinari; Sergio Bernardini; Maria Golato; Giuseppe Lippi; Walter Ageno; Elena Santagostino Journal: Blood Transfus Date: 2019-02-04 Impact factor: 3.443
Authors: Bruno M D C Godinho; Nils Henninger; James Bouley; Julia F Alterman; Reka A Haraszti; James W Gilbert; Ellen Sapp; Andrew H Coles; Annabelle Biscans; Mehran Nikan; Dimas Echeverria; Marian DiFiglia; Neil Aronin; Anastasia Khvorova Journal: Mol Ther Date: 2018-08-08 Impact factor: 11.454