2. Academic Validation
  3. Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort

Targeting of antithrombin in hemophilia A or B with investigational siRNA therapeutic fitusiran-Results of the phase 1 inhibitor cohort

  • J Thromb Haemost. 2021 Jun;19(6):1436-1446. doi: 10.1111/jth.15270.
K John Pasi 1,  Toshko Lissitchkov 2,  Vasily Mamonov 3,  Tim Mant 4 5,  Margarita Timofeeva 6,  Catherine Bagot 7,  Pratima Chowdary 8,  Pencho Georgiev 9,  Liana Gercheva-Kyuchukova 10,  Kate Madigan 11,  Huy Van Nguyen 11,  Qifeng Yu 12,  Baisong Mei 12,  Craig C Benson 12,  Margaret V Ragni 13 14
Affiliations

Affiliations

  • 1 Royal London Haemophilia Centre, Barts and The London School of Medicine and Dentistry, London, UK.
  • 2 Clinic of Haematology, National Specialized Hospital for Active Treatment of Haematologic Diseases, Sofia, Bulgaria.
  • 3 National Research Center for Hematology, Moscow, Russia.
  • 4 Iqvia, Reading, UK.
  • 5 Guy's and St Thomas' NHS Foundation Trust and Kings College London, London, UK.
  • 6 Federal State Budget Institution of Science "Kirov Scientific Research Institute of Hematology and Blood Transfusion of the Federal Medical-Biological Agency", Kirov, Russia.
  • 7 Department of Haematology, Glasgow Royal Infirmary, Glasgow, UK.
  • 8 Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK.
  • 9 University Multiprofile Hospital for Active Treatment "Sveti Georgi" and Medical University Plovdiv, Plovdiv, Bulgaria.
  • 10 Department of Hematology, University Hospital of St. Marina, Varna, Bulgaria.
  • 11 Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • 12 Sanofi, Cambridge, MA, USA.
  • 13 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
  • 14 Hemophilia Center of Western Pennsylvania, Pittsburgh, PA, USA.
PMID: 33587824 DOI: 10.1111/jth.15270
Abstract

Background: Fitusiran, an investigational small interfering RNA therapy, reduces antithrombin production to rebalance hemostasis in people with hemophilia A or B, with or without inhibitors.

Objectives: To evaluate the safety and efficacy of fitusiran treatment for people with moderate/severe hemophilia A or B with inhibitors.

Patients/methods: In this open-label phase 1, part D study, 17 males with hemophilia A or B with inhibitors received three once-monthly subcutaneous injections of fitusiran 50 mg (n = 6) or 80 mg (n = 11); followed for up to 112 days. Endpoints included safety (primary), pharmacokinetics/pharmacodynamics (secondary), annualized bleeding rate, and patient-reported outcomes (exploratory).

Results: The most common adverse event was injection site erythema (n = 8). No thrombotic events were reported. At nadir, mean (standard error of the mean [SEM]) antithrombin activity decreased from baseline by 82.0% (2.2) and 87.4% (0.7) in the 50 mg and 80 mg groups, respectively. Antithrombin reduction was associated with increased Thrombin generation. 11/17 (64.7%) participants had no bleeds during the observation period (mean [standard deviation] 69.4 [16.3] days). Mean (SEM) changes from baseline in Haemophilia Quality of Life Questionnaire for Adults total (-9.2 [2.9]) and physical health (-12.3 [3.9]) domain scores suggested clinically meaningful improvement.

Conclusions: Monthly fitusiran was generally well tolerated, lowered antithrombin levels from baseline, and resulted in improved Thrombin generation. These preliminary results suggest that monthly fitusiran treatment may reduce bleeding episodes and improve quality of life in participants with hemophilia A or B with inhibitors.

Keywords

antithrombin; fitusiran; hemophilia; inhibitors; siRNA.

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