Longitudinal Assessment of Thrombin Generation in Patients with Hemophilia Receiving Fitusiran Prophylaxis: Phase II Study Results
Authors: Négrier Claude , Ragni Margaret V. , Pasi John , Pipe Steven W. , Kenet Gili , Rangarajan Savita , Kichou Salim , Mei Baisong , Andersson Shauna R. 
Published: November 2020

Introduction:
Thrombin plays a central role in hemostasis: in the initiation, amplification, and propagation phases of coagulation and in the formation of a stable fibrin clot. Normal hemostatic function requires a balance between procoagulant and anticoagulant proteins that regulate thrombin generation (Negrier et al. Blood Reviews. 2019). Co-inheritance of antithrombin deficiency in people with hemophilia is associated with a milder bleeding phenotype (Shetty et al. Br J Haematol. 2007; Bolliger et al. Thromb Haemost. 2010), supporting the hypothesis that a reduction in antithrombin levels will increase thrombin generation and thus normalize hemostasis in people with hemophilia. Fitusiran is a subcutaneously administered investigational RNA interference therapeutic targeting antithrombin for prophylactic treatment of patients with hemophilia A and B, with or without inhibitors. In a completed Phase I study, monthly subcutaneous administration of fitusiran was found to lower antithrombin levels, increase thrombin generation, and was generally well tolerated (Pasi et al. Blood. 2016; Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe the longitudinal assessment of thrombin generation with fitusiran in the Phase I/II open-label extension study (NCT02554773).
Methods:
The fitusiran Phase I dose-escalation study (NCT02035605) was followed by the Phase II open-label extension study (NCT02554773), which included male patients, &gt;18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors, who were eligible to continue dosing with monthly subcutaneous fixed doses of fitusiran 50 mg or 80 mg. Thrombin generation was assessed monthly for the first 2 years and every 6 months thereafter using the calibrated automated thrombogram (CAT) assay.
Results:
Thirty-four patients aged 19-61 with hemophilia A (n=27; 13 with inhibitors and 14 without inhibitors) or hemophilia B (n=7; 2 with inhibitors and 5 without inhibitors) were treated for up to 4.7 years with a median exposure of approximately 2.6 years at the time of the data cut (March 10, 2020). Peak thrombin generation was assessed over the length of the study for each patient. Once-monthly subcutaneous dosing of 50 mg or 80 mg fitusiran prophylaxis over a period of 48 months resulted in sustained antithrombin lowering (a reduction of between 85% to 72% from baseline), which led to peak thrombin levels and an endogenous thrombin potential approaching the normal range seen in healthy volunteers (see figure). Additional subgroup analyses (hemophilia A and B, with or without inhibitor) will be conducted for presentation at the congress.
Conclusions:
Monthly fitusiran prophylaxis resulted in consistent peak thrombin generation levels in patients with hemophilia A and B, with or without inhibitors over an extended period of time. With the thrombin generation levels in people with hemophilia on fitusiran approaching that of normal healthy adults, this sustained lowering of thrombin has the potential to provide consistent bleed protection in patients over time.

Disclosures
Négrier: CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Ragni:Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Pasi:BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Roche: Honoraria, Other; Pfizer: Other; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; Sigilon: Research Funding; Tremeau: Research Funding; Sobi: Consultancy, Honoraria, Other. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rangarajan:Sangamo: Research Funding; Takeda, Grifols, Roche, Reliance Life Sciences: Other: Conference support, Speakers Bureau. Kichou:Sanofi: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company.