Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: Updated Results from a Phase 1 and Phase 1/2 Extension Study in Patients without Inhibitors (2016)

Abstract Background: Hemophilia is a bleeding disorder characterized by a profound defect in the ability to generate sufficient thrombin for effective hemostasis. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting the endogenous anticoagulant antithrombin (AT) as a means to improve thrombin generation and promote hemostasis in patients with hemophilia. Preliminary data from an ongoing Phase 1, four part (Part A: healthy volunteers; Parts B and C: patients with moderate to severe hemophilia A or B; Part D: patients with hemophilia A or B with inhibitors), multi-center, study showed that fitusiran was generally well tolerated and that administration of once-monthly SC doses of fitusiran led to dose-dependent AT lowering, thrombin generation increase, and decrease in bleeding frequency (Pasi KJ, et al. Haemophilia 2016, 22[Suppl 4]). The purpose of this abstract is to report the updated safety, pharmacodynamics (PD), and clinical activity of fitusiran in patients with hemophilia without inhibitors from the Phase 1 (Part C) as well as long term data from the Phase 1/2 extension study. Methods: We are conducting a multi-center Phase 1 study (NCT02035605) followed by a multi-center Phase 1/2 extension study (NCT02554773) in hemophilia A and B patients. Patients received SC administered, weekly (Part B) or once-monthly (Part C) weight-based or fixed doses of fitusiran. Primary endpoints include safety and tolerability; secondary endpoints include AT activity, thrombin generation and exploratory evaluation of bleed pattern. After receiving 3 monthly doses in the Phase 1 study, all patients were eligible to continue monthly dosing in the Phase 1/2 extension study. Standard replacement factor VIII or IX was utilized to manage any breakthrough bleeds. Results: Previously reported safety data demonstrated that fitusiran was generally well tolerated in hemophilia A or B patients without inhibitors (Phase 1, Parts B and C) and that there were no serious adverse events related to study drug and no thromboembolic events. In Phase 1, Part C, patients initially received weight-based doses ranging from 225 to 1800mcg/kg or a fixed dose of 80mg. Fitusiran dosing resulted in dose-dependent lowering of AT with a mean maximal AT lowering of 87 ± 1% at the 80mg fixed dose and mean thrombin generation increase of 289% relative to baseline with AT lowering &gt;75%. Exploratory analysis of bleed events (Phase 1, Part C) showed a median annualized bleeding rate (ABR) of zero during the defined observation period. As of July 2016, a total of 25 non-inhibitor patients have been enrolled in the entire Phase 1 study and 16 of these patients have entered the ongoing Phase 1/2 extension study. All patients who enrolled in the Phase 1/2 extension study transitioned to a fixed monthly fitusiran dose of 50mg or 80mg. Updated safety, tolerability and clinical activity among all non-inhibitor patients will be presented. Conclusions: Emerging clinical data suggest that targeting AT is generally safe and could be a promising approach for promoting hemostasis in hemophilia. The potential for low volume SC administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy. Disclosures Ragni: Tacere Benitec: Consultancy; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; OPKO: Research Funding; Vascular Medicine Institute: Research Funding; SPARK: Research Funding. Georgiev:Alnylam Pharmaceuticals: Consultancy. Chowdary:Sobi: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria. Rangarajan:Novo Nordisk: Research Funding; Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Pfizer: Research Funding; Grifols: Consultancy, Research Funding. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Sorenson:Alnylam Pharmaceuticals: Employment, Equity Ownership. Pasi:Pfizer: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria; Biogen: Consultancy, Honoraria.