Fitusiran, an RNAi Therapeutic Targeting Antithrombin to Restore Hemostatic Balance in Patients with Hemophilia a or B with or without Inhibitors: Management of Acute Bleeding Events

Background Fitusiran is a once-monthly subcutaneously administered investigational RNA interference (RNAi) therapeutic targeting antithrombin (AT) to enhance thrombin generation (TG) and rebalance hemostasis in patients with hemophilia A (HA) or hemophilia B (HB) with or without inhibitors. Phase 1 and 2 data show dose-dependent lowering of AT, increased TG, and a decrease in the frequency of spontaneous and traumatic bleeds on fitusiran. Given AT knockdown with fitusiran, bleed management guidelines supporting the use of low-dose and reduced-frequency factor or bypassing agent (BPA) were developed and implemented to manage breakthrough bleeds in subjects participating in clinical trials of fitusiran (Table 1). Aim To report the available results on the management of breakthrough bleeding events in subjects on prophylactic therapy with fitusiran using low-dose and reduced-frequency factor or BPA. Methods The ongoing Phase 2 study includes subjects with HA or HB with or without inhibitors who were previously exposed to fitusiran in the Phase 1 study. Subjects received monthly fixed doses of fitusiran 50 mg or 80 mg subcutaneously. To assess the effectiveness of the bleed management guidelines, analyses of 11 months of available data on breakthrough bleeds and treatment after the implementation of the guidelines were performed. Presented are data from an interim ad hoc analysis of a Phase 2 open-label extension study. Results Of the 26 subjects included in this study population, 20 have HA (with inhibitors, n=10; without inhibitors, n=10) and 6 have HB (with inhibitors, n=2; without inhibitors, n=4). Fifteen subjects had ≥1 bleed and 12 subjects (80%) were compliant with the bleed management guidelines. A total of 107 bleeding events evaluable for compliance with the guidelines at the time of data cutoff in 14 subjects required treatment with factor or BPA. A single reduced dose of factor or BPA was sufficient to manage 62 of 107 bleeds (60%) requiring treatment (HA with inhibitors, 21 of 27 bleeds [78%]; HA without inhibitors, 23 of 25 bleeds [92%]; HB with inhibitors, 17 of 51 bleeds [33%]; HB without inhibitors, 1 of 4 bleeds [25%]). Of the 28 bleeds in 5 subjects requiring repeat dosing, 15 (54%) were treated according to the recommended dose and frequency of factor or BPA (HA with inhibitors, 1 of 5 bleeds [20%]; HA without inhibitors, 2 of 2 bleeds [100%]; HB with inhibitors, 9 of 18 bleeds [50%]; HB without inhibitors, 3 of 3 bleeds [100%]). Updated data reflecting additional (≥9 months) exposure to fitusiran will be presented at the time of the meeting. Conclusions Bleed management guidelines were implemented to support the management of breakthrough bleeding events in subjects on prophylactic therapy with fitusiran. Since implementation of the bleed management guidelines, all treated bleeding events in subjects with HA or HB with or without inhibitors have been successfully managed with factor or BPA, and most have been managed using reduced and less frequent dosing of factor or BPA in accordance with the guidelines. Study funded by Alnylam and Sanofi. Disclosures Pipe: Spark Therapeutics: Consultancy; Freeline: Consultancy; Shire: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Catalyst Bioscience: Consultancy; Novo Nordisk: Consultancy; uniQure: Consultancy; CSL Behring: Consultancy; Roche/Genentech: Consultancy; Pfizer: Consultancy; Apcintex: Consultancy. Ragni:Spark Therapeutics: Other: Advisory Board, Research Funding; Sangamo: Research Funding; Alnylam/Sanofi: Other: Advisory Board, Research Funding; BioMarin: Other: Advisory Board, Research Funding; Bioverativ/Sanofi: Other: Advisory Board, Research Funding; OPKO: Research Funding; Shire/Takeda: Other: Advisory Board, Research Funding. Négrier:Shire/Takeda: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding, Speakers Bureau; Spark Therapeutics: Honoraria, Research Funding, Speakers Bureau; Alnylam (Sanofi): Honoraria, Speakers Bureau; Sobi: Honoraria, Research Funding, Speakers Bureau; Freeline: Research Funding; LFB (laboratoire français du fractionnement et des biotechnologies): Research Funding; Novo Nordisk: Honoraria, Research Funding, Speakers Bureau; Octapharma: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Patents: Patents & Royalties: Patents related to FVIII and FIX; Catalyst Biosciences: Honoraria, Speakers Bureau; Bayer: Consultancy, Research Funding. Yu:Sanofi: Employment. Bajwa:Sanofi: Employment. Caminis:Sanofi: Employment. Mei:Sanofi: Employment. Andersson:Sanofi: Employment.