Fitusiran: A “Rebalancing Agent”

Fitusiran is an inhibitory double-stranded RNA (RNAi, also called small interfering RNA, siRNA). Fitusiran, termed a “rebalancing agent,” suppresses the nuclear production of antithrombin (AT) messenger RNA (mRNA). AT is a major coagulation control protein that binds and disables thrombin and FXa (also FIXa and FXIa to a lesser extent). By suppressing AT production, fitusiran enhances thrombin activity. In hemophilia A or B, FVIII or FIX production, respectively, is reduced, leading to low thrombin activity and the risk of anatomic bleeding. Fitusiran balances the coagulation mechanism, allowing for adequate thrombin activity in hemophilia. Currently in clinical trials, fitusiran, injected monthly, lowers the antithrombin level to 15–25%, reducing the annual bleed rates of hemophilia patients with or without inhibitors to near zero. A small nucleic acid molecule, fitusiran does not trigger inhibitor formation. Risks include overdose-related thrombosis and elevated liver enzymes. Breakthrough bleeds may be treated with factor concentrates. Medical laboratories will provide periodic AT assays to manage dosing. See the attached open access review, Young G, Lenting PJ, Croteau SE. Antithrombin lowering in hemophilia: a closer look at fitusiran. Res Pract Thromb Haemost. 2023;7:100179. doi: 10.1016/j.rpth.2023.100179. PMID: 37358958; PMCID: PMC10285540.