NM_000132.4(F8):c.602-11T>C

For F8 c.602-11T>C, a likely pathogenic intronic variant that disrupts factor VIII splicing and causes hemophilia A, fitusiran (Alhemo, Sanofi) is an RNA interference therapy that takes a fundamentally different approach: rather than replacing the missing procoagulant factor, fitusiran is a subcutaneously administered GalNAc-conjugated siRNA that silences antithrombin (SERPINC1) in hepatocytes, rebalancing hemostasis by reducing the natural anticoagulant that restrains thrombin generation. This approach is entirely genotype-agnostic and effective regardless of the specific F8 mutation, including in patients with inhibitory antibodies against factor VIII — a major unmet need in hemophilia care.

Fitusiran received FDA approval in December 2024 for routine prophylaxis in hemophilia A and B patients with or without inhibitors. The ATLAS Phase 3 program demonstrated that monthly subcutaneous fitusiran reduced annualized bleeding rate (ABR) by >90% compared to on-demand treatment, and significantly reduced ABR compared to factor prophylaxis. Mean antithrombin levels were reduced to ~15-20% of normal, rebalancing the coagulation cascade sufficiently to prevent spontaneous bleeding while maintaining hemostatic reserve. The mechanism is validated by natural human genetics: heterozygous antithrombin deficiency (AT levels ~50%) causes thrombophilia, while the targeted ~80% reduction with fitusiran achieves a controlled partial deficiency that compensates for absent FVIII. For splice variants like c.602-11T>C, which may produce no functional FVIII or trace amounts via cryptic splicing, the genotype-agnostic nature of fitusiran is particularly valuable.

Fitusiran carries a thrombotic risk — by reducing antithrombin, it lowers the threshold for pathological clot formation. Thromboembolic events (including cerebral sinus venous thrombosis) occurred in clinical trials, leading to a temporary clinical hold in 2017 and subsequent protocol modifications requiring withholding fitusiran around surgeries and breakthrough bleeds treated with bypassing agents. Monthly subcutaneous injections are required indefinitely. Fitusiran does not restore normal hemostasis — it creates a new hemostatic equilibrium with reduced anticoagulant reserve, which may be fragile in high-risk situations (surgery, trauma). Compared to AAV-mediated F8 gene therapy (valoctocogene roxaparvovec, FDA approved 2023), fitusiran requires chronic dosing but avoids the hepatotoxicity, variable durability, and high cost of gene therapy. For the specific variant c.602-11T>C at position -11, computational splicing prediction should assess whether this creates a cryptic splice site or merely weakens the branch point, as residual FVIII production would influence the optimal therapeutic strategy.