Fitusiran is an RNA interference therapeutic that targets
antithrombin (AT) in the liver and interferes with AT translation by binding and degrading
messenger RNA-AT, thereby silencing AT gene expression and preventing AT synthesis. In both preclinical and clinical studies, AT knockdown results in dose-dependent AT lowering when
fitusiran is given weekly or monthly subcutaneously. In clinical trials,
fitusiran dose escalation has resulted in improved
thrombin generation and clinical hemostasis as measured by reduction in annualized bleed rate. Unlike currently licensed drugs, this improvement was not only in patients with
hemophilia A but in also those with
hemophilia B, with or without inhibitors. In dental and
surgical procedures,
fitusiran also provided perioperative hemostasis in association with AT lowering.
Fitusiran is well tolerated, with minor local
injection site reactions, but in one subject with severe
hemophilia A, the concomitant use of daily high-dose
factor VIII, inconsistent with trial guidance to avoid high, repeat doses of
clotting factor, was associated with fatal
thrombosis, suggesting the need for caution when using
hemostatic agents in conjunction with
fitusiran. Preclinical in vitro and in silico studies indicate improvement in
thrombin generation in rare
bleeding disorder plasmas, including in plasmas from patients with severe factors V, VII, and X deficiency, suggesting potential therapeutic benefit.