Fitusiran: A Potential Option for Patients with Hemophilia A or B, with or Without Inhibitors

Replacement with clotting factor concentrates remains the standard of care for hemophilia but requires frequent infusions. Management of patients who develop inhibitors (antibodies) against exogenously administered clotting factor is complicated by bleeding diathesis and relies on infusion of bypassing agents. Fitusiran, an investigational small interfering RNA therapeutic, is designed to rebalance hemostasis by reducing antithrombin synthesis in patients with hemophilia.

Two industry-sponsored, multinational, open-label, phase 3 randomized trials evaluated the safety and efficacy of fitusiran in patients with and without inhibitors. In both trials, males aged ≥12 years with severe hemophilia A or B who were receiving treatment with on-demand clotting factors or bypassing agents and had at least 6 bleeding diatheses within the last 6 months were randomized (2:1) to fitusiran prophylaxis (80 mg subcutaneously once per month) with on-demand treatment or to continuation of on-demand treatment alone for 9 months.

In the trial of 120 patients without inhibitors, the median annualized bleeding rate (ABR) — the primary outcome — was significantly lower in the fitusiran arm than the on-demand arm (0.0 vs. 21.8). Transient alanine transaminase (ALT) elevation occurred in 23% of the fitusiran arm and resolved after discontinuation of the agent. In the fitusiran arm, mean antithrombin levels remained between 12% and 14% from day 43 after the first dose until the end of the trial; 3 patients had antidrug antibodies against fitusiran (at the lowest detectable titers) but that did not affect efficacy. No thrombotic event occurred.

In the trial of 57 patients with inhibitors, the mean ABR was also significantly lower in the fitusiran arm (1.7 vs. 18.1). Transient ALT elevation was noted in 32% of patients in the fitusiran arm, suspected or confirmed thrombotic events in 5%, and antidrug antibodies in 3%.