New therapies using nonfactor products for patients with hemophilia and inhibitors

Abstract

Regular prophylaxis with factor (F)VIII or FIX products to prevent bleeding in patients with severe hemophilia (H)A and HB, respectively, results in marked suppressions of the onset of arthropathy, and contributes greatly to improvements in quality of life. Some issues remain with the use of clotting factor replacement therapy, however. The need for multiple intravenous administrations is associated with a substantial mental and physical burden, and the hemostatic effect of bypassing agents (BPAs) in patients with inhibitor is inconsistent. The development of subcutaneous products with prolonged hemostatic efficiency, irrespective of the presence of inhibitors, has been a longtime wish for patients of this nature. A new class of therapeutic agents which act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these non-factor products are on-going. The current findings have demonstrated that prophylaxis by non-factor products supports marked reductions of bleeding episodes in hemophilia patients with or without inhibitor. Emicizumab has been already approved for use internationally. Some concerns are evident, however. Thrombotic microangiopathy and thromboembolism have occurred in five emicizumab-treated patients receiving the repeated infusions of activated prothrombin complex concentrates, and a sinus vein thrombosis has occurred in a fitusiran-treated patient receiving the repeated infusions of FVIII product. Moreover, reliable techniques to monitor hemostatic function in patients received non-factor products with concomitant BPA or FVIII/FIX therapies require further assessment. These novel therapeutic agents have promising hemostatic properties, although wider experience in hemophilia centers is warranted to establish appropriate therapeutic strategies.