New therapies using nonfactor products for patients with hemophilia and inhibitors

Abstract

Regular prophylaxis with factor VIII (FVIII) or FIX products to prevent bleeding in patients with severe hemophilia A (HA) and HB, respectively, results in marked suppression 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 IV infusions 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. A new class of therapeutic agents that act by enhancing coagulation (emicizumab) and inhibiting anticoagulant pathways (fitusiran and concizumab) have been established, and clinical trials using these nonfactor products are ongoing. The current findings have demonstrated that prophylaxis by nonfactor products supports marked reductions of bleeding episodes in hemophilia patients with or without inhibitor. Emicizumab has already been approved for use internationally. Some concerns are evident, however. Thrombotic microangiopathy and thromboembolism have occurred in 5 emicizumab-treated patients receiving repeated infusions of activated prothrombin complex concentrates, and a sinus vein thrombosis has occurred in a fitusiran-treated patient receiving repeated infusions of FVIII product. Moreover, reliable techniques to monitor hemostatic function in patients receiving nonfactor 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.

Antithrombin inhibition using nanobodies to correct bleeding in hemophilia

“…In an effort to improve treatment options for PWH, a number of alternative therapeutic approaches have been explored in recent years (Callaghan et al , ). Emicizumab (Hemlibra; Chugai Roche) is a humanized bispecific antibody administered subcutaneously that has a half‐life of 3–4 weeks (Nogami & Shima, ). By binding to both FIXa and FX, emicizumab mimics the normal procoagulant cofactor role of FVIIIa.…”

“…By binding to both FIXa and FX, emicizumab mimics the normal procoagulant cofactor role of FVIIIa. Recent phase 3 clinical trials have demonstrated the clinical efficacy of emicizumab in patients with hemophilia A (Nogami & Shima, ). Consequently, emicizumab has recently been licensed in a number of different jurisdictions for prevention of bleeding episodes in patients with severe hemophilia A with or without FVIII inhibitors.…”

“…Consequently, emicizumab has recently been licensed in a number of different jurisdictions for prevention of bleeding episodes in patients with severe hemophilia A with or without FVIII inhibitors. Although generally well tolerated, some cases of venous and arterial thrombotic complications have been described in PWH receiving emicizumab (Nogami & Shima, ).…”

Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

“…In this context, the bispecific antibody, emicizumab, which mimics the procoagulant function of activated FVIII (FVIIIa) has been approved in over 60 countries and now offers an effective option for prophylactic treatment for patients with hemophilia A irrespective of the presence of inhibitors. The efficacy of emicizumab in clinical trials was excellent, and tolerable safety was confirmed, although some adverse events, including thromboembolic TMA and neutralizing antidrug antibodies (ADAs) were reported in specific circumstances 10 . More recently, however, several questions have become apparent for the clinical use of emicizumab.…”

Recurrent and novel disease‐causing F8 variants in boys with severe haemophilia A in Poland

“…The pharmacological approach to haemophilia is currently a dynamically changing area, and there are several reports on innovative and highly effective, though mechanistically distinct, treatment options. These new therapeutics might be likely guided by comprehensive molecular diagnosis in each case to justify treatment choice 2,8,9. Still, at this time of rapid technological advances, haemophilia remains an area with unanswered basic questions such as the impact of coagulation factor concentrate origin (recombinant vs plasma-derived) or brand on inhibitor development, and this cannot be addressed without genetic data 10.…”