Novel therapeutics for hemophilia and other bleeding disorders

Abstract

Hemophilia and von Willebrand disease are the most common congenital bleeding disorders. Treatment of these disorders has focused on replacement of the missing coagulation factor to prevent or treat bleeding. New technologies and insights into hemostasis have driven the development of many promising new therapies for hemophilia and von Willebrand disease. Emerging bypass agents including zymogen-like factor IXa and Xa molecules are in development and a bispecific antibody, emicizumab, demonstrated efficacy in a phase 3 trial in people with hemophilia A and inhibitors. Tissue factor pathway inhibitor, the protein C/S system, and antithrombin are targets of novel compounds in development to alter the hemostatic balance and new approaches using modified factor VIII molecules are being tested for prevention and eradication of inhibitor antibodies in hemophilia A. The first recombinant von Willebrand factor (VWF) product has been approved and has unique VWF multimer content and does not contain factor VIII. These new approaches may offer better routes of administration, improved dosing regimens, and better efficacy for prevention and treatment of bleeding in congenital bleeding disorders.

Emicizumab: Review of the literature and critical appraisal

“…In order to put emicizumab into context of the many haemophilia novel therapies currently evolving, it is important to mention the recent report of Callaghan et al They have stated that although management of haemophilia has focused on replacement of the missing coagulation factor to prevent or treat bleeding, new technologies and insights into haemostasis, in addition to emicizumab, have driven the development of several promising new therapies for haemophilia. Tissue factor pathway inhibitor, the protein C/S system, and antithrombin are targets of novel compounds in development to alter the haemostatic balance and new approaches utilizing modified factor VIII molecules are being studied for prevention and eradication of inhibitor antibodies in haemophilia A …”

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, ).…”

How I approach: Previously untreated patients with severe congenital hemophilia A

“…Approximately 250 young children are diagnosed with severe hemophilia A per year in the United States . This review focuses on the management of previously untreated patients (PUPs) with severe hemophilia A and takes into consideration the rapidly evolving treatment landscape with continuous introduction of new options for clotting factor replacement and novel therapies . The review also discusses the approach to diagnosis, education, and comprehensive care within the hemophilia treatment center (HTC).…”

“…As novel therapies are developed, there may be other strategies to prevent bleeding and mitigate inhibitor risk in PUPs. Nonfactor replacement products are therapeutic agents which substitute the function of the missing clotting factor or rebalance the coagulation system to prevent bleeding without replacing the missing clotting factor . As mentioned above, emicizumab‐kxwh is a bispecific monoclonal antibody which substitutes the function of FVIII by binding factors IX and X.…”