2017 Clinical trials update: Innovations in hemophilia therapy

A surge in therapeutic clinical trials over recent years is paving the way for transformative treatment options for patients with hemophilia. The introduction of recombinant factor concentrates in the early 1990s facilitated the use of prophylactic replacement as standard care for hemophilia rather than on-demand treatment. This has revolutionized health outcomes for hemophilia patients, enabling participation in physical activities and reducing debilitating, chronic joint damage. Challenges of prophylactic factor infusion include the frequency of infusions needed to maintain factor levels greater than 1%, patient adherence, reliable intravenous access, and development of neutralizing alloantibodies ("inhibitors"). Novel therapeutics seek to improve upon current factor concentrates by several different mechanisms: (1) extending the half-life of circulating exogenous factor protein, (2) replacing the gene necessary for production of endogenous factor protein, (3) employing bispecific antibody technology to mimic the coagulation function of factor VIII, (4) disrupting anticoagulant proteins, such as tissue factor pathway inhibitor (TFPI) or antithrombin (AT3) with antibodies, aptamers, or RNA interference technology. Emerging treatment options may reduce the frequency of (extended half-life products) or eliminate (gene therapy) the need for scheduled factor concentrate infusions, or provide a subcutaneous administration option (bispecific antibody, AT3, and TFPI targeting therapies). In addition, the nonfactor replacement strategies provide a promising treatment option for patients with inhibitors, presently the greatest unmet medical need in hemophilia. This review highlights current and recently completed clinical trials that are driving a paradigm shift in our approach to hemophilia care for patients with and without inhibitors. Am. J. Hematol. 91:1252-1260, 2016. © 2016 Wiley Periodicals, Inc.