The future of bypassing agents for hemophilia with inhibitors in the era of novel agents.

Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high-titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case-by-case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once-weekly or every-other-week prophylactic dosing in inhibitor patients. Other non-traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non-factor-based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.