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

Abstract

Summary 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.

Intrinsic differences between FVIIIa mimetic bispecific antibodies and FVIII prevent assignment of FVIII‐equivalence

“…In short, no single assay or assay parameter has been shown to correlate with therapeutic efficacy or safety, making it difficult to determine optimal dosing strategies for prophylactic treatment with bsAbs as well as safe and efficacious methods for treating breakthrough bleeds, trauma, or surgery . Our inability to assign FVIII‐equivalence to bsAbs and the higher incidence of thrombotic complications observed when combining bypassing agents with emicizumab compared to rFVIIa or aPCCs alone warrant improved monitoring and further study to understand the precise mechanisms of FVIIIa mimetic bsAbs . Control of bleeds during surgery or trauma is an area of great concern.…”

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

“…60 Severe bleeds should continue to be treated quickly and aggressively. 60 Severe bleeds should continue to be treated quickly and aggressively.…”

“…This result is consistent with the lack of thrombotic events thus far observed with emicizumab/rFVIIa use and may be related to its short half-life, lack of binding to emicizumab and rFVIIa clearance mechanisms that include antithrombin and tissue factor pathway inhibitor. 60 Severe bleeds should continue to be treated quickly and aggressively. It is not yet clear whether non-severe bleeds should be treated as quickly and as aggressively as they are with rFVIIa alone; or whether they should be left untreated to see if they resolve on their own.…”

Engineering the serpin α1‐antitrypsin: A diversity of goals and techniques

“…In hemophilia B fIX knockout mice, α 1 ‐AT KRK administered subcutaneously at 15 mg/kg body weight eliminated the bleeding diathesis and reduced bleeding to levels seen in wild type mice, using a tail clip model. If these promising results hold in further preclinical development, α 1 ‐AT KRK could become a drug candidate for hemophilia A and B treatment, one of a new class of “inhibitors of coagulation inhibitors.” The same group, in a follow‐up study, randomized the P2 and P1' residues and screened a library of α 1 ‐AT M358R variants, but did not find one superior to α 1 ‐AT KRK for APC inhibition …”