Emicizumab: the hemophilia A game-changer

Abstract

In hemophilia, the unmet needs regarding adherence to prophylaxis and lack of effective long-term prophylaxis regimens, especially in patients with inhibitors, led to the production of emicizumab, the first non-factor medicine for subcutaneous administration in patients with severe and moderate hemophilia A with or without factor VIII inhibitors. This review describes the research steps behind the development of this game-changing medication as well as its success in the prophylaxis of bleeding episodes, as witnessed by the results of pivotal clinical trials but also by real-life use in the frame of a still expanding global market. We also discuss potential and actual adverse events and the nuances related to clinical use, such as laboratory monitoring, development of neutralizing antidrug antibodies, risk of thrombosis/hypercoagulability and role in the management of surgical operations. The potential of emicizumab to prevent bleeding in other congenital and acquired coagulation disorders is also outlined.

Figure 1.

Development of emicizumab. Over 2,400 engineered monoclonal IgG molecules were tested and methodically modified and optimized to minimize non-specific binding and immunogenicity and to maximize physicochemical stability and their activated factor VIII-cofactor activity, leading to the development of ACE910, subsequently named emicizumab. In vivo studies were developed using primate models of acquired hemophilia A, in which bleeding events were successfully treated and prevented, and a once-weekly subcutaneous dosing provided the rationale for a prophylaxis protocol in people with hemophilia A. The first in-human study, started in 2013, was designed as a randomized and placebo-controlled, phase I trial using a single subcutaneous dose of emicizumab in healthy volunteers and demonstrated efficacy, high bioavailability from subcutaneous administration, without evidence of hypercoagulability. These findings were corroborated in short-term and long-term extension studies (12 weeks to 33.3 months, respectively) of weekly subcutaneous administration to patients with severe hemophilia A over 12 years old with or without inhibitors, which showed a decrease in annualized bleeding rate close to zero, regardless of the presence of inhibitors, and four cases of antidrug antibodies, which were non-neutralizing and did not cause changes in treatment.

Figure 2.

Procoagulant properties of emicizumab. Activated factor VIII (FVIIIa) is a cofactor of the intrinsic tenase complex, along with activated factor IX (FIXa) and factor X (FX). Once FX is activated, the prothrombinase complex is formed along with activated factor V (FVa) and factor II (FII aka prothrombin), which leads to thrombin generation. Emicizumab is a humanized monoclonal antibody, directed to FIXa and FX, which restores missing FVIIIa function in the tenase complex in patients with hemophilia A allowing for thrombin generation and restoring hemostasis. Emicizumab has also shown efficacy in patients with acquired hemophilia A, in whom FVIIIa function is impaired by the presence of an autoantibody. In vitro studies have shown that even small amounts of FIXa are enough to guarantee effective hemostasis, making emicizumab a potential treatment option for patients with mild and moderate hemophilia B. In patients with von Willebrand disease, particularly type 3, levels of both von Willebrand factor and FVIII are markedly reduced because von Willebrand factor prevents degradation and clearance of FVIII. It is therefore reasonable that emicizumab, in the presence of FIXa, could restore hemostasis in patients with von Willebrand disease. Before the intrinsic tenase complex is formed, FIX is activated by FXIa. In vitro studies have shown that emicizumab restores thrombin generation in FXI-deficient plasma, but it is unclear if this is due to residual FIXa levels, which are required for the procoagulant effect of emicizumab. PL: phospholipids; vWD: von Willebrand disease; vWF: von Willebrand factor.