Bispecific Antibodies and Advances in Non–Gene Therapy Options in Hemophilia

Abstract

Regular prophylaxis has markedly improved the treatment for patients with hemophilia A, especially after the introduction of highly purified factor VIII (FVIII) concentrates. However, frequent intravenous infusions and the development of FVIII inhibitors remain as unsolved difficulties. To overcome these unmet needs, a bispecific antibody mimicking activated FVIII has been developed in Japan. This bispecific antibody, emicizumab, recognizes activated factor IX (FIXa) and activated factor X (FXa), and promotes FIXa‐catalyzed activation of FX in the absence of FVIII. Emicizumab initially reacts with FIXa generated by the action of factor VIIa/tissue factor complexes. Subsequently, thrombin generation is enhanced in the presence of higher amounts of FIXa derived from FXIa‐dependent mechanisms. Hence, emicizumab‐driven FXa and thrombin generation is maintained by a FXI activation loop in the intrinsic coagulation pathway. Reactions downstream of emicizumab are regulated by natural anticoagulants including activated protein C, antithrombin, and tissue factor pathway inhibitor. Phase 3 studies (HAVEN 1‐4 and HOHOEMI studies) demonstrated a remarkable reduction in bleeding rates together with a high percentage of patients with zero treated bleeds irrespective of the presence of inhibitors. In general, emicizumab proved to be well tolerated, although isolated thromboembolic and thrombotic microangiopathic complications were observed in the HAVEN 1 studies, and 3 out of a total of 400 patients developed neutralizing antidrug antibodies. In addition, several questions remain to be discussed with respect to open‐use clinical practice, including when to start treatment, how to monitor therapy, and optimum dosage for surgical procedures and immune tolerance induction.

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001–2018

“…36 Lastly, compared to treatment with clotting factor products, novel non-gene therapy options such as emicizumab offer better bleeding management (especially for patients with an inhibitor) and possibly a better safety profile as well. 37 In conclusion, a decrease in mortality and an increase in life expectancy in patients with hemophilia in the Netherlands over the period 1973 to 2018 was seen. However, survival is still lower than that of the general population and warrants further improvements in hemophilia care.…”

“…For example, direct‐acting antivirals that are used to treat HCV have an almost 100% success rate 36 . Lastly, compared to treatment with clotting factor products, novel non‐gene therapy options such as emicizumab offer better bleeding management (especially for patients with an inhibitor) and possibly a better safety profile as well 37 …”

Should emicizumab be used in patients with acquired hemophilia A?

“…1 Emicizumab is approved for the prophylaxis of bleeding in congenital hemophilia A (HA) and in HA with inhibitors (HA-I). 2 As compared with on-demand treatment, emicizumab reduced the annualized rate of treated bleeding events in HA and HA-I by >90% and 88%, respectively. 3,4 Emicizumab is injected subcutaneously in intervals of 1 to 4 weeks, which is more convenient than conventional intravenous clotting factor replacement.…”

“…It consists of two monospecific, antigen‐binding arms that recognize activated FIX and FX, respectively, placing them into appropriate positions to support the activation of FX 1 . Emicizumab is approved for the prophylaxis of bleeding in congenital hemophilia A (HA) and in HA with inhibitors (HA‐I) 2 . As compared with on‐demand treatment, emicizumab reduced the annualized rate of treated bleeding events in HA and HA‐I by >90% and 88%, respectively 3,4 .…”

Factor VIII products: key aspects of development, clinical research and use (part 1)

“…В обзорных статьях авторов-разработчиков (M. Shima и T. Kitazawa) нового препарата приведена информация о молекулярной характеристике, этапах доклинического и клинического изучения препарата [47,60,61].…”