Due to the heavy social, health and economic burden represented by the use of inhibitors13, it is not surprising that investigators have dedicated their research over the last decade to understanding the pathogenic mechanisms of inhibitors and to the development of even more effective haemostatic therapies14C17

Due to the heavy social, health and economic burden represented by the use of inhibitors13, it is not surprising that investigators have dedicated their research over the last decade to understanding the pathogenic mechanisms of inhibitors and to the development of even more effective haemostatic therapies14C17. to combine technological solutions aimed at improving haemostatic efficacy and security. In the last twenty-five years, the availability of a high standard of haemophilia care has greatly improved the quality of life of haemophilia patients, and, at least in developed countries, their life expectancy has reached that of males in the general population9. In this context, the most challenging complication in the treatment of haemophilia A today is the development of anti-FVIII alloantibodies, which impact approximately one-third of patients with severe haemophilia A. Inhibitors make traditional replacement therapy ineffective, prevent access to a safe and effective standard of care (particularly prophylaxis in children), and predispose them to Sav1 an unacceptably high risk of morbidity and mortality10,11. The current management of bleeding episodes in haemophilia A patients with inhibitors includes the use of the bypassing brokers activated prothrombin complex concentrate (aPCC) (Factor Eight Inhibitor Bypassing Activity-FEIBA, Shire pcl, Lexington, MA, USA) and recombinant activated factor VII (rFVIIa) (NovoSeven, Novo Nordisk, Bagsv?rd, Denmark)10,12. Due to the heavy social, health and economic burden represented by the use of inhibitors13, it is not surprising that investigators have dedicated their research over the last decade to understanding the pathogenic mechanisms of inhibitors and to the development of even more effective haemostatic therapies14C17. In particular, the most recent research has been focused on newer therapies not based on FVIII replacement17. In this review, we summarise the current knowledge on emicizumab, one of the LY-2584702 hydrochloride most interesting of these innovative haemostatic brokers, and that which is usually currently at the most advanced stage of development. Search methods We analysed the medical literature for published studies on the use of emicizumab in haemophilia A patients with inhibitors. The MEDLINE electronic database was searched without any time limitations, using English language as a restriction. The Medical Subject Heading and key words used were: newer haemostatic brokers AND novel haemostatic brokers AND investigational drugs AND alternate therapies AND haemophilia A AND inhibitors AND by-passing brokers AND emicizumab AND ACE910 AND haemlibra AND innovative therapies. We also screened the reference lists of the most important review articles for additional studies not captured in our initial literature search. Search terms were also applied to abstracts from the latest international congresses on haemostasis and thrombosis and haematology. LY-2584702 hydrochloride Mechanism of action and development of emicizumab Emicizumab (Roche, Basel, Switzerland) is usually a chimeric bispecific humanised antibody directed against FIXa and FX, which mimics the co-factor function of FVIII. It binds to the enzyme FIXa with one arm and to the FX zymogen with the other, placing both in spatially appropriate positions, thereby promoting FIXa-catalysed FX activation and tenase formation18,19. However, despite their amazing similarity, recent analyses indicate that FVIII and emicizumab differ profoundly from each other in terms of affinity for the antigen, regulation, topology, and FIXa-enhancing activity20. The result of emicizumab-induced haemostasis is usually, therefore, a disruption of the natural physiological on-off switch mechanism with FVIII-induced haemostasis leading to a permanent on setting20. In a short-term primate model of acquired haemophilia A conducted by Muto FVIII neutralised plasma of the study participants, the bispecific antibody shortened activated partial thromboplastin time and increased peak height of thrombin generation in a dose-dependent manner. No serious adverse events were recorded24. A subsequent open-label, non-randomised, dose-escalation phase I study enrolling 18 Japanese severe haemophilia A patients (11 with and 7 without inhibitors) receiving once-weekly subcutaneous administration of emicizumab at doses of 0.3, 1 or 3 mg/kg for 12 weeks was published in 2016 by Shimaet al.no prophylaxis in haemophilia A participants) is still ongoing. Table I Main characteristics of the pivotal HAVEN trials on emicizumab in haemophilia A. no prophylaxis resulted in an 87% reduction of ABR5 SAEs (3 thrombotic microangiopathies and 2 thromboses)HAVEN 2, 201727Phase III non-randomised open-label60 (paediatric haemophilia A with inhibitors)Loading dose: 3 mg/kg/week for 4 weeksno prophylaxis resulted in a 99% reduction of ABRNo thrombotic eventsHAVEN LY-2584702 hydrochloride 3, 201828Phase III randomised open-label152 (adolescent and adult haemophilia A without inhibitors)Loading dose: 3 mg/kg/week for 4 weeks23.3 events (95% CI: 12.3C43.9) among those assigned to no prophylaxis, representing a significant difference of 87% in favor of emicizumab prophylaxis (p 0.001). Emicizumab prophylaxis resulted LY-2584702 hydrochloride in a significant reduction in treated bleeds of 79% (p 0.001) compared to previous treatment with bypassing agent prophylaxis in a non-interventional study prior to enrollment26. Serious side effects, including thrombotic microangiopathy in three subjects and other thrombotic events in two subjects, were reported and were associated with cumulative doses of aPCC 100.