“The times they are a-changin”, ... or maybe not?

The current treatment of haemophilia is based on replacement of the missing coagulation factor and this can be done when the bleeding actually occurs (on-demand therapy) or as part of a preventive approach (prophylaxis)^1,2. Nowadays, prophylaxis of bleeding, involving the regular infusion of the deficient coagulation factor, represents the mainstay of haemophilia care. Indeed, its early implementation reduces the risk of joint bleeding and the resulting development of arthropathy, allowing patients to lead a life comparable to that of non-affected individuals³.

The last three decades have been an exciting time for replacement therapy for individuals with haemophilia A with the development of successive generations of recombinant factor VIII (FVIII) products (from first generation to the current extended half-life [EHL] FVIII products) able to combine technological solutions aimed at improving haemostatic efficacy and safety^4–6. In this context of high standards of haemophilia therapy, the most challenging complication is the development of anti-FVIII alloantibodies, which affect approximately one-third of patients with severe haemophilia A⁴. Inhibitors render traditional replacement therapy ineffective, compromise access to a safe and effective standard of care (particularly prophylaxis), and predispose patients to an unacceptably high risk of morbidity and mortality⁷. Although the introduction of bypassing agents (i.e., activated prothrombin complex concentrate and recombinant activated factor VII) has represented a major advance in the treatment and prevention of bleeds in inhibitor patients, their management is still suboptimal if compared with that of haemophilia patients without inhibitors^8–10. With the aim of improving the management of patients with inhibitors, newer therapies that are not based on FVIII replacement have been recently investigated^11,12. These novel drugs, targeting different proteins in the coagulation cascade, act by enhancing the potential of the coagulation cascade to generate thrombin (the bispecific monoclonal antibody emicizumab which mimics the co-factor function of FVIII) or by inhibiting naturally occurring anticoagulant pathways (fitusiran inhibits antithrombin and concizumab inhibits tissue factor pathway inhibitor)¹³. Among them, emicizumab has been recently licensed for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in paediatric and adult patients with haemophilia A with inhibitors¹⁴. Following the positive results of the pivotal trials HAVEN 1 and HAVEN 2 in inhibitor patients, the efficacy and safety of this agent was also assessed in non-inhibitor haemophilia A individuals (HAVEN 3 and HAVEN 4 trials), obtaining approval from the US Drug and Food Administration and the European Medicines Agency also for this clinical indication^14,15.

With this background, the question that Aledort et al. ask the readers of the narrative review published in this issue of Blood Transfusion¹⁶ is quite simple: to what extent can emicizumab be used in individuals with haemophilia A without inhibitors. After an in-depth analysis of the clinical efficacy and safety of the newer EHL FVIII products and emicizumab, the authors conclude that FVIII replacement therapy should be still considered the standard of care in this rare coagulation disorder. On the whole, we agree with their well presented evidence and conclusions. Management of haemophilia A patients with emicizumab is still very complex with some unsolved issues and “grey areas” (well discussed in the paper by Aledort et al.) that require further investigation in adequately powered trials¹⁵. In addition, the safety concerns of this novel haemostatic agent deserve more in-depth analyses from real world studies. Finally, we would like to point out that also FVIII products are rapidly evolving in order to overcome some patients’ unmet needs (i.e., less frequent infusions through subcutaneous or oral administration) that will improve treatment compliance and, ultimately, patients’ quality of life. A new class of bioengineered FVIII molecules, independent from the von Willebrand factor (vWF) half-life ceiling effect and produced using XTEN fusion technology with the IgG₁ Fc fragment and the vWF domain D’D3, are being investigated in phase I/II studies¹³. If the results from these trials demonstrate the safety and efficacy of these highly engineered haemostatic agents, also patients affected by haemophilia A will finally have a class of products that will permit once-weekly, or even less frequent, prophylaxis dosing regimens. Alternative modes of FVIII administration (i.e., subcutaneous route) are also under development¹³. In conclusion, to paraphrase the title of the celebrated song of the Nobel prize singer and poet Bob Dylan, “The times they are a-changin’ “, … or maybe not.