Anouk Donners

13 General Introduction when maintaining FVIII activity above 1% [15, 16]. The main challenges of FVIII therapy are the FVIII-inhibitor development in 30% of PwHA, which renders the treatment ineffective, the burden of intravenous administration and the costs. Financial restraints lead to poor access and health inequalities worldwide, as the cost of prophylaxis therapy is estimated at ~150,000 euros per person per year [17, 18]. A new therapeutic strategy became available with the introduction of non-factor replacement therapies. Emicizumab, which was approved in 2018, was the first therapy offering prophylaxis in PwHA with and without FVIII inhibitors. This recombinant, bispecific, monoclonal antibody (mab) effectively mimics the FVIII function to an equivalent of 10–20% FVIII activity [19-21]. Because there is no sequence homology to FVIII, the PwHA with FVIII inhibitors have an effective prophylactic option for the first time. Compared to FVIII products, the other revolutionising benefits of emicizumab are the subcutaneous instead of intravenous administration and the monthly instead multiple-weekly dosing frequency. Side effects, which rarely occur, include thrombotic events with concomitant use of activated prothrombin complex concentrate [22] and <0.6% immunogenicity with declining plasma concentrations [23]. While most PwHA in the Netherlands wish to start emicizumab prophylaxis, patient access is limited due to the financial impact on healthcare budget. Public pricing of emicizumab therapy is higher than FVIII therapy and is set at ~400,000 euros per person per year, although non-public pricing is probably close to the costs of the current FVIII therapies [24-26]. Another disadvantage of emicizumab is that it does not fully correct coagulation, and is therefore not suitable for the management of acute bleeds or major surgery [5]. Several other non-factor replacement products are currently under clinical investigation and are expected to be approved in the near future [27]. Their mode of action is either mimicking the FVIII function (i.e., similar to emicizumab) or targeting the natural coagulation inhibitors (i.e., antithrombin, tissue factor pathway inhibitor, or activated protein C). Rare thromboembolic events have been reported and warrant continuous post-marketing surveillance, although the overall safety profile looks promising [28]. The ultimate goal of haemophilia treatment is a phenotypical cure, which is achievable today, as Roctavian® valoctocogene roxaparvovec, the first gene therapy product of its kind, was approved in June 2022 [29]. Gene therapy allows PwHA to avoid the fears and obligations of haemophilia A treatment for a number of years [30, 31]. Monitoring Prescribing drugs involves more than writing a prescription and following the drug label [32, 33]. It also includes monitoring of the individual by continuous evaluation of the benefit-risk balance of pharmacotherapy and optimisation. Monitoring can involve the clinical observation of the individual or actually measuring markers that indicate a disease status. Many of these markers are biomarkers measured in a laboratory or by the 1