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Emicizumab dose capping in obese patients with Haemophilia A: Early outcomes at a single centre

Dear Editor, During phase 3 clinical trials and since its commercialization, emicizumab (Hemlibra), a bispecific monoclonal antibody acting as a substitute for activated coagulation factorVIII (FVIII), has proven effective for bleeding prevention in persons with haemophilia A (PwHA) with andwithout inhibitors. It is administered subcutaneously, requires less frequent injections compared to intravenously administered factor replacement products and thereby reduces the treatment burden.1 For all these reasons, emicizumab is a potentially life-changing treatment option for PwHA, especially those with inhibitors. Safety concerns include thrombotic microangiopathy and thrombosis after concomitant use of activated prothrombin complex concentrate (aPCC) and occurrence of anti-drug antibodies (ADA).1 Emicizumab can be administered following different maintenance dosing regimens, after a loading dose of 3 mg/kg once a week during 4weeks: 1.5mg/kg onceweekly (Q1W), 3mg/kg every 2weeks (Q2W) or 6mg/kg every 4weeks (Q4W). After the loading dose period, plasma concentrations of emicizumab will remain stable over time, in contrast to conventional factor replacement products, whose pharmacokinetics are marked by peaks and troughs. The total body weight-based dosing scheme currently used in clinical trials and clinical practice, and which applies to paediatric and adult patients with or without inhibitors, is supported by population pharmacokinetic analysis.2,3 However, little is known about emicizumab dosing strategies in obese patients (i.e., individuals with a BMI greater than 30 kg/m2 as per theWHOdefinition4). Considering that the prevalence of overweight and obesity in PwH is approaching that of the general population,5 this is an important issue. The impact of obesity on pharmacokinetics and usage of coagulation factor concentrate has been previously discussed in the literature5,6 and adds to other potential problems associated with obesity in PwH such as cardiovascular disease and musculoskeletal and psychological health. Apart from a post-hoc analysis of the HAVEN 1, 3, and 4 studies by Recht et al. presented at the ISTH 2021 congress,7 there is no data available on efficacy of emicizumab in overweight and obese PwHA. The authors concluded that emicizumab was as efficacious in obese patients as in non-obese patients, which is shown by annual bleeding rates (ABRs) that are not significantly different and therapeutic plasma concentrations (> 30 μg/ml) achieved in both groups. In the reviewed HAVEN studies, emicizumab dosing was based on total body weight, but information on the highest amount of emicizumab administered or on individual pharmacokinetic profiles is not publicly available. On its website, emicizumab manufacturer Roche provides a dosing guide for body weights of up to 150 kg.8 For a PwHAweighing 150 kg, thiswould require for example four-weekly injectionsof900mgof emicizumab on a Q4W dosing scheme, which is supposed to be associated with the lowest treatment burden. Importantly, such high doses of emicizumab represent relatively high injection volumes for subcutaneous administration: an injection of 900 mg of emicizumab would equal a total injection volume of 6 ml, requiring three separate injections per administration. According to the manufacturer’s recommendations, volumes greater than 2 ml should be subdivided into multiple injections,9 since larger injection volumesmay cause injection site pain and increase the risk of injection site reactions.10 In a simulation study on the pharmacokinetic implications of dosing emicizumab based on vial size, the authors mention that emicizumab dose may be calculated based on ideal weight in obese patients, in analogy to factor VIII replacement therapy, where ideal weight may be the adequate reference for dose calculation.11,12 The latter is due to the relatively small increase in plasma volume in relation to adipose tissue with increasing body weight and thus an increased in vivo recovery of FVIII in obese patients. Dosing based on ideal weight may avoid overtreatment of patients and would also be more beneficial from an economic point of view.11 In our view, in the case of emicizumab, dose adaptation should also aim to reduce the number of subcutaneous injections per administration to reduce the “injection burden” associated with treatment and, in theory, improve treatment adherence. We therefore adopted a dose capping approach to treatment of obese PwHA with emicizumab at our haemophilia treatment centre (HTC) at Cliniques universitaires Saint-Luc, Brussels. Among 86 adult patients with moderate or severe haemophilia A currently followed at the HTC, 45 are treated with emicizumab. Among the emicizumabtreated patients, 16 are overweight (defined by a BMI greater than 25 kg/m24) and five have a BMI ≥ 30 kg/m2, therefore considered obese. Ages of these PwHA range from 31 to 49 years and they have been treated with emicizumab for 17, 20, 23, 29, and 30 months now. All had received prophylaxis with standard or extended half-life recombinant FVIII before switching to emicizumab. One of them had undergone successful immune tolerance induction (ITI) for eradication of a FVIII inhibitor during childhood. Details of the obese PwHA are presented in Table 1. After completion of the loading dose period, patients were put on an emicizumab maintenance dosing regimen of 600 mg Q4W