Anouk Donners

105 Systematic review on PK of emicizumab Trough concentrations with corresponding errors (standard deviation [SD] and 95% confidence interval [95%-CI]) from steady-state conditions per study subgroup were primarily extracted from text. However, when data were presented in graphs only and the data requests remained unanswered, the data were extracted from the graphs [1820]. To minimize bias, first, two independent and blinded reviewers (AD, LB) visually scored the data with magnification and a set square. Secondly, the data were scored using WebPlotDigitizer, a reliable and validated web-based tool for extracting underlying numerical data from plots ( [21]) [22]. Both the visually and digitally extracted values were compared and if necessary reassessed. The data were entered (LB/AD) into a database for systematic data extraction and were double-checked by a second reviewer (AD/LB). Data synthesis Extracted data relating to study and population characteristics were categorized and summarized. The PK data (Ctrough,ss) were plotted according to doses of the multipleinjection regimens in PwHA and for the single-injection regimens in volunteers (primary and secondary parameters). The coefficient of variation (%CV, or the variability) of trough concentrations was calculated as (SD/mean)×100%. If unavailable, the SD was derived from the 95%−CI using the formula √n×((upper limit − lower limit)/3.92), or from the interquartile range (IQR) using (IQRmax−IQRmin)/1.35 [23]. Exposure effects modelling was conducted with weighted (study size) non-linear least squares regression using a standard inhibitory maximum effect (Emax) model. The ABRs of treated bleeds and treated joint bleeds were used as efficacy parameters if calculated by means of negative binominal regression (model-based). As data for the extremes of the curve were lacking, values for baseline ABR and Emax, derived from other sources, were assumed and the Hill coefficient was fixed to 1. The baseline ABRs for treated bleeds and treated joint bleeds were assumed at values of 28.0 and 21.6, respectively, as reported for severe PwHA treated with on demand-therapy in a real-world setting [6]. These values were in line with the reported baseline ABRs for treated bleeds of 21.9, 23.3 and 38.2, and for treated joint bleeds of 6.7 and 26.5 in severe PwHA without prophylactic treatment [18, 19, 24]. The Emax for treated bleeds was set at a value of 0.96 (i.e., 96% drug effect at infinite exposure, corresponding to an ABR of 1) and for treated joint bleeds the Emax was set at 0.98 (corresponding to an ABR of 0.5). This was done to account for the occurrence of traumatic bleeding (based on clinical experience) and the lack of complete of coagulation by emicizumab (based on mouse and primate models). In addition, the FVIII-equivalent (hemostatic) activity of emicizumab was hypothesized at only 10−20% in humans [24-26]. An ABR of 1 was, therefore, perceived as more realistic than an ABR of 0, and is also in line with the reported ABRs range of 0.2−5.1 (Supplemental Table ST2). The ABR baseline values were also used to calculate the Relative Risk Reduction (RRR). Sensitivity analysis was performed to assess validity of the ABR baseline and Emax assumptions. 6