Anouk A. M. T. Donners

Introduction Emicizumab effectively prevents bleeding in people with haemophilia A (PwHA), but is a burden for national healthcare budgets and consequently may limit access. According to the drug label, dosing of emicizumab is based on body weight with fixed intervals of 7, 14 or 28 days, which leads to mean plasma concentrations of 55 µg/mL (SD 15 µg/mL). However, a moderate variability of concentrations and a minimal effective concentration of 30 µg/mL have been suggested in studies. Therefore, a dose of emicizumab that targets a trough concentration of 30 µg/mL is hypothesised to be equally effective as conventional dosing in the prevention of bleeding. Methods and analysis We designed a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of bleed control of ≥6 months on conventional dosing in comparison to ≥6 months on dose intervention. This dose intervention consists of reducing the dose of emicizumab to target a trough concentrations of 30 µg/mL using individual pharmacokinetic (PK) parameters. Ninety-five PwHA aged >1 years who received conventional dosing of emicizumab for ≥12 months with good bleeding control during the last 6 months will be recruited from all Dutch haemophilia treatment centres. The study is powered to detect a clinically relevant decrease (risk difference) of 15% in the proportion of patients without treated bleeds during follow-up. Secondary endpoints are spontaneous joint or muscle bleeds, and annualised treated bleeding rates (using negative binomial regression). Cost-effectivity between conventional dosing and individualised PK-guided dosing of emicizumab will be compared. Ethics and dissemination The DosEmi study was approved by the Medical Ethics Review Committee NedMec of the University Medical Center of Utrecht, The Netherlands. Study results will be communicated through publications in international scientific journals and presentations at (inter)national conferences. Trial registration number EUCTR2021-004039-10-NL at https://trialsearch.who.int. Protocol version V.4.1 on 28 October 2022 (DosEmi protocol_V4.1; NL81112.041.22).

Introduction Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose–concentration–response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted. Methods The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (E_max) model. Results The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA. Conclusion This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

Introduction Haemophilia A is a hereditary bleeding disorder caused by a factor VIII (FVIII) deficiency. As biomarker, FVIII activity is used to classify disease severity and to monitor treatment. The one-stage clotting assay (OSA) is performed to measure FVIII activity, but OSA's limitations may result in misclassification of disease severity or suboptimal monitoring of treatment. Measurement of FVIII plasma concentration with liquid chromatography-tandem mass spectrometry (LC-MS/MS) might overcome these challenges. The objective is to investigate the correlation between FVIII activity and concentration, and determinants for differences between the two methods. Methods In this cross-sectional study, all haemophilia A patients receiving standard-of-care were eligible for inclusion. Within the activity categories of 5-40 IU/dL, >40-150 IU/dL and >150-600 IU/dL, we randomly selected 15-20 plasma samples and compared FVIII concentration (LC-MS/MS) to FVIII activity (OSA) with linear regression and Bland-Altman analysis. Potential determinants for differences were analysed with linear regression. Results Inclusion was 87 samples. Bland-Altman analysis demonstrated an overall mean difference of -1% with an SD of 64% between the two methods. Large differences were correlated with the presence of anti-FVIII antibodies (133% [95% CI: 81, 185] n = 5) and use of exogenous FVIII products (-37% [95% CI: -65,-9] n = 58), for example plasma-derived and B-domain-modified FVIII products. Conclusions Despite good overall correlation between the two methods, relative differences were large, especially for samples with anti-FVIII antibodies or exogenous FVIII products. These differences may have clinical impact. More research is needed to determine the value of FVIII plasma concentration in comparison with FVIII activity.