Anouk Donners

103 Systematic review on PK of emicizumab INTRODUCTION Haemophilia A is an inherited bleeding disorder caused by an absence or dysfunction of coagulation factor VIII (FVIII) [1]. Without adequate treatment, people with haemophilia A (PwHA) who are severely affected suffer from recurrent bleeds, predominantly in joints, which results in crippling arthropathy, functional limitations and a significantly reduced life expectancy [2, 3]. The primary goal in the management of these PwHA is to prevent bleeds, preferably through regular coagulation factor replacement therapy (prophylaxis) [1, 4]. Prophylaxis with plasma-derived and, later, recombinant FVIII products has effectively reduced episodes of bleeding from an annual average of 20−30 to 1−4 [5-8]. However, replacement therapy with FVIII products has some disadvantages. This treatment is invasive requiring intravenous administration every 24−48 hours, usually starting before the age of 2 years [9]. Additionally, neutralizing antibodies against FVIII (known as inhibitors) develop in 30% of severely affected PwHA, rendering treatment with FVIII products ineffective [4, 10]. Emicizumab (Hemlibra®) is the first non-factor replacement product and was approved in 2018 by the U.S. Food and Drug Administration and the European Medicines Agency as prophylaxis for PwHA, both with and without FVIII inhibitors. This humanized, IgG4, bispecific monoclonal antibody (mAb) effectively restores the hemostatic function of missing FVIII by bridging activated factor IX and factor X. Moreover, the subcutaneous administration and the less frequent dosing interval of once per 1−4 weeks offer dosing convenience especially for (pediatric) PwHA with difficult venous access. Emicizumab has limited toxicity, although concomitant use of high doses activated prothrombin complex concentrate increases the thrombotic risk, and should be avoided [11, 12]. A body-weight-based standard dosing regimen for emicizumab (1.5 mg/kg per week, 3 mg/ kg per two weeks, 6 mg/kg per four weeks) without the requirement of dose adjustments based on laboratory monitoring has been approved by the regulatory authorities [13]. This dosing recommendation assumes clear dose−concentration (pharmacokinetics [PK]) and concentration−response (pharmacodynamics [PD]) relationships with acceptable variability due to factors other than body weight. Unexpected variability (e.g., resulting from anti-drug antibodies or population characteristics) should be absent, as differences in concentration and even response require monitoring and individualized dose tailoring [14, 15]. Therefore, the objective of this study was to investigate these basic principles by conducting a systematic review on the PK and associated efficacy of emicizumab in humans. 6