Lower-Dose Emicizumab Prophylaxis: Can Less Be More?

Authors: Srivastava, A; Iorio, A

Affiliations: Department of Haematology, Christian Medical College Vellore, Ranipet Campus, Tamil Nadu, India. Department of Health Research Methods, Evidence, and Impact, and Department of Medicine, McMaster University, Hamilton, Ontario, Canada.

Publication: Journal of thrombosis and haemostasis: JTH; 2024; 22. 922–925

Abstract: The shifting paradigm in hemophilia prophylaxis of targeting higher than 1% trough levels starting about a decade ago with extended halflife (EHL) clotting factor concentrates (CFCs) producing much better hemostatic outcomes, got a boost with the advent of the first non-clotting factor hemostatic product, emicizumab, a factor VIII mimetic, which was introduced in clinical practice about 5 years ago. This humanized bivalent antibody mimicking FVIII by simultaneously targeting FIXa and FX can be used in all patients with hemophilia A, with or without inhibitors. Its administration in weekly to monthly doses of 1.5 to 6 mg/kg as subcutaneous injections, depending on the interval between doses, provides excellent hemostasis and protection from bleeding with very low annualized bleeding rates (ABRs). Therapeutic plasma levels of emicizumab at a steady state are very predictable within the recommended dose range [1,2]. Most importantly and unlike CFCs, given the long half-life, there are no peaks and troughs but a steady state of hemostasis, irrespective of the frequency of administration. Though there are no good models to estimate the clinical equivalence of hemostasis through emicizumab with plasma FVIII levels in a clinically meaningful manner, the current assumption is that a plasma level of 50 ug/mL of emicizumab (the average plasma level measured in the population enrolled in the HAVEN study program) [3] corresponds to a plasma clotting FVIII activity level in the range of mild hemophilia (approximately 0.1-0.4 IU/mL of FVIII) [4]. The observed variability is related to an inter-individual range of emicizumab concentrations in response to the standard dose (IQR, 25-75 ug/mL) and to the same plasma level of emicizumab translating to varying FVIIIc equivalent activity in different patients [5], which can vary between 0.07 and 0.48 IU/mL.