Towards optimization of emicizumab therapy: Challenges in the changing haemophilia A landscape

Abstract

Haemophilia A is an X-linked recessive bleeding disorder resulting from a deficiency of coagulation factor VIII (FVIII). Affected individuals experience spontaneous or trauma-induced bleeding, primarily in joints and muscles, with recurrent hemarthroses ultimately causing severe arthropathy. Over recent decades, therapeutic advances have markedly reduced bleeding episodes and treatment burden, and novel therapies continue to emerge. Emicizumab (Hemlibra®) is the first approved non-factor replacement therapy for haemophilia A in the Netherlands. It functions as a FVIII-mimicking antibody by bridging activated factor IX and factor X (FX), thereby promoting FX activation and thrombin generation. Emicizumab substantially reduces annualized (joint) bleeding rates (A[J]BR) in patients with and without FVIII inhibitors. Its subcutaneous administration and prolonged half-life enable less frequent dosing compared to conventional FVIII replacement therapy. This thesis aimed to optimize emicizumab therapy, evaluate its efficacy and safety in a large paediatric cohort, investigate the role of thrombin generation assays in treatment monitoring, and examine off-label applications in other coagulopathies. Chapter 2 investigated 177 children with haemophilia A (median age 8.6 years). Emicizumab significantly reduced both ABR and AJBR. In patients without FVIII inhibitors, ABR decreased from 2.41 to 1.11 and AJBR from 0.74 to 0.31 (p<0.001). In patients with inhibitors, ABR decreased from 5.08 to 0.75 and AJBR from 1.90 to 0.34 (p<0.001). Reduced bleeding and less frequent injections substantially decreased treatment burden, from 129 to 35 injections per year in children without inhibitors, and from 364 to 52 in those with inhibitors. Treatment-related adverse events occurred in 3% of patients, predominantly injection site reactions. One patient developed anti-drug antibodies, resulting in breakthrough bleeding and therapy discontinuation. Chapter 3 evaluated thrombin generation assays (TGA) in 49 patients at 3 and 12 months of steady-state emicizumab therapy. Weak correlations were observed between emicizumab concentrations and both endogenous thrombin potential (ETP, r = 0.42) and peak height (r = 0.41). Minimal changes in TGA parameters with increasing concentrations suggest coagulation is saturated at standard dosing. Despite reliable assay performance, substantial intra-patient variability limits TGA utility for individual monitoring. No differences were observed between patients with and without bleeding episodes. Chapters 4–6 examined dosing strategies. Entire-vial dosing, aligning maintenance doses with available flacons, reduced drug wastage by 9% while maintaining efficacy (mean ABR 0.8; median emicizumab 63 µg/mL). The DosEmi study compared conventional dosing to pharmacokinetic (PK)-guided reduced dosing targeting a trough of 30 ± 5 µg/mL. Interim results (n=26) demonstrated that reduced dosing was safe and effective, with no significant changes in treated bleeds and a 39% mean dose reduction. Pediatric patients have now been included, with final results anticipated in 2027. Chapters 7 and 8 describe emicizumab use in type 3 von Willebrand disease and acquired haemophilia A. In a patient with VWD and alloantibodies, emicizumab achieved haemostasis during postpartum hemorrhage and prevented rebleeding in an arthropathic joint for 2.5 years. In a patient with acquired haemophilia A, therapy stabilized haemostasis until complete remission was achieved, without bleeding or thrombotic events.