Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A

Background Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab.Material and Methods Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1-4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors.Results TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement.Conclusion Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Automated summary

This study found that global coagulation assays (GCA) can serve as indicators to monitor the biological response to non-factor replacement therapy, such as emicizumab. After treatment, PwHA patients showed improved coagulation activity and fibrin clot composition, although thrombin generation (TG) results remained slightly below the normal reference range. Remarkably, individual patients exhibited varying degrees of response to emicizumab, despite having similar plasma concentrations of the drug.