Pharmacokinetics and coagulation biomarkers in children and adults with hemophilia A receiving emicizumab prophylaxis every 1, 2, or 4 weeks

Abstract

Background: Emicizumab is a bispecific antibody that bridges activated factor (F)IX and FX, mimicking the function of missing activated FVIII and thus improving hemostasis in people with hemophilia A. The efficacy and safety of emicizumab were demonstrated in 4 phase III clinical trials (HAVEN 1-4).

Objectives: Here, we describe pharmacokinetics (PKs), pharmacodynamics (PDs), and exploratory safety biomarkers in HAVEN 1 to 4.

Methods: Participants received emicizumab at a loading dose of 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 1.5 mg/kg weekly, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks. PKs, PDs, and safety biomarkers were assessed in samples collected at regular intervals during the trials.

Results: Emicizumab plasma trough concentrations increased during the loading dose period, reaching a mean of 52.9 μg/mL (SD, 13.6 μg/mL) at week 5, and were sustained at 42.1 to 52.3 μg/mL thereafter with maintenance dosing. Activated partial thromboplastin time shortened following the first emicizumab dose. Mean FVIII-like activity and thrombin generation peak height increased to 25.2 IU/dL (SD, 6.9 IU/dL) and 115.2 nM (SD, 42.5 nM) at week 5, with levels sustained at 17 to 23 IU/dL and >116 nM thereafter, respectively. Emicizumab did not notably affect FIX or FX plasma antigen levels, prothrombin time, or concentrations of exploratory safety markers of coagulation activation (D-dimer, prothrombin fragment 1 + 2, and fibrinogen).

Conclusion: In HAVEN 1 to 4, emicizumab demonstrated sustained PKs and PDs and improved coagulation parameters without affecting safety biomarkers.

Keywords: biomarkers; emicizumab; hemophilia A; pharmacodynamics; pharmacokinetics.

Figure 1

Analysis of pharmacodynamics in people with hemophilia A receiving emicizumab: (A) emicizumab trough plasma concentrations, (B) activated partial thromboplastin time (aPTT), (C) chromogenic factor (F)VIII-like activity, and (D) peak height of thrombin generation. FVIII activity was measured using a chromogenic assay containing human coagulation factors. QW, once weekly; Q2W, every 2 weeks; Q4W, every 4 weeks.

Figure 2

Correlation between emicizumab plasma concentrations and (A) chromogenic factor (F)VIII-like activity, (B) peak height of thrombin generation, and (C) activated partial thromboplastin time (aPTT). Gap at 10 IU/dL reflects the use of 2 different calibration curves.

Figure 3

Correlation between emicizumab plasma concentrations and chromogenic factor (F)VIII-like activity between people with and without FVIII inhibitors.

Figure 4

Concentrations of exploratory safety biomarkers: (A) factor (F)IX, (B) FX, (C) prothrombin time, (D) D-dimer, (E) fibrinogen, and (F) prothrombin fragment 1+2. FIX and FX plots are only presented up to 120 weeks as measurements were discontinued after that point due to no changes being observed in any of the studies up to 109 weeks of follow-up. CI, confidence interval; FEU, fibrinogen equivalent unit; FIX, factor IX; FX, factor X; IQR, interquartile range; PT, prothrombin time.

Figure 5

Factor (F)VIII inhibitor titer over time in participants with inhibitors. CBU, chromogenic Bethesda unit; FVIII, factor VIII; IQR, interquartile range.

Figure 6

Emicizumab concentration over time by factor VIII inhibitor status for participants receiving (A) emicizumab 1.5 mg/kg once weekly (QW), (B) 3 mg/kg every 2 weeks (Q2W), and (C) 6 mg/kg every 4 weeks (Q4W). This analysis includes data from different studies, so not all participants have been tested at each time point.

Figure 7

Emicizumab concentration over time according to age category for participants who received the once weekly dosing regimen. Mean data were presented when participants with available data represented ≥30% of the total participants in a given age group. CI, confidence interval.