Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study

Authors: Schmitt, C., Adamkewicz, J. I., Xu, J., Petry, C., Catalani, O., Young, G., Negrier, C., Callaghan, M. U., and Levy, G. G.

Publication: Thromb Haemost.

Affiliations: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland ; Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, United States ; Department of Clinical Research, Genentech, Inc., South San Francisco, California, United States ; Department of Pharma-Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland ; Hemostasis and Thrombosis Program, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California, United States ; Hematology Department, Louis Pradel Hospital, University Claude Bernard, Lyon, France ; Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, Michigan, United States ; Department of Pharma Development, Genentech, Inc., South San Francisco, California, United States.

Abstract: Emicizumab, a bispecific monoclonal antibody, bridges activated factor IX (FIXa) and FX, replacing the function of missing FVIIIa to restore effective hemostasis in persons with hemophilia A (PwHA). Here we assess pharmacokinetic (PK) and pharmacodynamic (PD) biomarkers in PwHA with FVIII inhibitors in the Phase III HAVEN 1 study (NCT02622321). Blood samples from 112 PwHA receiving 1.5 mg/kg once-weekly subcutaneous emicizumab were analyzed at central laboratories. Emicizumab concentrations for PK analysis were measured via validated immunoassay. PD effects were assessed using FVIII chromogenic activity assay containing human factors (Hyphen Biophen FVIII:C), and by FXIa-triggered thrombin generation (TG). Activated partial thromboplastin time (aPTT), prothrombin time (PT), antigen levels of FIX and FX, fibrinogen, D-dimer, and prothrombin fragment 1.2 (PF1.2) levels were determined. Emicizumab trough concentrations ≥ 50 μg/mL were maintained throughout the study. FVIII-like activity and TG (peak height) correlated with emicizumab concentrations and remained above 20 U/dL and 100 nM, respectively, with a weekly maintenance dose, theoretically converting persons with severe hemophilia A to a mild disease phenotype. aPTT was normalized at subtherapeutic concentrations of emicizumab. Plasma concentrations of target antigens FIX and FX were not significantly affected by emicizumab treatment; nor were fibrinogen, PT (international normalized ratio), D-dimer, or PF1.2. The PK profile of once-weekly emicizumab in HAVEN 1 provides sustained therapeutic plasma levels, consistent with population PK models. Both the PK profile and the PD and safety biomarkers are consistent with the established efficacy of emicizumab prophylaxis in PwHA with FVIII inhibitors.