CC BY-NC-ND 4.0 · Thromb Haemost 2021; 121(03): 351-360
DOI: 10.1055/s-0040-1717114
New Technologies, Diagnostic Tools and Drugs

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

Christophe Schmitt
1  Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Joanne I. Adamkewicz
2  Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, United States
Jin Xu
3  Department of Clinical Research, Genentech, Inc., South San Francisco, California, United States
Claire Petry
1  Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Olivier Catalani
4  Department of Pharma-Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland
Guy Young
5  Hemostasis and Thrombosis Program, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California, United States
Claude Negrier
6  Hematology Department, Louis Pradel Hospital, University Claude Bernard, Lyon, France
Michael U. Callaghan
7  Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, United States
Gallia G. Levy
8  Department of Pharma Development, Genentech, Inc., South San Francisco, California, United States
› Author Affiliations
Funding This study was sponsored by F. Hoffmann-La Roche Ltd.


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.

Authors' Contributions

C.S., J.I.A., C.N., M.U.C., and G.G.L. contributed to the development of the HAVEN 1 study design. C.P. and O.C. contributed to the acquisition of data for these analyses. C.S., J.I.A., J.X., C.P., O.C., G.Y., C.N., M.U.C., and G.G.L. contributed to data analysis and interpretation. All authors critically reviewed this manuscript and approved the final version for submission.

Supplementary Material

Publication History

Received: 23 April 2020

Accepted: 18 August 2020

Publication Date:
21 October 2020 (online)

© 2020. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (

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