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Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study.
Thromb Haemost. 2021 Mar; 121(3):351-360.TH

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.

Authors+Show 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 Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland.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.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

33086400

Citation

Schmitt, Christophe, et al. "Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons With Hemophilia a With Factor VIII Inhibitors: HAVEN 1 Study." Thrombosis and Haemostasis, vol. 121, no. 3, 2021, pp. 351-360.
Schmitt C, Adamkewicz JI, Xu J, et al. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thromb Haemost. 2021;121(3):351-360.
Schmitt, C., Adamkewicz, J. I., Xu, J., Petry, C., Catalani, O., Young, G., Negrier, C., Callaghan, M. U., & Levy, G. G. (2021). Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. Thrombosis and Haemostasis, 121(3), 351-360. https://doi.org/10.1055/s-0040-1717114
Schmitt C, et al. Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons With Hemophilia a With Factor VIII Inhibitors: HAVEN 1 Study. Thromb Haemost. 2021;121(3):351-360. PubMed PMID: 33086400.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study. AU - Schmitt,Christophe, AU - Adamkewicz,Joanne I, AU - Xu,Jin, AU - Petry,Claire, AU - Catalani,Olivier, AU - Young,Guy, AU - Negrier,Claude, AU - Callaghan,Michael U, AU - Levy,Gallia G, Y1 - 2020/10/21/ PY - 2020/10/22/pubmed PY - 2021/10/26/medline PY - 2020/10/21/entrez SP - 351 EP - 360 JF - Thrombosis and haemostasis JO - Thromb Haemost VL - 121 IS - 3 N2 - 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. SN - 2567-689X UR - https://www.unboundmedicine.com/medline/citation/33086400/Pharmacokinetics_and_Pharmacodynamics_of_Emicizumab_in_Persons_with_Hemophilia_A_with_Factor_VIII_Inhibitors:_HAVEN_1_Study_ L2 - http://www.thieme-connect.com/DOI/DOI?10.1055/s-0040-1717114 DB - PRIME DP - Unbound Medicine ER -