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

Autor:	Schmitt C; Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Adamkewicz JI; Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, California, United States., Xu J; Department of Clinical Research, Genentech, Inc., South San Francisco, California, United States., Petry C; Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Catalani O; Department of Pharma-Development, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Young G; Hemostasis and Thrombosis Program, Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, California, United States., Negrier C; Hematology Department, Louis Pradel Hospital, University Claude Bernard, Lyon, France., Callaghan MU; Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan, United States., Levy GG; Department of Pharma Development, Genentech, Inc., South San Francisco, California, United States.
Jazyk:	angličtina
Zdroj:	Thrombosis and haemostasis [Thromb Haemost] 2021 Mar; Vol. 121 (3), pp. 351-360. Date of Electronic Publication: 2020 Oct 21.
DOI:	10.1055/s-0040-1717114
Abstrakt:	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. Competing Interests: C.S., J.I.A., C.P., and G.G.L. are employees of F. Hoffmann-La Roche Ltd/Genentech, Inc. and hold stocks in F. Hoffmann-La Roche Ltd. J.X. is an employee of Gilead Sciences, and previous employee of F. Hoffmann-La Roche Ltd/Genentech, Inc. with stocks in F. Hoffmann-La Roche Ltd. O.C. is an employee of F. Hoffmann-La Roche Ltd. G.Y. has received grants and personal fees from Genentech, Inc./F. Hoffmann-La Roche Ltd, Takeda, and Grifols and personal fees from Novo Nordisk, UniQure, Sanofi, Spark Therapeutics, and BioMarin. C.N. has received personal fees from Bayer, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Shire, and Spark Therapeutics; and personal fees and other from Sobi and F. Hoffmann-La Roche Ltd. M.U.C. has received personal fees from F. Hoffmann-La Roche Ltd, Genentech, Inc., Bayer, Shire/Takeda, Pfizer, Novo Nordisk, Bioverative/Sanofi, Global Blood Therapeutics, Spark Therapeutics, BioMarin, Kedrion, Octapharma, Grifols; and has equity in Alnylam. (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. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)
Databáze:	MEDLINE
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