Dataset Information

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

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.

SUBMITTER: Schmitt C

PROVIDER: S-EPMC7895541 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Schmitt Christophe C Adamkewicz Joanne I JI Xu Jin J Petry Claire C Catalani Olivier O Young Guy G Negrier Claude C Callaghan Michael U MU Levy Gallia G GG

Thrombosis and haemostasis 20201021 3

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 ...[more]

PMID: 33086400

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Project description:Hemophilia A is a genetic disorder that results in the deficiency of functional factor VIII protein, which plays a key role in blood coagulation. Currently, the majority of hemophilia A patients are treated with repeated infusions of factor VIII protein. Approximately 30% of severe hemophilia A patients develop neutralizing antibodies to factor VIII (known as factor VIII inhibitors) due to treatment, rendering factor VIII protein infusions ineffective. Previously, mice receiving murine IL-2 complexed with α-murine IL-2 mAbs (JES6-1A12) showed a lack of factor VIII inhibitor formation after factor VIII treatment, which was associated with the proliferation and the activation of factor VIII-specific regulatory T cells (Tregs). In this paper, we evaluated if an Fc-fused mutated protein analog of mouse IL-2, named Fc.Mut24, engineered to selectively promote the expansion of Tregs in vivo can modulate factor VIII-specific immune responses. The mice received one intraperitoneal injection of Fc.Mut24. When the regulatory T cell population reached its highest frequency and peak activation, the mice received a hydrodynamic injection of factor VIII plasmid (day 4) followed by a second Fc.Mut24 dose (day 7). Peripheral blood was collected weekly. Flow cytometry was used to characterize the peripheral blood cell populations, while ELISA and Bethesda assays were used to assess the inhibitor concentrations and the functional titers in plasma. The activated partial thromboplastin time assay was used to assess the functional activities of factor VIII in blood. The mice receiving Fc.Mut24 showed a dramatic and transient increase in the population of activated Tregs after Fc.Mut24 injection. Factor VIII gene therapy via hydrodynamic injection resulted in high anti-factor VIII inhibitor concentrations in control PBS-injected mice, whereas the mice treated with Fc.Mut24 produced no inhibitors. Most significantly, there were no inhibitors generated after a second hydrodynamic injection of factor VIII plasmid administered at 19 weeks after the first injection in Fc.Mut24-treated mice. The mice receiving Fc.Mut24 maintained high levels of factor VIII activity throughout the experiment, while the control mice had the factor VIII activity dropped to undetectable levels a few weeks after the first factor VIII plasmid injection. Our data show that human therapies analogous to Fc.Mut24 could potentially provide a method to prevent inhibitor formation and induce long-term immune tolerance to factor VIII in hemophilia patients.

Dataset Information

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

Publications

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

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