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BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

ABSTRACT: Background:Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. Objectives:To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. Methods:In this phase 1, single-blind, parallel-group, placebo-controlled, dose-escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60-minute intravenous infusion of BAY 1213790 (0.015-10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. Results:BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose-dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin-triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose-dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose-dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. Conclusions:Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

SUBMITTER: Thomas D

PROVIDER: S-EPMC6462747 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

Thomas Dirk D Thelen Kirstin K Kraff Stefanie S Schwers Stephan S Schiffer Sonja S Unger Sigrun S Yassen Ashraf A Boxnick Stefanie S

Research and practice in thrombosis and haemostasis 20190214 2

<h4>Background</h4>Coagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target.<h4>Objectives</h4>To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men.<h4>Methods</h4>In this phase 1, single-blind, parallel-group, placebo-controlled, dose ...[more]

PMID: 31011708

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Project description:BACKGROUND: Preclinical studies have demonstrated that pharmacological mobilization and recruitment of endogenous bone marrow stem cells and immunoregulatory cells by a combination of plerixafor and low-dose tacrolimus (MRG-001) improves wound healing, promotes tissue regeneration and prevents allograft rejection. This first‐in‐human phase I dose‐escalation study evaluates the safety, tolerability, pharmacokinetics and pharmacodynamics of MRG-001, a novel fixed-dose combination drug. METHODS: In this Phase 1, double‐blind, randomized, placebo-controlled study, multiple ascending dose (MAD) cohorts are randomized to receive MRG-001 containing up to 0.02 mL/kg (plerixafor 24 mg/mL and tacrolimus 0.5 mg/mL) or saline placebo, subcutaneously every other day (SC, QAD) for 5 days (ClinicalTrials.gov: NCT04646603)The primary outcome is safety and tolerability. Safety and functional assessments are performed throughout the study. Blood samples are collected to evaluate systemic exposure. Fluorescence-activated cell sorting analysis and RNA expression of peripheral blood mononuclear cells (PBMCs) are used to evaluate the pharmacodynamics. RESULTS: Fourteen subjects received MRG-001 and 7 received a placebo. MRG-001 is safe and well-tolerated over the selected dose range. No deaths or severe adverse events are reported. There are no clinically significant laboratory changes after MRG-001 administration, apart from the predicted generalized leukocytosis. The intermediate dose group (0.01 mL/kg) showed the most significant white blood cell mobilization over time and increased by 2-4 fold from baseline and returned to baseline levels prior to the next injection. Circulating immune cells including FOXP3+ regulatory T cells and hematopoietic stem cells (CD45IntCD34+) increased significantly after MRG-001 injection. PBMC RNA sequencing and gene set enrichment analysis revealeds 31 down-regulated pathways in the intermediate dose MRG-001 group compared to no changes in the placebo group. CONCLUSION: MRG-001 is safe and well-tolerated across the full dose ranges tested. MRG-001 may be a clinically useful therapy for immunoregulation and tissue regeneration. A Phase II trial to treat severely and critically ill COVID-19 patients with MRG-001 has been initiated (NCT04646603) and a second phase II trial will explore the potential of MRG-001 to accelerate wound healing (NCT05844527),

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BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

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BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics.

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