Clinical Pharmacology of Factor XI Inhibitors: New Therapeutic Approaches for Prevention of Venous and Arterial Thrombotic Disorders

Article Medicine, Research & Experimental

First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor

Vidya Perera et al.

Summary: The study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of Milvexian in healthy adults, showing that the drug's properties are suitable for further clinical development.

CTS-CLINICAL AND TRANSLATIONAL SCIENCE (2022)

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Article Hematology

Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa

Byungdoo A. Yi et al.

Summary: Abelacimab, a novel fully human monoclonal antibody targeting Factor XI, demonstrates dual activity against the inactive and activated FXI. Studies show that abelacimab effectively reduces free FXI levels after intravenous and subcutaneous administration, with a favorable safety profile, supporting its clinical development.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2022)

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Article Urology & Nephrology

Phase 2 Study of the Factor XI Antisense Inhibitor IONIS-FXIRx in Patients With ESRD

Michael Walsh et al.

Summary: This study demonstrates that IONIS-FXIRx can effectively reduce FXI activity in patients with ESRD receiving HD, with few treatment-related serious adverse events. Further research is needed to determine the benefits and risks of targeting FXI as a therapeutic target for patients receiving HD.

KIDNEY INTERNATIONAL REPORTS (2022)

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Article Pharmacology & Pharmacy

Single-Dose Pharmacokinetics of Milvexian in Participants with Mild or Moderate Hepatic Impairment Compared with Healthy Participants

Vidya Perera et al.

Summary: This study evaluated the pharmacokinetic effects of hepatic impairment on the drug Milvexian. The results showed that Milvexian was well tolerated in patients with normal and mild to moderate hepatic impairment, and dose adjustments are unlikely to be necessary.

CLINICAL PHARMACOKINETICS (2022)

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Article Chemistry, Medicinal

Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy

Andrew K. Dilger et al.

Summary: FXIa, an enzyme in the coagulation cascade, has limited role in hemostasis but is thought to amplify thrombin generation. Inhibitors of FXIa have potential as antithrombotic agents with superior efficacy and safety. The discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety has led to the identification of milvexian as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

JOURNAL OF MEDICINAL CHEMISTRY (2022)

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Article Hematology

First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men

Bettina Nowotny et al.

Summary: BAY 1831865, a humanized monoclonal antibody targeting factor XI, was well tolerated in healthy volunteers when administered via intravenous or subcutaneous injection, with no evidence of bleeding or adverse reactions reported. The drug showed dose-dependent prolongation of activated partial thromboplastin time and sustained inhibition of factor XI.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2022)

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Article Hematology

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

Stefan Heitmeier et al.

Summary: Asundexian is an oral inhibitor targeting FXIa, which has antithrombotic effects on arterial and venous thrombosis without increasing the risk of bleeding.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2022)

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Article Medicine, General & Internal

Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study

Jonathan P. Piccini et al.

Summary: This study compared the incidence of bleeding in patients with atrial fibrillation between Asundexian and apixaban, showing that Asundexian resulted in lower rates of bleeding compared with standard dosing of apixaban.

LANCET (2022)

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Article Hematology

The Association between Factor XI Deficiency and the Risk of Bleeding, Cardiovascular, and Venous Thromboembolic Events

Sarah Sharman Moser et al.

Summary: This study found that patients with any FXI deficiency were at higher risk of severe bleeding and clinically relevant nonsevere bleeding compared to the general population, while demonstrating a lower risk of cardiovascular events and venous thromboembolisms.

THROMBOSIS AND HAEMOSTASIS (2022)

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Review Hematology

Coagulation factors XI and XII as possible targets for anticoagulant therapy

Karsten Engseth Kluge et al.

Summary: In this review, observational and experimental studies on factors XI and XII as potential targets for anticoagulant therapy are discussed. Low concentrations of FXI are found to be protective against ischemic stroke and venous thrombosis, indicating its potential as a target for antithrombotic therapy. The potential of targeting FXII for preventing thrombosis is still unclear, with conflicting results from different studies.

THROMBOSIS RESEARCH (2022)

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Article Cardiac & Cardiovascular Systems

A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction

Sunil Rao et al.

Summary: This study investigated the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). The results showed that asundexian effectively inhibited coagulation activity without increasing the risk of bleeding or ischemic events.

CIRCULATION (2022)

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Article Neurosciences

Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention

Mukul Sharma et al.

Summary: The study aims to evaluate the dose-response relationship of the oral medication Milvexian in patients with ischemic stroke or TIA to reduce the risk of stroke.

JOURNAL OF STROKE & CEREBROVASCULAR DISEASES (2022)

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Review Peripheral Vascular Disease

Factor XI Inhibition for the Prevention of Venous Thromboembolism: An Update on Current Evidence and Future perspectives

Geraldine Poenou et al.

Summary: The emergence of DOACs has greatly improved the prevention of thrombosis. However, there are still unmet needs in thrombosis prevention. The discovery of coagulation factor XI as a therapeutic target offers potential solutions. Key data on compounds targeting factor XI have been published, and ongoing clinical studies show promise for improving the care of patients requiring thrombosis prevention.

VASCULAR HEALTH AND RISK MANAGEMENT (2022)

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Article Cardiac & Cardiovascular Systems

2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)

Gerhard Hindricks et al.

EUROPEAN HEART JOURNAL (2021)

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Article Medicine, General & Internal

Milvexian for the Prevention of Venous Thromboembolism

Jeffrey Weitz et al.

Summary: The study results showed that in knee arthroplasty patients receiving different doses of milvexian treatment, the incidence of venous thromboembolism with twice-daily dosing was significantly lower than the prespecified benchmark of 30%, with a lower risk of bleeding compared to enoxaparin.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Hematology

Contact Activation Inhibitor, AB023, in Heparin-Free Hemodialysis: Results of a Randomized Phase 2 Clinical Trial

Christina U. Lorentz et al.

BLOOD (2021)

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Review Cardiac & Cardiovascular Systems

Factor XI Inhibition to Uncouple Thrombosis From Hemostasis JACC Review Topic of the Week

Charles Hsu et al.

Summary: Hemostasis and thrombosis are closely linked, with factor XI inhibitors potentially providing a safer alternative to current anticoagulants. Clinical studies are ongoing to determine the efficacy of factor XI inhibitors in attenuating thrombosis without disrupting hemostasis.

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY (2021)

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Article Hematology

First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa

Dirk Thomas et al.

Summary: This study evaluated the safety, pharmacokinetic, and pharmacodynamic properties of the orally administered small molecule targeting FXIa in healthy men. The results showed that BAY 2433334 demonstrated favorable safety and tolerability, exhibited dose-dependent inhibition of FXIa activity, and is considered a promising oral anticoagulant drug candidate.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2021)

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Article Medicine, General & Internal

Abelacimab for Prevention of Venous Thromboembolism

Peter Verhamme et al.

Summary: Factor XI plays a significant role in the development of postoperative venous thromboembolism. Inhibition of Factor XI with a single intravenous dose of abelacimab after total knee arthroplasty was effective in preventing venous thromboembolism and had a low risk of bleeding.

NEW ENGLAND JOURNAL OF MEDICINE (2021)

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Article Medicine, General & Internal

Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty The FOXTROT Randomized Clinical Trial

Jeffrey I. Weitz et al.

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (2020)

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Article Hematology

American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism

Thomas L. Ortel et al.

BLOOD ADVANCES (2020)

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Article Hematology

MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans

Alexander W. Koch et al.

BLOOD (2019)

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Article Hematology

Contact Activation Inhibitor and Factor XI Antibody, AB023, Produces Safe, Dose-Dependent Anticoagulation in a Phase 1 First-In-Human Trial

Christina U. Lorentz et al.

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (2019)

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Review Hematology

Treatment of bleeding complications in patients on anticoagulant therapy

Siavash Piran et al.

BLOOD (2019)

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Article Biochemistry & Molecular Biology

Allosteric Inhibition as a New Mode of Action for BAY 1213790, a Neutralizing Antibody Targeting the Activated Form of Coagulation Factor XI

Martina Schaefer et al.

JOURNAL OF MOLECULAR BIOLOGY (2019)

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Article Hematology

BAY1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics

Dirk Thomas et al.

RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS (2019)

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Review Clinical Neurology

Outcome of intracerebral haemorrhage related to non-vitamin K antagonists oral anticoagulants versus vitamin K antagonists: a comprehensive systematic review and meta-analysis

Gregoire Boulouis et al.

JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY (2018)

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Review Clinical Neurology

Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation A Systematic Review and Meta-Analysis

Marco Proietti et al.

STROKE (2018)

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Review Hematology

Tissue Factor: An Essential Mediator of Hemostasis and Trigger of Thrombosis

Steven P. Grover et al.

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY (2018)

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Review Hematology

Contact System Activation and Cancer: New Insights in the Pathophysiology of Cancer-Associated Thrombosis

E. Campello et al.

THROMBOSIS AND HAEMOSTASIS (2018)

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Article Clinical Neurology

Outcome of intracerebral hemorrhage associated with different oral anticoagulants

Duncan Wilson et al.

NEUROLOGY (2017)

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Review Pharmacology & Pharmacy

Pharmacokinetics interactions of monoclonal antibodies

Nicola Ferri et al.

PHARMACOLOGICAL RESEARCH (2016)

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Article Medicine, General & Internal

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

Torben Bjerregaard Larsen et al.

BMJ-BRITISH MEDICAL JOURNAL (2016)

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Article Medicine, General & Internal

Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study

Torben Bjerregaard Larsen et al.

BMJ-BRITISH MEDICAL JOURNAL (2016)

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Article Medicine, General & Internal

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

Harry R. Bueller et al.

NEW ENGLAND JOURNAL OF MEDICINE (2015)

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Review Clinical Neurology

Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis

Daniel Caldeira et al.

JOURNAL OF NEUROLOGY (2015)

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Article Hematology

The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis

Chatree Chai-Adisaksopha et al.

BLOOD (2014)

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Article Hematology

Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys

Husam S. Younis et al.

BLOOD (2012)

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Article Hematology

Circulating microparticles in carriers of factor V Leiden with and without a history of venous thrombosis

Elena Campello et al.

THROMBOSIS AND HAEMOSTASIS (2012)

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Article Hematology

Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis

Ophira Salomon et al.

THROMBOSIS AND HAEMOSTASIS (2011)

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Article Hematology

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI

Erik I. Tucker et al.

BLOOD (2009)

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Article Biochemistry & Molecular Biology

Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa

Wenman Wu et al.

JOURNAL OF BIOLOGICAL CHEMISTRY (2008)

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Article Hematology

Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice

X Wang et al.

JOURNAL OF THROMBOSIS AND HAEMOSTASIS (2005)

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Article Medicine, General & Internal

High levels of coagulation factor XI as a risk factor for venous thrombosis.

JCM Meijers et al.

NEW ENGLAND JOURNAL OF MEDICINE (2000)

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Clinical Pharmacology of Factor XI Inhibitors: New Therapeutic Approaches for Prevention of Venous and Arterial Thrombotic Disorders

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