PDF herunterladen
Hamostaseologie 2023; 43(01): 028-036
DOI: 10.1055/a-1984-7021
Review Article

A Review of FXIa Inhibition as a Novel Target for Anticoagulation

Ioannis Koulas
1   The Institute of Health Systems Science at the Feinstein Institutes for Medical Research, Manhasset, New York, United States
,
Alex C. Spyropoulos
1   The Institute of Health Systems Science at the Feinstein Institutes for Medical Research, Manhasset, New York, United States
2   Northwell Health at Lenox Hill Hospital, New York, New York, United States
3   The Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
› Institutsangaben Funding/Acknowledgment This work was made possible in part by funding from the Broxmeyer Fellowship in Clinical Thrombosis.
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Limitations of vitamin K antagonists as chronic oral anticoagulant therapy have largely been supplanted by direct factor IIa and factor Xa inhibitor oral anticoagulants with similar efficacy but an overall better safety profile, lack of routine monitoring, and very limited drug–drug interactions compared with agents such as warfarin. However, an increased risk of bleeding remains even with these new-generation oral anticoagulants in fragile patient populations, in patients requiring dual or triple antithrombotic therapy, or high bleed risk surgeries. Epidemiologic data in patients with hereditary factor XI deficiency and preclinical studies support the notion that factor XIa inhibitors have the ability to be an effective but potentially safer alternative to existing anticoagulants, based on their ability to prevent thrombosis directly within the intrinsic pathway without affecting hemostatic mechanisms. As such, various types of factor XIa inhibitors have been studied in early phase clinical studies, including inhibitors of the biosynthesis of factor XIa with antisense oligonucleotides or direct inhibitors of factor XIa using small peptidomimetic molecules, monoclonal antibodies, aptamers, or natural inhibitors. In this review, we discuss how different types of factor XIa inhibitors work and present findings from recently published Phase II clinical trials across multiple indications, including stroke prevention in atrial fibrillation, dual pathway inhibition with concurrent antiplatelets post–myocardial infarction, and thromboprophylaxis of orthopaedic surgery patients. Finally, we refer to ongoing Phase III clinical trials of factor XIa inhibitors and their potential to provide definitive answers regarding their safety and efficacy in preventing thromboembolic events in specific patient groups.

Keywords

factor XIa inhibitors - direct oral anticoagulants - thrombosis - bleeding


Publikationsverlauf

Eingereicht: 10. Oktober 2022

Angenommen: 19. November 2022

Artikel online veröffentlicht:
20. Februar 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Fredenburgh JC, Weitz JI. Factor XI as a target for new anticoagulants. Hamostaseologie 2021; 41 (02) 104-110
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 2 Fredenburgh JC, Weitz JI. New anticoagulants: moving beyond the direct oral anticoagulants. J Thromb Haemost 2021; 19 (01) 20-29
    CrossrefPubMedGoogle Scholar
  • 3 Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol 2019; 39 (03) 331-338
    CrossrefPubMedGoogle Scholar
  • 4 Jackson SP, Darbousset R, Schoenwaelder SM. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms. Blood 2019; 133 (09) 906-918
    CrossrefPubMedGoogle Scholar
  • 5 Hsu C, Hutt E, Bloomfield DM, Gailani D, Weitz JI. Factor XI inhibition to uncouple thrombosis from hemostasis: JACC review topic of the week. J Am Coll Cardiol 2021; 78 (06) 625-631
    CrossrefPubMedGoogle Scholar
  • 6 Lewandowska MD, Connors JM. Factor XI deficiency. Hematol Oncol Clin North Am 2021; 35 (06) 1157-1169
    CrossrefPubMedGoogle Scholar
  • 7 Preis M, Hirsch J, Kotler A. et al. Factor XI deficiency is associated with lower risk for cardiovascular and venous thromboembolism events. Blood 2017; 129 (09) 1210-1215
    CrossrefPubMedGoogle Scholar
  • 8 Georgi B, Mielke J, Chaffin M. et al. Leveraging human genetics to estimate clinical risk reductions achievable by inhibiting factor XI. Stroke 2019; 50 (11) 3004-3012
    CrossrefPubMedGoogle Scholar
  • 9 Yang DT, Flanders MM, Kim H, Rodgers GM. Elevated factor XI activity levels are associated with an increased odds ratio for cerebrovascular events. Am J Clin Pathol 2006; 126 (03) 411-415
    CrossrefPubMedGoogle Scholar
  • 10 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High levels of coagulation factor XI as a risk factor for venous thrombosis. N Engl J Med 2000; 342 (10) 696-701
    CrossrefPubMedGoogle Scholar
  • 11 Duga S, Salomon O. Congenital factor XI deficiency: an update. Semin Thromb Hemost 2013; 39 (06) 621-631
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Tillman BF, Gruber A, McCarty OJT, Gailani D. Plasma contact factors as therapeutic targets. Blood Rev 2018; 32 (06) 433-448
    CrossrefPubMedGoogle Scholar
  • 13 Buchmueller A, Wilmen A, Strassburger J, Schmidt MV, Laux V. The anti-factor XIa antibody BAY 1213790 is a novel anticoagulant that shows strong antithrombotic efficacy without an increased risk of bleeding in rabbit models. International Society on Thrombosis and Haemostasis Congress; 2017 DOI: 10.3252/pso.eu.ISTH2017.2017
    CrossrefPubMedGoogle Scholar
  • 14 Poenou G, Dumitru Dumitru T, Lafaie L, Mismetti V, Heestermans M, Bertoletti L. Factor XI inhibition for the prevention of venous thromboembolism: an update on current evidence and future perspectives. Vasc Health Risk Manag 2022; 18: 359-373
    CrossrefPubMedGoogle Scholar
  • 15 Presume J, Ferreira J, Ribeiras R, Mendes M. Achieving higher efficacy without compromising safety with factor XI inhibitors versus low molecular weight heparin for the prevention of venous thromboembolism in major orthopedic surgery - systematic review and meta-analysis. J Thromb Haemost 2022; 20 (12) 2930-2938
    CrossrefPubMedGoogle Scholar
  • 16 Piccini JP, Caso V, Connolly SJ. et al; PACIFIC-AF Investigators. 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. Lancet 2022; 399 (10333): 1383-1390
    Google Scholar
  • 17 Rao SV, Kirsch B, Bhatt DL. et al; PACIFIC AMI Investigators. 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. Circulation 2022; 146 (16) 1196-1206
    CrossrefPubMedGoogle Scholar
  • 18 Shoamanesh A, Mundl H, Smith EE. et al; PACIFIC-Stroke Investigators. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. Lancet 2022; 400 (10357): 997-1007
    CrossrefPubMedGoogle Scholar
  • 19 Sharma M, Molina CA, Toyoda K. et al. 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. J Stroke Cerebrovasc Dis 2022; 31 (10) 106742
    CrossrefPubMedGoogle Scholar
  • 20 Milvexian shows potential to reduce the risk of ischaemic stroke. Accessed November 30, 2022 at: https://www.escardio.org/The-ESC/Press-Office/Press-releases/Milvexian-shows-potential-to-reduce-the-risk-of-ischaemic-stroke
    PubMedGoogle Scholar
  • 21 Liu Q, Bethune C, Dessouki E. et al. ISIS-FXIRx, a novel and specific antisense inhibitor of factor XI, caused significant reduction in FXI antigen and activity and increased aPTT without causing bleeding in healthy volunteers. Blood 2011; 118: 209
    CrossrefPubMedGoogle Scholar
  • 22 Lorentz CU, Verbout NG, Wallisch M. et al. Contact activation inhibitor and factor XI antibody, AB023, produces safe, dose-dependent anticoagulation in a Phase 1 first-in-human trial. Arterioscler Thromb Vasc Biol 2019; 39 (04) 799-809
    CrossrefPubMedGoogle Scholar
  • 23 Beale D, Dennison J, Boyce M. et al. ONO-7684 a novel oral FXIa inhibitor: safety, tolerability, pharmacokinetics and pharmacodynamics in a first-in-human study. Br J Clin Pharmacol 2021; 87 (08) 3177-3189
    CrossrefPubMedGoogle Scholar
  • 24 Thomas D, Kanefendt F, Schwers S, Unger S, Yassen A, Boxnick S. First evaluation of the safety, pharmacokinetics, and pharmacodynamics of BAY 2433334, a small molecule targeting coagulation factor XIa. J Thromb Haemost 2021; 19 (10) 2407-2416
    CrossrefPubMedGoogle Scholar
  • 25 Perera V, Wang Z, Luettgen J. et al. First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor. Clin Transl Sci 2022; 15 (02) 330-342
    CrossrefPubMedGoogle Scholar
  • 26 Perera V, Abelian G, Li D. et al. Single-dose pharmacokinetics of milvexian in participants with mild or moderate hepatic impairment compared with healthy participants. Clin Pharmacokinet 2022; 61 (06) 857-867
    CrossrefPubMedGoogle Scholar
  • 27 Kubitza D, Heckmann M, Distler J, Koechel A, Schwers S, Kanefendt F. Pharmacokinetics, pharmacodynamics and safety of BAY 2433334, a novel activated factor XI inhibitor, in healthy volunteers: a randomized phase 1 multiple-dose study. Br J Clin Pharmacol 2022; 88 (07) 3447-3462
    CrossrefPubMedGoogle Scholar
  • 28 Yi BA, Freedholm D, Widener N. et al. Pharmacokinetics and pharmacodynamics of Abelacimab (MAA868), a novel dual inhibitor of Factor XI and Factor XIa. J Thromb Haemost 2022; 20 (02) 307-315
    CrossrefPubMedGoogle Scholar
  • 29 Nowotny B, Thomas D, Schwers S. et al. First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men. J Thromb Haemost 2022; 20 (07) 1684-1695
    CrossrefPubMedGoogle Scholar
  • 30 Büller HR, Bethune C, Bhanot S. et al; FXI-ASO TKA Investigators. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med 2015; 372 (03) 232-240
    CrossrefPubMedGoogle Scholar
  • 31 Weitz JI, Strony J, Ageno W. et al; AXIOMATIC-TKR Investigators. Milvexian for the prevention of venous thromboembolism. N Engl J Med 2021; 385 (23) 2161-2172
    CrossrefPubMedGoogle Scholar
  • 32 Weitz JI, Bauersachs R, Becker B. et al. Effect of osocimab in preventing venous thromboembolism among patients undergoing knee arthroplasty: the FOXTROT randomized clinical trial. JAMA 2020; 323 (02) 130-139
    CrossrefPubMedGoogle Scholar
  • 33 Verhamme P, Yi BA, Segers A. et al; ANT-005 TKA Investigators. Abelacimab for prevention of venous thromboembolism. N Engl J Med 2021; 385 (07) 609-617
    CrossrefPubMedGoogle Scholar
  • 34 Lorentz CU, Tucker EI, Verbout NG. et al. The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial. Blood 2021; 138 (22) 2173-2184
    CrossrefPubMedGoogle Scholar