The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials

Abstract

Although anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

Keywords

thrombosis - factor XI - factor XII - contact pathway - sepsis - hemostasis

• References

• 1 Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124 (15) 2450-2458
• 2 Puy C, Rigg RA, McCarty OJ. The hemostatic role of factor XI. Thromb Res 2016; 141 (Suppl. 02) S8-S11
• 3 Long AT, Kenne E, Jung R, Fuchs TA, Renné T. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14 (03) 427-437
• 4 Ivanov I, Shakhawat R, Sun MF. , et al. Nucleic acids as cofactors for factor XI and prekallikrein activation: different roles for high-molecular-weight kininogen. Thromb Haemost 2017; 117 (04) 671-681
• 5 Silasi R, Keshari RS, Lupu C. , et al. Inhibition of contact-mediated activation of factor XI protects baboons against S. aureus-induced organ damage and death. Blood Adv 2019; 3 (04) 658-669
• 6 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
• 7 Mumford AD, Ackroyd S, Alikhan R. , et al; BCSH Committee. Guideline for the diagnosis and management of the rare coagulation disorders: a United Kingdom Haemophilia Centre Doctors' Organization guideline on behalf of the British Committee for Standards in Haematology. Br J Haematol 2014; 167 (03) 304-326
• 8 Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood 2012; 120 (22) 4296-4303
• 9 Lippi G, Harenberg J, Mattiuzzi C, Favaloro EJ. Next generation antithrombotic therapy: focus on antisense therapy against coagulation factor XI. Semin Thromb Hemost 2015; 41 (02) 255-262
• 10 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
• 11 Koch AW, Schiering N, Melkko S. , et al. MAA868, a novel FXI antibody with a unique binding mode, shows durable effects on markers of anticoagulation in humans. Blood 2019; 133 (13) 1507-1516
• 12 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. Berlin, Germany: International Society on Thrombosis and Haemostasis; 2017
• 13 Thomas D, Thelen K, Kraff S. , et al. BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: first evaluation of safety, pharmacodynamics, and pharmacokinetics. Res Pract Thromb Haemost 2019; 3 (02) 242-253
• 14 Hayward NJ, Goldberg DI, Morrel EM, Friden PM, Bokesch PM. Abstract 13747: phase 1a/1b study of EP-7041: a novel, potent, selective, small molecule FXIa inhibitor. Circulation 2017; 136 (Suppl. 01) A13747-A13747
• 15 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
• 16 Cheng Q, Tucker EI, Pine MS. , et al. A role for factor XIIa-mediated factor XI activation in thrombus formation in vivo. Blood 2010; 116 (19) 3981-3989
• 17 Lämmle B, Wuillemin WA, Huber I. , et al. Thromboembolism and bleeding tendency in congenital factor XII deficiency--a study on 74 subjects from 14 Swiss families. Thromb Haemost 1991; 65 (02) 117-121
• 18 Cao H, Biondo M, Lioe H. , et al. Antibody-mediated inhibition of FXIIa blocks downstream bradykinin generation. J Allergy Clin Immunol 2018; 142 (04) 1355-1358
• 19 Larsson M, Rayzman V, Nolte MW. , et al. A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk. Sci Transl Med 2014; 6 (222) 222ra17