For five decades, the only option for oral anticoagulation used in patients with venous thromboembolic disease and atrial fibrillation was warfarin (Coumadin®), a vitamin K antagonist originally derived from a rodenticide.1 Warfarin works by inhibiting the body’s synthesis of clotting factors that require vitamin K: Factors II, VII, IX, and X.
Starting in the first decade of this century, the anticoagulation field advanced with more targeted agents, first dabigatran (Pradaxa®) that only interfered with the function of Factor II (also known as thrombin), and then rivaroxaban (Xarelto®), apixaban (Eliquis®), edoxaban (Savaysa®), and betrixaban (Bevyxxa®), which only interfered at the Factor X level. The word “interfered” is used here because, unlike the mechanism of action of warfarin, these so-called “NOACs” (non-vitamin K-dependent oral anticoagulants) do not inhibit the synthesis of their target clotting factors, but instead they block the activity of those factors.
NOACs produce less serious bleeding, especially intracranial bleeding, than warfarin, and therefore represent a pharmacologic advance over the older agent.2,3 That being said, serious bleeding still occurs with the NOACs, even when used properly . . . the annual rate of major bleeding with the NOACs in patients with atrial fibrillation is 2-3%, and the annual rate of intracranial bleeding is 0.3-0.5%.2 Therefore, there remains a need for safer anti¬coagulants for long-term indications
So, we have mentioned Factors II, VII, IX, and X. We haven’t yet mentioned Factor XI. Might that factor be a therapeutic target for anticoagulation. Let’s review (striving for simplicity) the coagulation cascade, which occurs through two separate pathways that interact, the intrinsic and the extrinsic pathway. The Extrinsic Pathway is activated by external trauma (think stab wound) that causes blood to escape from the vascular system and is triggered by Tissue Factor and Factor VII. This pathway is quicker than the intrinsic pathway. The Intrinsic Pathway is activated by trauma inside the vascular system (think plaque rupture inside a coronary artery), and is activated by platelets, exposed endothelium, chemicals like thrombin, or collagen. This pathway is slower than the extrinsic pathway, but in disease is generally more important. It involves factors XII, XI, IX, VIII. Both pathways meet and finish the pathway of clot production in what is known as the Common Pathway, where Factors I, II, V, and X are involved.
So, what about Factor XI? (BTW, note that much of what appears here also potentially applies to Factor XII, but Factor XI is the target on which several pharmaceutical companies are working now.) There are patients with congenital Factor XI deficiency. It turns out that while most patients who have no or defective Factor XI do not seem to have significant problems with bleeding (think about what happens in hemophilia because those patients are born without Factor VIII), they are at lower risk for venous thromboembolic disease and ischemic/embolic stroke.4–6 With congenital FXI deficiency, (a) spontaneous bleeding is rare, (b) hemorrhage can occur with surgery or injury, and (c) pathologic thrombosis is uncommon.
This is of great interest because the ultimate goal of therapeutic anticoagulation is to prevent pathologic thrombosis without unduly exposing the anticoagulated patient to excess bleeding risk. This potential advantage is driving pharmaceutical exploration and development.7 The strategies for FXI inhibition include antisense oligonucleotides (ASOs) that reduce hepatic synthesis of FXI,8 monoclonal antibodies that block Factor XI activation or Factor XIa activity,9,10 aptamers that bind Factor XI/XIa,11 and small molecules that block the active site of Factor XIa or cause allosteric modulation.12(p70033093),13(p13747)
The first Factor XI-targeted anticoagulant to be tested in humans was IONIS-416858, the FXI-directed ASO, which is given subcutaneously (SQ).8 In a Phase 2 study in patients undergoing elective total knee arthroplasty (TKA), 300 patients were randomized to receive SQ IONIS-416858 (200 or 300 mg starting 35 days pre-surgery) or enoxaparin (40 mg once daily, with the first dose given 12 hours before or after surgery). Bilateral venography was conducted in all patients after at least ten days of therapy, and the primary efficacy endpoint was VTE and VTE-related mortality. (Adding asymptomatic DVT detected by venography obviously enriches the sample. VTE occurred in 27% of the 200mg and 4% of the 300mg IONIS patients, vs 30% who received enoxaparin (200mg noninferior, 300mg superior). The rates of major and clinically relevant nonmajor bleeding were 3% in both IONIS-416858 groups and 8% in the enoxaparin group, but those differences were not statistically significant.8
EP-7041 is an intravenous small molecule Factor Xia antagonist (note: not Factor XI, but Xia) now in active development. The first focus for this drug is safe and effective thromboembolic prophylaxis in patients undergoing extracorporeal membrane oxygenation (ECMO), which is a thrombogenic process in which adequate heparinization puts patients at risk of bleeding. It is based on the premise that by blocking Factor Xia, thrombin production from the intrinsic pathway is produced, but there is no impact on the extrinsic pathway, which lowers bleeding risk. Phase 1 human studies showed EP-7041 to be safe and well-tolerated.13
The IONIS asset is now being studied as an anticoagulant in chronic hemodialysis patients, a group that is also the target for a Phase 3 study of osocimab, is a fully humanized G1 antibody that inhibits Factor XIa. This follows on the heels of a generally successful Phase 2 study that compared osocimab to enoxaparin and apixaban in TKA patients. In the FOXTROT study, postoperative osocimab at doses of 0.6 mg/kg, 1.2 mg/kg, and 1.8 mg/kg were noninferior to enoxaparin, and the preoperative dose of 1.8 mg/kg was superior to enoxaparin with regard to the primary outcome of incidence of VTE at 10 to 13 days postoperatively. “The observation that 3 dosage levels of osocimab administered postoperatively (0.6, 1.2, and 1.8 mg/kg) met criteria for noninferiority compared with enoxaparin supports the concept that feedback activation of factor XI by thrombin is critical for thrombus formation,” the authors reported. Rates of serious adverse events with osocimab were similar to those with enoxaparin and apixaban, and none of the infusion-related reactions with osocimab led to study drug interruption or discontinuation.14
An oral Factor Xia inhibitor, which appears in the literature both as BMS986177 and JNJ-70033093, has undergone single and multiple ascending-dose phase 1 evaluation in healthy volunteers with or without concomitant aspirin.15(p70033093),16(p986177),17(p986177) There is an ongoing phase 2 study (NCT03766581) comparing BMS986177 (at 25, 50, 100, or 200 mg doses once or twice daily) with placebo in patients with high-risk transient ischemic attack or small ischemic stroke.18(p03766581) All patients will be treated with aspirin plus clopidogrel for 30 days, followed by aspirin alone thereafter. This agent is also being studied in a second phase 2 study will compare similar doses of BMS-986177 with enoxaparin in patients undergoing elective TKA.15
In summary, Factor XI is a promising target for therapeutic anticoagulation that has the potential to be safer than those that inhibit downstream enzymes such as factor Xa or thrombin. Anti-Factor XI/Xia therapeutics may be this generation’s last advance in the anticoagulant space.
1. Lim GB. Warfarin: from rat poison to clinical use. Nature Reviews Cardiology. December 2017. doi:10.1038/nrcardio.2017.172
2. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955-962. doi:10.1016/S0140-6736(13)62343-0
3. van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(3):320-328. doi:10.1111/jth.12485
4. Salomon O, Steinberg DM, Zucker M, Varon D, Zivelin A, Seligsohn U. Patients with severe factor XI deficiency have a reduced incidence of deep-vein thrombosis. Thromb Haemost. 2011;105(2):269-273. doi:10.1160/TH10-05-0307
5. Salomon O, Steinberg DM, Koren-Morag N, Tanne D, Seligsohn U. Reduced incidence of ischemic stroke in patients with severe factor XI deficiency. Blood. 2008;111(8):4113-4117. doi:10.1182/blood-2007-10-120139
6. Seligsohn U. Factor XI deficiency in humans. J Thromb Haemost. 2009;7 Suppl 1:84-87. doi:10.1111/j.1538-7836.2009.03395.x
7. Weitz JI, Chan NC. Novel antithrombotic strategies for treatment of venous thromboembolism. Blood. 2020;135(5):351-359. doi:10.1182/blood.2019000919
8. Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis | NEJM. https://www.nejm.org/doi/full/10.1056/NEJMoa1405760. Accessed March 3, 2020.
9. 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(2):242-253. doi:10.1002/rth2.12186
10. 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. doi:10.1182/blood-2018-10-880849
11. Woodruff RS, Ivanov I, Verhamme IM, Sun M-F, Gailani D, Sullenger BA. Generation and characterization of aptamers targeting factor XIa. Thromb Res. 2017;156:134-141. doi:10.1016/j.thromres.2017.06.015
12. A Study of JNJ-70033093 (BMS-986177) Versus Subcutaneous Enoxaparin in Participants Undergoing Elective Total Knee Replacement Surgery. BioPortfolio. https://www.bioportfolio.com/resources/trial/235238/A-Study-of-JNJ-70033093-BMS-986177-Versus-Subcutaneous-Enoxaparin-in-Participants.html. Accessed March 3, 2020.
13. Hayward Neil J, Goldberg Dennis I, Morrel Eric M, Friden Phillip M, Bokesch Paula M. Abstract 13747: Phase 1a/1b Study of EP-7041: A Novel, Potent, Selective, Small Molecule FXIa Inhibitor. Circulation. 2017;136(suppl_1):A13747-A13747. doi:10.1161/circ.136.suppl_1.13747
14. Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial | Orthopedics | JAMA | JAMA Network. https://jamanetwork.com/journals/jama/article-abstract/2758600. Accessed March 3, 2020.
15. A Study of JNJ-70033093 (BMS-986177) Versus Subcutaneous Enoxaparin in Participants Undergoing Elective Total Knee Replacement Surgery – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03891524. Accessed March 3, 2020.
16. An Investigational Study to Assess the Effect of BMS-986177 on Aspirin in Healthy Participants – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03341390. Accessed March 3, 2020.
17. Safety and Tolerability Study of BMS-986177 in Healthy Subjects – Full Text View – ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02608970. Accessed March 3, 2020.
18. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT01583374.