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Open Access 17-08-2024 | Acute Coronary Syndrome | Review

Milvexian: An Oral, Bioavailable Factor XIa Inhibitor

Authors: Shyon Parsa, Sneha S. Jain, Olu Akinrimisi, Carolyn S. P. Lam, Kenneth W. Mahaffey

Abstract

Direct oral anticoagulants have a dose-dependent increased bleeding risk which limits use in certain populations. Studies in both animals and humans with inherited variations in factor XI levels provide a theoretical basis for a drug target capable of addressing current unmet needs. Milvexian is an oral factor XIa inhibitor that has the potential to provide robust anticoagulant effect without increased bleeding compared with current standard of care. Several key studies in the preclinical, phase I, and phase II stages have reported promising safety data in venous thromboembolism and stroke prevention without compromising hemostasis. The planned phase III trials will examine the efficacy of milvexian for prevention of thrombotic events in patients with acute stroke, acute coronary syndrome, and atrial fibrillation.

Rymer JA, Chiswell K, Young L, et al. Analysis of oral anticoagulant dosing and adherence to therapy among patients with nonvalvular atrial fibrillation. JAMA Netw Open. 2023;6(6): e2317156. https://doi.org/10.1001/jamanetworkopen.2023.17156.CrossRefPubMedPubMedCentral

Ballestri S, Romagnoli E, Arioli D, et al. Risk and management of bleeding complications with direct oral anticoagulants in patients with atrial fibrillation and venous thromboembolism: a narrative review. Adv Ther. 2023;40(1):41–66. https://doi.org/10.1007/s12325-022-02333-9.CrossRefPubMed

Jackevicius CA, Lu L, Ghaznavi Z, Warner AL. Bleeding risk of direct oral anticoagulants in patients with heart failure and atrial fibrillation. Circ Cardiovasc Qual Outcomes. 2021;14(2): e007230. https://doi.org/10.1161/circoutcomes.120.007230.CrossRefPubMed

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):269–73. https://doi.org/10.1160/TH10-05-0307.CrossRefPubMed

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):4113–7. https://doi.org/10.1182/blood-2007-10-120139.CrossRefPubMed

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(9):1210–5. https://doi.org/10.1182/blood-2016-09-742262.CrossRefPubMed

Meijers JCM, Tekelenburg WLH, 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. https://doi.org/10.1056/NEJM200003093421004.CrossRefPubMed

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(2):330–42. https://doi.org/10.1111/cts.13148.CrossRefPubMed

Harrington J, Piccini JP, Alexander JH, Granger CB, Patel MR. Clinical evaluation of factor XIa inhibitor drugs: JACC review topic of the week. J Am Coll Cardiol. 2023;81(8):771–9. https://doi.org/10.1016/j.jacc.2022.11.057.CrossRefPubMed

10.

Renné T, Schmaier AH, Nickel KF, Blombäck M, Maas C. In vivo roles of factor XII. Blood. 2012;120(22):4296–303. https://doi.org/10.1182/blood-2012-07-292094.CrossRefPubMedPubMedCentral

11.

Nopp S, Kraemmer D, Ay C. Factor XI inhibitors for prevention and treatment of venous thromboembolism: a review on the rationale and update on current evidence. Front Cardiovasc Med. 2022;9: 903029. https://doi.org/10.3389/fcvm.2022.903029.CrossRefPubMedPubMedCentral

12.

Grover SP, Mackman N. Intrinsic pathway of coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2019;39(3):331–8. https://doi.org/10.1161/ATVBAHA.118.312130.CrossRefPubMed

13.

Periayah MH, Halim AS, Mat Saad AZ. Mechanism action of platelets and crucial blood coagulation pathways in hemostasis. Int J Hematol Oncol Stem Cell Res. 2017;11(4):319–27.PubMedPubMedCentral

14.

Reitsma SE, Pang J, Raghunathan V, et al. Role of platelets in regulating activated coagulation factor XI activity. Am J Physiol Cell Physiol. 2021;320(3):C365–74. https://doi.org/10.1152/ajpcell.00056.2020.CrossRefPubMedPubMedCentral

15.

Uchiyama S, Ibayashi S, Matsumoto M, et al. Dabigatran and factor Xa inhibitors for stroke prevention in patients with nonvalvular atrial fibrillation. J Stroke Cerebrovasc Dis. 2012;21(3):165–73. https://doi.org/10.1016/j.jstrokecerebrovasdis.2012.01.011.CrossRefPubMed

16.

Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. https://doi.org/10.1056/NEJMoa1107039.CrossRefPubMed

17.

Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527–39. https://doi.org/10.1161/01.cir.84.2.527.CrossRef

18.

Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. https://doi.org/10.1056/NEJMoa0905561.CrossRefPubMed

19.

Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. https://doi.org/10.1056/NEJMoa1009638.CrossRefPubMed

20.

Fang MC, Reynolds K, Fan D, et al. Clinical outcomes of direct oral anticoagulants vs warfarin for extended treatment of venous thromboembolism. JAMA Netw Open. 2023;6(8): e2328033. https://doi.org/10.1001/jamanetworkopen.2023.28033.CrossRefPubMedPubMedCentral

21.

Carnicelli AP, Hong H, Connolly SJ, et al. Direct oral anticoagulants versus warfarin in patients with atrial fibrillation: patient-level network meta-analyses of randomized clinical trials with interaction testing by age and sex. Circulation. 2022;145(4):242–55. https://doi.org/10.1161/CIRCULATIONAHA.121.056355.CrossRefPubMedPubMedCentral

22.

PubChem. Milvexian. https://pubchem.ncbi.nlm.nih.gov/compound/118277544. Accessed 3 Sep 2023.

23.

Discovery of milvexian, a high-affinity, orally bioavailable inhibitor of factor XIa in clinical studies for antithrombotic therapy. https://doi.org/10.1021/acs.jmedchem.1c00613.

24.

Wang X, Smith PL, Hsu MY, et al. Effects of factor XI deficiency on ferric chloride-induced vena cava thrombosis in mice. J Thromb Haemost. 2006;4(9):1982–8. https://doi.org/10.1111/j.1538-7836.2006.02093.x.CrossRefPubMed

25.

Rosen ED, Gailani D, Castellino FJ. FXI is essential for thrombus formation following FeCl3-induced injury of the carotid artery in the mouse. Thrombosis Haemostasis. 2002;87(4):774–6.CrossRefPubMed

26.

Wang X, Cheng Q, Xu L, et al. Effects of factor IX or factor XI deficiency on ferric chloride-induced carotid artery occlusion in mice. J Thromb Haemost. 2005;3(4):695–702. https://doi.org/10.1111/j.1538-7836.2005.01236.x.CrossRefPubMed

27.

Wang X, Li Q, Du F, Shukla N, Nawrocki AR, Chintala M. Antithrombotic effects of the novel small-molecule factor XIa inhibitor milvexian in a rabbit arteriovenous shunt model of venous thrombosis. TH Open. 2023;7(2):e97–104. https://doi.org/10.1055/a-2061-3311.CrossRefPubMedPubMedCentral

28.

Small-Molecule Factor XIa Inhibitor, BMS-986177/JNJ-70033093, prevents and treats arterial thrombosis in rabbits at doses that preserve hemostasis. ISTH Congress Abstracts. https://abstracts.isth.org/abstract/small-molecule-factor-xia-inhibitor-bms-986177-jnj-70033093-prevents-and-treats-arterial-thrombosis-in-rabbits-at-doses-that-preserve-hemostasis/. Accessed 3 Sep 2023.

29.

Bristol-Myers Squibb. A study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of BMS-986177 in Healthy Subjects. clinicaltrials.gov; 2017. https://clinicaltrials.gov/study/NCT02608970. Accessed 1 Sep 2023.

30.

Janssen Research & Development, LLC. An Open-Label, Randomized, Crossover Study to Evaluate the Relative Oral Bioavailability, Pharmacokinetics, and Food Effect After Single Dose (for Part 1, Part 3, Part 4 and Part 5) or Multiple-Dose (for Part 2) Administration of JNJ-70033093 (Milvexian) in Healthy Adult Participants Using Tablet, Capsule and Dispersed Tablet Formulations. clinicaltrials.gov; 2022. Accessed September 1, 2023. https://clinicaltrials.gov/study/NCT04844424. Accessed 1 Sep 2023.

31.

Weitz JI, Strony J, Ageno W, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med. 2021;385(23):2161–72. https://doi.org/10.1056/NEJMoa2113194.CrossRefPubMedPubMedCentral

32.

Antithrombotic treatment with factor XIa inhibition to optimize management of acute thromboembolic events for secondary stroke prevention. American College of Cardiology. Accessed September 3, 2023. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2022/08/27/04/12/http%3a%2f%2fwww.acc.org%2fLatest-in-Cardiology%2fClinical-Trials%2f2022%2f08%2f27%2f04%2f12%2fAXIOMATIC-SSP. Accessed 3 Sep 2023.

33.

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. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106742.CrossRefPubMedPubMedCentral

34.

Sharma M, Molina CA, Toyoda K, et al. Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2024;23(1):46–59. https://doi.org/10.1016/S1474-4422(23)00403-9.CrossRefPubMed

35.

Lyden P, Brott T, Tilley B, et al. Improved reliability of the NIH stroke scale using video training NINDS TPA stroke study group. Stroke. 1994;25(11):2220–6. https://doi.org/10.1161/01.str.25.11.2220.CrossRefPubMed

36.

Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet. 2007;369(9558):283–92. https://doi.org/10.1016/S0140-6736(07)60150-0.CrossRefPubMed

37.

Standardized Bleeding Definitions for Cardiovascular Clinical Trials | Circulation. Accessed September 7, 2023. https://www.ahajournals.org/doi/10.1161/circulationaha.110.009449. Accessed 7 Sep 2023.

38.

Franco L, Becattini C, Beyer-Westendorf J, et al. Definition of major bleeding: prognostic classification. J Thromb Haemost. 2020;18(11):2852–60. https://doi.org/10.1111/jth.15048.CrossRefPubMed

39.

Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57. https://doi.org/10.1056/NEJMoa0904327.CrossRefPubMed

40.

Janssen Research & Development, LLC. A phase 3, randomized, double-blind, parallel-group, placebo-controlled study to demonstrate the efficacy and safety of Milvexian, an oral factor XIa inhibitor, for stroke prevention after an acute ischemic stroke or high-risk transient ischemic attack. clinicaltrials.gov; 2023. Accessed September 1, 2023. https://clinicaltrials.gov/study/NCT05702034. Accessed 1 Sep 2023.

41.

Janssen Research & Development, LLC. A phase 3, randomized, double-blind, placebo-controlled, event-driven study to demonstrate the efficacy and safety of milvexian, an oral factor XIa inhibitor, after a recent acute coronary syndrome. clinicaltrials.gov; 2023. Accessed September 1, 2023. https://clinicaltrials.gov/study/NCT05754957. Accessed 1 Sep 2023.

42.

Janssen Research & Development, LLC. A phase 3, randomized, double-blind, double-dummy, parallel group, active-controlled study to evaluate the efficacy and safety of milvexian, an oral factor XIa inhibitor, versus apixaban in participants with atrial fibrillation. clinicaltrials.gov; 2023. https://clinicaltrials.gov/study/NCT05757869. Accessed 1 Sep 2023.

43.

Campello E, Simioni P, Prandoni P, Ferri N. Clinical pharmacology of factor XI inhibitors: new therapeutic approaches for prevention of venous and arterial thrombotic disorders. J Clin Med. 2022;11(21):6314. https://doi.org/10.3390/jcm11216314.CrossRefPubMedPubMedCentral

44.

Piccini JP, Caso V, Connolly SJ, et al. 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. The Lancet. 2022;399(10333):1383–90. https://doi.org/10.1016/S0140-6736(22)00456-1.CrossRef

45.

Shoamanesh A, Mundl H, Smith EE, et al. Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic stroke (PACIFIC-Stroke): an international, randomised, double-blind, placebo-controlled, phase 2b trial. The Lancet. 2022;400(10357):997–1007. https://doi.org/10.1016/S0140-6736(22)01588-4.CrossRef

46.

Rao SV, Kirsch B, Bhatt DL, et al. 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):1196–206. https://doi.org/10.1161/CIRCULATIONAHA.122.061612.CrossRefPubMed

47.

OCEANIC-AF study stopped early due to lack of efficacy. OCEANIC-AF study stopped early due to lack of efficacy. https://www.bayer.com/media/en-us/oceanic-af-study-stopped-early-due-to-lack-of-efficacy/. Accessed 15 Jan 2024.

48.

Verhamme P, Yi BA, Segers A, et al. Abelacimab for prevention of venous thromboembolism. N Engl J Med. 2021;385(7):609–17. https://doi.org/10.1056/NEJMoa2105872.CrossRefPubMed

49.

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(2):130–9. https://doi.org/10.1001/jama.2019.20687.CrossRefPubMedPubMedCentral

50.

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):2173–84. https://doi.org/10.1182/blood.2021011725.CrossRefPubMedPubMedCentral

51.

Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. N Engl J Med. 2015;372(3):232–40. https://doi.org/10.1056/NEJMoa1405760.CrossRefPubMed

52.

Walsh M, Bethune C, Smyth A, et al. Phase 2 study of the factor XI antisense inhibitor IONIS-FXIRx in patients with ESRD. Kidney Int Rep. 2021;7(2):200–9. https://doi.org/10.1016/j.ekir.2021.11.011.CrossRefPubMedPubMedCentral

Title: Milvexian: An Oral, Bioavailable Factor XIa Inhibitor
Authors: Shyon Parsa
Sneha S. Jain
Olu Akinrimisi
Carolyn S. P. Lam
Kenneth W. Mahaffey
Publication date: 17-08-2024
Publisher: Springer Healthcare
Keywords: Acute Coronary Syndrome
Ischemic Stroke
Atrial Fibrillation
Stroke
Enoxaparin
Venous Thrombosis
Published in: Cardiology and Therapy
Print ISSN: 2193-8261
Electronic ISSN: 2193-6544
DOI: https://doi.org/10.1007/s40119-024-00379-0

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Milvexian: An Oral, Bioavailable Factor XIa Inhibitor

Abstract

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» View more highlights on the 2024 ESC Congress hub page

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ERS Congress 2024

Springer Medicine

Abstract

Please log in to get access to this content

2024 ESC Congress

Noise pollution dangerous for heart health

Post-TAVI follow up: deploying virtual assistants

Antihypertensives: more effective at morning or night?

Low Lp(a) levels unlikely to increase the risk of diabetes

» View more highlights on the 2024 ESC Congress hub page

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Keynote webinar | Spotlight on medication adherence