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What Is the Future of Factor XI Inhibitors?

2022; Lippincott Williams & Wilkins; Volume: 146; Issue: 25 Linguagem: Inglês

10.1161/circulationaha.122.061132

1524-4539

Jeffrey I. Weitz, John W. Eikelboom,

Urticaria and Related Conditions

HomeCirculationVol. 146, No. 25What Is the Future of Factor XI Inhibitors? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessArticle CommentaryPDF/EPUBWhat Is the Future of Factor XI Inhibitors? Jeffrey I. Weitz and John W. Eikelboom Jeffrey I. WeitzJeffrey I. Weitz Correspondence to: Jeffrey Weitz, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Email E-mail Address: [email protected] https://orcid.org/0000-0002-1092-7550 Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.I.W., J.W.E.). Departments of Medicine (J.I.W., J.W.E.), McMaster University, Hamilton, Ontario, Canada. Biochemistry and Biomedical Sciences (J.I.W.), McMaster University, Hamilton, Ontario, Canada. and John W. EikelboomJohn W. Eikelboom https://orcid.org/0000-0003-4126-1285 Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada (J.I.W., J.W.E.). Departments of Medicine (J.I.W., J.W.E.), McMaster University, Hamilton, Ontario, Canada. Population Health Research Institute, Hamilton, Ontario, Canada (J.W.E.). Originally published19 Dec 2022https://doi.org/10.1161/CIRCULATIONAHA.122.061132Circulation. 2022;146:1899–1902Parenteral and oral factor XI (FXI) inhibitors, the next potential generation of anticoagulants, are undergoing phase-3 evaluation with the hope that they will be safer than currently available agents.1 This article (1) addresses the unmet needs in anticoagulation therapy; (2) explains why FXI may be more important for thrombosis than for hemostasis; (3) identifies the FXI inhibitors in advanced stages of development; (4) describes the results of the phase 2 trials; and (5) provides perspective on the opportunities and challenges for this new class of anticoagulants.Unmet NeedsOral anticoagulants are a cornerstone for the prevention and treatment of thrombosis. The goal of anticoagulant therapy is to attenuate thrombosis without disruption of hemostasis. Although direct oral anticoagulants come closer to this goal than warfarin, bleeding remains the major side effect. Bleeding—or the fear of it—contributes to the underuse of anticoagulants in eligible patients with atrial fibrillation (AF) and to inappropriate use of low-dose direct oral anticoagulant regimens.1 Therefore, safer anticoagulants are needed.Rationale for Targeting FXICurrent anticoagulants target FXa or thrombin, enzymes in the common pathway of coagulation. Attention is now focused on FXI, which resides in the intrinsic pathway where it is activated by FXIIa or thrombin. FXI was selected as a target because there is emerging evidence that FXI is essential for thrombosis but mostly dispensable for hemostasis.Thrombosis, an intravascular process, is usually initiated by tissue factor (TF) exposed upon atherosclerotic plaque disruption or expressed on activated monocytes or TF-bearing microvesicles, which triggers the generation of small amounts of thrombin. Thrombus expansion depends on the amplification of coagulation by thrombin-mediated activation of FXI. Thrombosis can also be triggered by the contact of blood with medical devices such as mechanical heart valves or extracorporeal circuits with resultant activation of FXII. Polyanions such as inorganic polyphosphate released from activated platelets and neutrophil extracellular traps are other activators of FXII. Therefore, FXI appears to be important for thrombosis regardless of whether it is triggered by TF or via the contact pathway.In contrast with thrombosis, hemostasis is predominantly an extravascular process initiated by the high concentrations of TF surrounding blood vessels. Upon vascular injury, extravascular TF triggers explosive thrombin generation, thereby rendering the back activation of FXI by thrombin mostly redundant for hemostasis.Epidemiological data and studies in animals support the concept that FXI is more important for thrombosis than for hemostasis. Thus, patients with severe congenital FXI deficiency rarely experience spontaneous bleeding and the risk of bleeding is poorly correlated with FXI levels. In contrast, FXI levels correlate with the risk of thrombosis because patients with FXI deficiency are at lower risk for venous thromboembolism and ischemic stroke than those with normal FXI levels, whereas patients with elevated FXI levels are at higher risk. Studies in animal models corroborate the finding in humans. Mice deficient in FXI exhibit attenuated thrombosis at sites of vascular injury without increased bleeding after tail tip amputation. Likewise, antibodies against FXI inhibit thrombosis in rodent models without increasing bleeding, and knockdown of FXI levels with an antisense oligonucleotide reduces shunt thrombosis in baboons and catheter thrombosis in rabbits. Therefore, animal and human evidence suggests that FXI deficiency or inhibition attenuates thrombosis with minimal disruption of hemostasis.FXI InhibitorsFXI inhibitors include (1) fesomersen, a second-generation antisense oligonucleotide that reduces the hepatic synthesis of FXI; (2) monoclonal antibodies that inhibit FXI activation, FXIa activity, or both (eg, osocimab and abelacimab); and (3) asundexian and milvexian, small molecule FXIa inhibitors. These agents have unique pharmacological properties; fesomersen and the antibodies require parenteral administration, while the small molecules are given orally. Fesomersen is given subcutaneously and requires a few weeks to lower FXI levels into the therapeutic range, whereas the antibodies have a rapid onset of action if administered intravenously, and the small molecules achieve maximum plasma concentrations 2 to 4 hours after oral administration. Fesomersen and the antibodies have long half-lives, which enables once-monthly subcutaneous administration, whereas asundexian and milvexian have short half-lives and require once- or twice-daily administration, respectively.Clinical TrialsClinical evaluation of new anticoagulants usually starts in patients undergoing elective hip or knee replacement surgery because of their risk of postoperative deep vein thrombosis that can be efficiently detected on venography. The first-generation antisense oligonucleotide, osocimab, abelacimab, and milvexian were compared with enoxaparin in such patients in the phase 2 proof-of-concept studies. Exploratory meta-analyses using postoperative venous thromboembolism and clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) for the efficacy and safety analysis, respectively, reported a 40% to 50% reduction in venous thromboembolism with FXI inhibition compared with enoxaparin and a 59% reduction in bleeding.2Once proof-of-concept was shown, attention shifted from thromboprophylaxis to indications with greater unmet needs. In separate, phase 2 studies, fesomersen and osocimab were compared with placebo in patients with end-stage kidney disease undergoing hemodialysis, a population at high risk for atherothrombotic complications and bleeding. Although the results have not been reported, both studies went to completion, and fesomersen was reported to be safe and well tolerated.New results have recently been reported with the small molecule inhibitors (Table).3–5 Asundexian was compared with apixaban in the PACIFIC-AF (Safety of the Oral Factor Xia Inhibitor Asundexian Compared With Apixaban in Patients With Atrial Fibrillation) trial. Although underpowered for efficacy, rates of bleeding severe enough to prompt medical care occurred one-third as often with asundexian than with apixaban. When compared with placebo on top of dual antiplatelet therapy in patients with acute MI in the PACIFIC-AMI study (Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack), the pooled results with asundexian revealed no significant increase in bleeding. Ischemic events were less common than episodes of bleeding, and there was no reduction in the principal efficacy outcome with asundexian.Table. Results of Phase 2 Trials With Small Molecule Factor XI Inhibitors in Atrial Fibrillation, Stroke, and Myocardial InfarctionTrial (clinicaltrials.gov unique identifier)NEligibilityExperimentalControlEfficacySafetyDefinition (composite)ResultDefinition (composite)ResultPACIFIC-AF(NCT04218266)755Age ≥45 y, atrial fibrillation, CHA2DS2-VASc score ≥2 (male) or ≥3 (female), increased bleeding riskAsundexian 20 or 50 mg odApixaban 5 mg bid (2.5 mg bid if criteria met for dose reduction)Ischemic stroke, systemic embolism, myocardial infarction, or cardiovascular deathAsundexian 20 mg od: 2 events; asundexian 50 mg od: 4 events; vs apixaban: 3 eventsISTH major or clinically relevant nonmajor bleedingAsundexian 20 mg od: 1.2%; asundexian 50 mg od: 0.4%; vs apixaban: 2.4%PACIFIC-Stroke(NCT04304508)1808Age ≥45 y, noncardioembolic ischemic stroke, to be treated with antiplatelet therapy, able to have magnetic resonance imagingAsundexian 10, 20, or 50 mg odPlaceboIschemic stroke or covert infarction detected by magnetic resonance imagingAsundexian 10 mg od: 19%; asundexian 20 mg od: 22%; asundexian 50 mg od: 20%; vs placebo 19%ISTH major or clinically relevant nonmajor bleedingAsundexian 10 mg od: 4%; asundexian 20 mg od: 3%; asundexian 50 mg od: 4%; vs placebo 2%PACIFIC-AMI(NCT04304534)1601Within 5 days of acute myocardial infarctionAsundexian 10, 20, or 50 mg odPlaceboCardiovascular death, myocardial infarction, stroke, stent thrombosisAsundexian 10 mg od: 6.8%, asundexian 20 mg od: 6.0%, asundexian 50 mg od: 5.5%, vs. placebo 5.5%BARC 2, 3, or 5 bleedingAsundexian 10 mg od: 7.6%; asundexian 20 mg od: 8.1%; asundexian 50 mg od: 10.5%; vs placebo: 9.0%AXIOMATIC-SSP(NCT03766581)2366Noncardioembolic ischemic stroke or transient ischemic attackMilvexian 25 mg od; or 25, 50, 100, or 200 mg bidPlaceboIschemic stroke or covert infarction detected by magnetic resonance imagingMilvexian 25 mg od: 16.2%;milvexian 25 mg bid: 18.5%;milvexian 50 mg bid: 14.1%;milvexian 100 mg bid: 14.8%;milvexian 200 mg bid: 16.4%; vsplacebo: 16.6%BARC 3 or 5 bleedingMilvexian 25 mg od: 0.6%; milvexian 25 mg bid: 0.6%; milvexian 50 mg bid: 1.5%; milvexian 100 mg bid: 1.6%;milvexian 200 mg bid: 1.5%; vs placebo: 0.6%AXIOMATIC-SSP indicates Antithrombotic Treatment With Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events for Secondary Stroke Prevention; BARC, bleeding academic research consortium; bid, twice daily; ISTH, International Society on Thrombosis and Haemostasis; od, once daily; PACIFIC-AF, Safety of the Oral Factor XIa Inhibitor Asundexian Compared With Apixaban in Patients With Atrial Fibrillation; PACIFIC-AMI, Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following an Acute Heart Attack; and PACIFIC-STROKE, Factor XIa Inhibition With Asundexian After Acute Noncardioembolic Ischaemic Stroke.Asundexian and milvexian were compared with placebo on top of dual or single antiplatelet therapy in noncardioembolic ischemic stroke in the PACIFIC-Stroke (Factor XIa Inhibition With Asundexian After Acute Noncardioembolic Ischemic Stroke) and AXIOMATIC-SSP (Antithrombotic Treatment With Factor XIa Inhibition to Optimize Management of Acute Thromboembolic Events for Secondary Stroke Prevention) trials, respectively. There was no reduction in the primary outcome, a composite that included covert brain infarction on imaging, and no significant increase in bleeding in either trial; however, post hoc analyses revealed a reduction in recurrent symptomatic ischemic stroke and transient ischemic attack. Therefore, these trials suggest that FXI inhibitors can be safely used in conjunction with antiplatelet therapy.Conclusions and Future DirectionsThe evidence from available phase 2 trials suggests that unlike direct oral anticoagulants, drugs that target FXI reduce thrombosis without a dose–response for bleeding, thereby raising the potential for a more favorable benefit–risk profile. Large phase-3 trials are needed to determine whether asundexian and milvexian can prevent stroke without increasing bleeding in AF. This is a high bar to achieve because postmarketing studies confirm the efficacy and safety of direct oral anticoagulants for this indication.Asundexian and milvexian may reduce recurrence in patients with noncardioembolic stroke, but choosing the right dose requires a balance between efficacy and safety. Capitalizing on the benefits of dual pathway inhibition with aspirin and low-dose rivaroxaban seen in the ATLAS ACS 2–TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 46) and COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trials, extended treatment with an FXI inhibitor in acute coronary syndrome may safely reduce recurrent ischemic events but large trials will be needed to show this. Abelacimab is being evaluated in patients with AF and with cancer-associated venous thromboembolism, trials that may identify a role for parenteral FXI inhibitors. Therefore, the future of FXI inhibitors appears bright but the promise of uncoupling thrombosis from hemostasis requires confirmation in phase-3 trials.Article InformationAcknowledgmentsDr Weitz holds the Canada Research Chair in Thrombosis and the Heart and Stroke Foundation J. F. Mustard Chair in Cardiovascular Research, and Dr Eikelboom holds the Jack Hirsh/Population Health Research Institute Chair in Thrombosis and Atherosclerosis.Sources of FundingNone.Nonstandard Abbreviations and AcronymsAFatrial fibrillationFXIfactor XITFtissue factorDisclosures Dr Weitz has served as a consultant and has received honoraria from Anthos, Bayer, Bristol Myers Squibb, Ionis, Janssen, Merck, Pfizer, Regeneron, and Servier. Dr Eikelboom reports personal fees and/or grant support from Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Eli Lilly/GlaxoSmithKline, Janssen, Medscape, Merck, Pfizer, Sanofi Aventis, Servier, and USV.FootnotesCirculation is available at www.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1901.Correspondence to: Jeffrey Weitz, Thrombosis and Atherosclerosis Research Institute, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Email weitzj@taari.caReferences1. Chan NC, Weitz JI. Antithrombotic agents.Circ Res. 2019; 124:426–436. doi: 10.1161/CIRCRESAHA.118.313155LinkGoogle Scholar2. 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. doi: 10.3389/fcvm.2022.903029CrossrefMedlineGoogle Scholar3. Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Jones WS, Gorog DA, Durdil V, Viethen T, Neumann C, 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; 399:1383–1390. doi: 10.1016/S0140-6736(22)00456-1CrossrefMedlineGoogle Scholar4. Shoamanesh A, Mundl H, Smith EE, Masjuan J, Milanov I, Hirano T, Agafina A, Campbell B, Caso V, Mas JL, 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.Lancet. 2022; 400:997–1007. doi: 10.1016/S0140-6736(22)01588-4CrossrefMedlineGoogle Scholar5. Rao SV, Kirsch B, Bhatt DL, Budaj A, Coppolecchia R, Eikelboom J, James SK, Jones WS, Merkely B, Keller L, 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 following acute myocardial infarction.Circulation. 2022; 146:1196–1206. doi: 10.1161/CIRCULATIONAHA.122.061612LinkGoogle Scholar eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Santostasi G, Denas G and Pengo V (2023) New pharmacotherapeutic options for oral anticoagulant treatment in atrial fibrillation patients aged 65 and older: factor XIa inhibitors and beyond, Expert Opinion on Pharmacotherapy, 10.1080/14656566.2023.2219391, 24:12, (1335-1347), Online publication date: 13-Aug-2023. Costamagna G, Navi B, Beyeler M, Hottinger A, Alberio L and Michel P (2023) Ischemic Stroke in Cancer: Mechanisms, Biomarkers, and Implications for Treatment, Seminars in Thrombosis and Hemostasis, 10.1055/s-0043-1771270 Omari M and Alkhalil M (2023) Advances in Cardiovascular Pharmacology in Atherosclerotic-Related Therapeutic Areas: Addressing Patients' Clinical Needs, Journal of Clinical Medicine, 10.3390/jcm12113665, 12:11, (3665) December 20, 2022Vol 146, Issue 25 Advertisement Article Information Metrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.122.061132PMID: 36534732 Originally publishedDecember 19, 2022 Keywordsanticoagulantsatrial fibrillationfactor XIPDF download Advertisement