10.4081/btvb.2022.22
For almost 90 years, the discovery and development of anticoagulant drugs have focused on maximizing their antithrombotic efficacy while minimizing the risk of bleeding, in addition to providing manageable compounds with predictable and/or monitorable effects [...].
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Walter Ageno
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Bleeding, Thrombosis and Vascular Biology
Venous thromboembolism
Milvexian and other drugs targeting Factor XI: a new era of anticoagulation?
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Invited Editorials
2022-04-15
2022-02-24
2022-03-22
2022-05-12
Bleed Thromb Vascul Biol
Walter Ageno
2022/04/15
10.4081/btvb.2022.22
Research Center on Thromboembolic Diseases and Antithrombotic Therapies, Department of Medicine and Surgery, University of Insubria, Varese; Thrombosis and Hemostasis Center, Ospedale di Circolo e Fondazione Macchi, Azienda Socio-Sanitaria territoriale dei Sette Laghi, Varese
2785-5309
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Venous thromboembolism
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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;138:2173-84.
Milvexian and other drugs targeting Factor XI: a new era of anticoagulation?
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                                                                                                                     EDITORIAL

Milvexian and other drugs targeting Factor XI: a new era of anticoagulation?
Marco P. Donadini,1,2 Walter Ageno1,2
1
 Research Center on Thromboembolic Diseases and Antithrombotic Therapies, Department of Medicine and Surgery, University of
Insubria, Varese, Italy; 2Thrombosis and Hemostasis Center, Ospedale di Circolo e Fondazione Macchi, Azienda Socio-Sanitaria
territoriale dei Sette Laghi, Varese, Italy




    For almost 90 years, the discovery and development                     role in thrombus growth, that is associated with a con-
of anticoagulant drugs have focused on maximizing their                    comitant marginal role in hemostasis.3
antithrombotic efficacy while minimizing the risk of                           A number of different molecules targeting Factor XI
bleeding, in addition to providing manageable compounds                    have been developed and a wide research program is cur-
with predictable and/or monitorable effects. Nowadays,                     rently ongoing. These molecules include antisense oligonu-
clinicians can rely on a large equipment of anticoagulants,                cleotides (ASO) that inhibit the hepatic synthesis as well
going from the first discovered unfractionated heparin to                  as agents that bind the target protein, such as monoclonal




                                                                                            ly
the latest approved direct oral anticoagulants, passing                    antibodies, small molecules and natural inhibitors.4




                                                                                     on
through vitamin K antagonists, low molecular weight he-                        Phase II clinical trials carried out in patients undergo-
parin/fondaparinux and parenteral anti-thrombin agents.                    ing elective major orthopedic surgery have been com-
    Nonetheless, in clinical scenarios requiring long-term                 pleted and published for fesomersen (IONIS-FXI-Rx)5



                                                                                e
or indefinite anticoagulation, such as stroke prevention in                and the antibodies osocimab and abelacimab.6,7 More re-
atrial fibrillation (AF) or secondary prevention of venous
thromboembolism (VTE), and/or in comorbid and fragile
                                                                          us
                                                                           cently, a phase II randomized clinical trial tested the use
                                                                           of the small molecule milvexian, a selective oral Factor
patients, there is still an underuse of anticoagulants and                 XIa inhibitor, for the prevention of VTE after total knee
                                                                          al
an inappropriate use of dose reductions,1,2 that are mainly                replacement (TKR).8 Milvexian was given postopera-
driven by concerns about the risk of bleeding.
                                                         ci

                                                                           tively in seven parallel groups at different doses and
    Therefore, over the last few years, research efforts                   schedules. The results confirmed a significant dose-re-
                                                       er



have focused on a new class of anticoagulants targeting                    sponse relationship for both once daily and twice daily
the contact system, with the aim to maximize safety by                     regimens. Moreover, the primary outcome (composite of
                                                      m




reducing the risk of bleeding while on therapy. Factor XI                  asymptomatic deep vein thrombosis and symptomatic
                                          om




appeared to be an ideal target, because of its important                   VTE) occurred in a significantly lower proportion of pa-
                                                                           tients receiving milvexian at a total daily dose of 100 to
                                                                           400 mg, as compared to enoxaparin. Overall, no episodes
                                    -c




                                                                           of major bleeding were registered with milvexian and
                                                                           clinically relevant bleeding (composite of major bleeding
                           on




    Correspondence: Walter Ageno, SC Pronto Soccorso e Medicina
    d’Urgenza, Viale Borri 57, 21100 Varese, Italy.                        and clinically relevant non major bleeding) occurred in
    Tel.: +39.0332278831 - Fax: +39.0332278818
                                                                           1% of patients on milvexian and 2% of patients on enoxa-
                      N




    E-mail: walter.ageno@uninsubria.it
                                                                           parin. Of note, no dose-response relationship was seen for
    Key words: Milvexian, Anti-XI agents, Venous thromboembolism.          milvexian with respect to bleeding.8
                                                                               This lower risk of clinically relevant bleeding was also
    Contributions: The authors contributed equally.
                                                                           observed in the first published phase II trial comparing
    Conflict of interest: WA: research grant from Bayer, fees for advi-    fesomersen to enoxaparin, even if the difference did not
    sory boards from Bayer, BMS/Pfizer, Norgine, Leo Pharma,               reach statistical significance (3% versus 8%, respec-
    Sanofi.                                                                tively).5 Of note, fesomersen inhibits hepatic biosynthesis
    Received for publication: 24 February 2022.
                                                                           of Factor XI and is therefore characterized by a very slow
    Accepted for publication: 29 March 2022.                               onset (and offset) of action, thus requiring to be started
                                                                           five weeks before surgery.
    This work is licensed under a Creative Commons Attribution Non-            A good safety profile also resulted with the two mon-
    Commercial 4.0 License (CC BY-NC 4.0).
                                                                           oclonal antibodies, osocimab, a fully human im-
    ©
     Copyright: the Author(s), 2022                                        munoglobulin G that binds the catalytic domain of FXIa
    Licensee PAGEPress, Italy                                              and blocks its activity, and abelacimab, that binds to factor
    Bleeding, Thrombosis and Vascular Biology 2022; 1:22                   XI and locks it in the zymogen (inactive precursor) con-
    doi:10.4081/btvb.2022.22
                                                                           formation. Osocimab met the non-inferiority criteria when

                                              Bleeding, Thrombosis and Vascular Biology 2022; 1:22
6                                                    M.P. Donadini, W. Ageno




administered at a single intravenous post-operative dose            long time, in the next few years clinicians may hopefully
of 0.6, 1.2 or 1.8 mg/kg compared with enoxaparin for the           be offered a new class of anticoagulant drugs, possibly ap-
prevention of VTE after elective TKR. Clinically relevant           plicable in different areas of vascular medicine.
bleeding occurred in 4.7% of patients treated with os-
ocimab 0.6 or 1.2 mg/kg and 5.9% with enoxaparin.6 Sim-
ilarly, abelacimab dose regimens of 30 mg and 75 mg/150             REFERENCES
mg showed either non-inferiority or superiority, respec-
                                                                     1. Sanghai S, Wong C, Wang Z, et al. Rates of potentially
tively, when compared to enoxaparin in preventing VTE
                                                                        inappropriate dosing of direct-acting oral anticoagulants and
after elective TKR. Clinically relevant bleeding occurred               associations with geriatric conditions among older patients
in 2%, 2%, and none of the patients in the 30-mg, 75-mg,                with atrial fibrillation: The SAGE-AF Study. J Am Heart
and 150-mg groups, respectively, and in none of the pa-                 Assoc 2020;9:e014108.
tients in the enoxaparin group.7                                     2. Trujillo-Santos J, Di Micco P, Dentali F, et al. Real-life
    The potential benefits of drugs targeting Factor XI                 treatment of venous thromboembolism with direct oral
may apply to several different clinical settings, in partic-            anticoagulants: The influence of recommended dosing and
ular when the risk-benefit of anticoagulation is often un-              regimens. Thromb Haemost 2017;117:382-9.
certain. A number of studies are currently ongoing for the           3. Hsu C, Hutt E, Bloomfield DM, et al. Factor XI inhibition
primary prevention of stroke in atrial fibrillation and the             to uncouple thrombosis from hemostasis: JACC review




                                                                                              ly
early secondary prevention of non-cardioembolic stroke                  topic of the week. J Am Coll Cardiol 2021;78:625-31.
                                                                     4. Fredenburgh JC, Weitz JI. New anticoagulants: Moving




                                                                                      on
(abelacimab, asundexian, milvexian), acute myocardial
                                                                        beyond the direct oral anticoagulants. J Thromb Haemost.
infarction (asundexian), and cancer-associated venous                   2021 Dec 30. doi: 10.1111/jth.15631
thromboembolism (abelacimab).4 Another area of partic-               5. Büller HR, Bethune C, Bhanot S, et al. Factor XI antisense



                                                                                e
ular interest involves patients with end stage renal disease            oligonucleotide for prevention of venous thrombosis. N Engl
undergoing hemodialysis. These patients have repeated
                                                                         us
                                                                        J Med 2015;372:232-40.
blood exposure to artificial surfaces that can activate the          6. Weitz JI, Bauersachs R, Becker B, et al. Effect of osocimab
coagulation system within the hemodialysis circuit. Fes-                in preventing venous thromboembolism among patients
                                                                  al

omersen, osocimab, milvexian, and xisomab have been                     undergoing knee arthroplasty: the foxtrot randomized
                                                       ci

evaluated in pilot studies aimed to understand the phar-                clinical trial. JAMA 2020;323:130-9.
macokinetics and pharmacodynamics of these drugs in                  7. Verhamme P, Yi BA, Segers A, et al. Abelacimab for
                                                     er



such a particular group of patients and to evaluate their               Prevention of Venous Thromboembolism. N Engl J Med
                                                                        2021;385:609-17.
                                                    m




ability to prevent occlusive events requiring hemodialysis
                                                                     8. Weitz JI, Strony J, Ageno W, et al. Milvexian for the
circuit exchange.9
                                                                        Prevention of Venous Thromboembolism. N Engl J Med
                                           om




    In conclusion, a new era of research on anticoagulants              2021;385:2161-72.
targeting Factor XI has already started, with preliminary            9. Lorentz CU, Tucker EI, Verbout NG, et al. The contact
encouraging results on their efficacy and, importantly, on              activation inhibitor AB023 in heparin-free hemodialysis:
                                     -c




a trend towards a better safety profile. Even if the discovery          results of a randomized phase 2 clinical trial. Blood
of the “magic bullet” is going to remain utopia for quite a
                              on




                                                                        2021;138:2173-84.
                         N




                                      Bleeding, Thrombosis and Vascular Biology 2022; 1:22
