10.4081/btvb.2023.76
The two last decades have witnessed a revolution in the field of anticoagulation, mainly due to the advent of direct anticoagulant with targeted action against single coagulation proteins. However, the residual risk of cardio- and cerebrovascular events, particularly in some critical settings, and the risk of major bleeding still represent unmet medical needs. Preclinical studies and experience from families with genetic deficiencies of factor XI or XII (FXI and FXII) allowed to identify these factors involved in the contact pathway of coagulation as potential targets for new anticoagulant approaches. To date, several pharmacological classes of FXI and FXII inhibitors have been developed, including antisense oligonucleotides, monoclonal antibodies, small molecules, natural inhibitors, and aptamers, and various molecules are currently under phase 2 or 3 clinical investigation. Particularly, promising results have been obtained in patients undergoing major orthopedic surgery, in those with end-stage kidney disease, atrial fibrillation and acute coronary syndrome. This review summarizes current knowledge on FXI and FXII inhibitors, with a particular focus on their pharmacological properties and potential clinical indications.
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Alessandra Bettiol
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Bleeding, Thrombosis and Vascular Biology
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The new era of anticoagulation: factor XI and XII inhibitors
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Bleed Thromb Vascul Biol
Alessandra Bettiol
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Liu M, Zaman K, Fortenberry YM. Overview of the therapeutic potential of aptamers targeting coagulation factors. Int J Mol Sci 2021;22.
The new era of anticoagulation: factor XI and XII inhibitors
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2
                                                                                                                                   REVIEW

The new era of anticoagulation: factor XI and XII inhibitors
Domenico Prisco,1,2 Irene Mattioli,1 Raffaele De Caterina,3 Alessandra Bettiol1

Department of Experimental and Clinical Medicine, University of Florence; 2Careggi University Hospital, Florence; 3Division of
1

Cardiology, Pisa University Hospital, and University of Pisa, Italy



ABSTRACT
     The two last decades have witnessed a revolution in the field of anticoagulation, mainly due to the advent of direct anticoagulant
with targeted action against single coagulation proteins. However, the residual risk of cardio- and cerebrovascular events, particularly
in some critical settings, and the risk of major bleeding still represent unmet medical needs. Preclinical studies and experience from
                                                                          families with genetic deficiencies of factor XI or XII (FXI and
                                                                          FXII) allowed to identify these factors involved in the contact
                                                                          pathway of coagulation as potential targets for new
   Correspondence: Irene Mattioli, Department of Experimental and         anticoagulant approaches. To date, several pharmacological
   Clinical Medicine, University of Florence, Largo Brambilla 3,          classes of FXI and FXII inhibitors have been developed,




                                                                                                 ly
   50134 Florence, Italy.                                                 including antisense oligonucleotides, monoclonal antibodies,
   E-mail: irene.mattioli@unifi.it                                        small molecules, natural inhibitors, and aptamers, and various




                                                                                         on
                                                                          molecules are currently under phase 2 or 3 clinical investigation.
   Citation: Prisco D, Mattioli I, De Caterina R, Bettiol A. The new      Particularly, promising results have been obtained in patients
   era of anticoagulation: factor XI and XII inhibitors. Bleeding,        undergoing major orthopedic surgery, in those with end-stage
   Thrombosis, and Vascular Biology 2023;2:76.




                                                                                   e
                                                                          kidney disease, atrial fibrillation and acute coronary syndrome.
   Key words: anticoagulation; bleeding; factor XI; factor XII; throm-
   bosis.
                                                                              us
                                                                          This review summarizes current knowledge on FXI and FXII
                                                                          inhibitors, with a particular focus on their pharmacological
                                                                          properties and potential clinical indications.
                                                                              al
    Contributions: DP, IM AND AB revised the pertinent literature;
    DP, IM and AB wrote the first draft of the manuscript, assisted by
                                                           ci

    RDC. All authors critically revised the manuscript and approved
    the final version to be published and agreed to be accountable for         Introduction
                                                         er


    all aspects of the work.
                                                                                   The last decades have witnessed a revolution in the field of
                                                        m



    Conflict of interest: DP reports grants and fees for his Institution       anticoagulation: after the long era of heparins and vitamin K
    from Daiichi-Sankyo, Takeda, Novo Nordisk, CS Behring and                  antagonists (VKAs), direct anticoagulant drugs with a targeted
                                            om




    Sanofi, outside the submitted work. RDC reports grants and per-            action against single coagulation proteins have reached the
    sonal fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi           clinical practice. Among them, the parenterally administered
    Sankyo, Milestone, Novartis, Menarini, Guidotti, Sanofi and
                                                                               agents fondaparinux, targeting factor (F) Xa, and bivalirudin,
    Roche, outside the submitted work. IM and AB declare no conflicts
                                      -c




    of interest.                                                               targeting thrombin, have been used for the acute treatment of
                                                                               venous thromboembolism (VTE) and acute coronary
                             on




    Availability of data and material: all data are available within the       syndromes, as well as during revascularization procedures,
    text.                                                                      whereas direct oral anticoagulants (DOACs) against thrombin
                                                                               or activated FXa have been widely used for the acute treatment
                       N




    Acknowledgments: the authors would thank all the people who                of VTE and long-term prophylaxis of pro-thrombotic conditions.
    contributed to this work.                                                  DOACs, while being non-inferior to VKAs for the prevention
                                                                               of stroke in atrial fibrillation and for the prevention and
    Received: 29 March 2023.
    Accepted: 22 May 2023.                                                     treatment of VTE,1-5 feature an easy handling, better compliance
                                                                               and more favorable safety profile, particularly in terms of
    Publisher’s note: all claims expressed in this article are solely those    bleeding risk.6 Thanks to these properties, DOACs are now
    of the authors and do not necessarily represent those of their affili-     preferred over traditional anticoagulants in most settings,7
    ated organizations, or those of the publisher, the editors and the re-     although not in all clinical indications: among the latter are
    viewers. Any product that may be evaluated in this article or claim        conditions associated to a high risk of bleeding (for example,
    that may be made by its manufacturer is not guaranteed or endorsed         patients candidate for dual or triple antiplatelet-anticoagulant
    by the publisher.                                                          therapy); diseases in which DOACs have reported unfavorable
                                                                               results (for example, in patients with mechanical heart valves
    ©
     Copyright: the Author(s), 2023
                                                                               or antiphospholipid antibody syndrome) or have not been
    Licensee PAGEPress, Italy
    Bleeding, Thrombosis and Vascular Biology 2023; 2:76                       adequately tested (for example, patients with extremely
    doi:10.4081/btvb.2023.76                                                   impaired renal or hepatic function, with extreme body weight
                                                                               or with sickle cell disease); or in case of possible non-negligible
    This work is licensed under a Creative Commons Attribution-                interactions with other drugs.8-11 Despite their wide use and
    NonCommercial 4.0 International License (CC BY-NC 4.0).                    indications, unmet therapeutic and prophylactic needs are still



                                                Bleeding, Thrombosis and Vascular Biology 2023; 2:76
12                                                             D. Prisco et al.




present in the field of anticoagulation, and the high human and            activation can be affected also by FXIa, which amplifies the
economic burden associated with cardiovascular events                      generation of thrombin, converting FIX into its activated form.22
underscore the need for new therapeutic alternatives for the                   The idea that inhibiting the contact pathway of coagulation
management of thrombotic diseases.                                         might be an effective anticoagulant approach came from the
    In recent years, the growing knowledge of diseases                     knowledge gained on hereditary diseases associated with FXI
associated with the congenital deficiency of factor XI and XII             deficiency (also called hemophilia C, plasma thromboplastin
(FXI and FXII) has paved the way to the development of new                 antecedent deficiency, or Rosenthal disease) and FXII deficiency.
anticoagulants directed against these two proteins of the                  FXI deficiency is a rare autosomal condition, with a prevalence
coagulation contact pathway.12-14 This review examines current             of one case per 100,000 people, and a higher frequency (up to 8-
evidence on FXI and FXII inhibitors, focusing on their                     9%) in some ethnic groups including Ashkenazi Jews and Iraqi
pharmacological features and possible therapeutic and                      Jews.23 Unlike the more common X-linked FVIII deficiency
prophylactic potentialities (Table 1).                                     (hemophilia A) or FIX deficiency (hemophilia B), patients with
                                                                           FXI have an only slightly increased risk of bleeding, mostly
                                                                           associated with surgical procedures in tissues with high
Identification of factor XI and XII                                        fibrinolytic activity (e.g., dental surgery, tonsillectomy, and
                                                                           prostate surgery), paired by a reduced risk of thrombosis.24 A study
as possible therapeutic targets                                            of more than 200 patients with FXI deficiency showed a
    FXI (also known as antihemophilic factor C) and FXII (also             significant reduction in the incidence of deep vein thrombosis




                                                                                                      ly
known as Hageman’s factor) are two circulating glycoproteins               (DVT) compared to the general population,25 while in another




                                                                                              on
involved in the contact pathway of coagulation (Figure 1).15 They          study on 115 patients, FXI deficiency was associated with a
are synthesized in the liver and circulate in the blood as inactive        significantly reduced incidence of ischemic stroke,26 but not of
zymogen that can be (auto)activated to FXIa and FXIIa in                   myocardial infarction.26,27 Regarding FXII, studies conducted on




                                                                                        e
response to extracellular nucleic acids, neutrophilic extracellular        familiar clusters of patients with moderate-to-severe FXII
                                                                           deficiency did not show an increase in the risk of bleeding or a
traps, pathogen-associated polyphosphates,16-18 or negatively
charged surfaces coming in contact with the blood, such as
mechanical heart valves and medical devices.19,20 FXIIa is a serine
                                                                                  us
                                                                           reduction in the risk of thrombotic risk.28-30 Conversely, FXII up-
                                                                           regulation has been associated with increased mortality and FXII
                                                                           is known to play a central role in initiating the process of device-
                                                                         al
protease that activates prekallikrein, which in turn stimulates
FXIIa activation via a positive feedback mechanism.21 FXII                 induced thrombosis.19
                                                           ci
                                                         er
                                                        m
                                              om
                                        -c
                                on
                           N




Figure 1. Factors XI and XII in the coagulation cascade.


                                         Bleeding, Thrombosis and Vascular Biology 2023; 2:76
                                            The new era of anticoagulation: factor XI and XII inhibitors                                                       13



Table 1. Pharmacodynamic and pharmacokinetic properties and clinical indications of anti-factor XI and anti-factor XII drugs that have
reached phase 2 or 3 of clinical development.
Compound                       Structure                  Pharmacodynamics                    Pharmacokinetics                Clinical indications
IONIS-FXIRX               2′-O-(2-methoxyethyl)            Inhibits FXI synthesis         Administration: subcutaneous     VTE prevention in surgery;
                     (2′-O-MOE) second-generation                in the liver                Clearance: 3.12 L/hPK                  ESRD
                         antisense oligonucleotide                                        not affected by hemodialysis
Fesomersen                   Triantennary                  Inhibits FXI synthesis         Administration: subcutaneous                 ESRD
                   N-acetyl galactosamine (GalNAc)               in the liver                        (monthly)
                   conjugated 2′-MOE chimeric ASO                                         Delivery: GalNAc conjugation
                                                                                             facilitates drug delivery
                                                                                                to the hepatocytes
                                                                                               Clearance: 12.8 L/h
Osocimab              Fully humanized monoclonal     Binds to a region adjacent     Administration: intravenous            VTE prevention in surgery;
                              G1 antibody        to the active site of FXIa causing Mean time-to-peak plasma                        ESRD
                                                   substantial structural changes     concentrations: 1-4 h
                                                                                        Half-life: 30-44 d
                                                                                     Clearance: 0.13-0.29 L/d




                                                                                                           ly
Abelacimab              Fully human monoclonal         Binds to the catalytic domain       Administration: intravenous     VTE prevention in surgery;
                                antibody                  of factor XI and locks           Mean time-to-peak plasma            atrial fibrillation;




                                                                                                  on
                                                            it in the zymogen                    concentrations:            cancer associated VTE
                                                           (inactive precursor)                    1.75-2.00 h
                                                               conformation                    Half-life: 25-30 d




                                                                                            e
                                                                                           Clearance: 0.006-0.012 L/h
Xisomab 3G3             Recombinant humanized
                              antibody
                                                         Binds to the apple 2 (A2)
                                                          domain of FXI and FXIa
                                                           and inhibits activation
                                                                                    usAdministration: intravenous   ESRD; catheter-related
                                                                                      Mean time-to-peak plasma thrombosis in cancer patients
                                                                                      concentrations: 0.08-1 h for
                                                                          al
                                                            of FXI by FXIIa in a     the 0.1 mg/kg-5 mg/kg doses
                                                          concentration-dependent      Half-life: 1.3 h-121.5 h for
                                                         ci

                                                        manner but does not inhibit the 0.1 mg/kg-5.0 mg/kg dose
                                                       thrombin-mediated activation Clearance: 0.094 - 0.014 L/h
                                                       er


                                                                  of FXI           for the 0.5 mg/kg -5 mg/kg doses
MK-2060                        Monoclonal                Designed to dually block          Administration: intravenous                 ESRD
                                                      m



                                Antibody                    the activation of FXI
                                                        and the downstream activity
                                           om




                                                          of the activated protein
Garadacimab             Fully human recombinant         Binds to the 99-, 140-, 180- Administration: intravenous, Catheter-related thrombosis
                                antibody               and 220- loop on the beta chain          subcutaneous                in cancer patients;
                                    -c




                                                             of activated FXII                Mean time-to-peak                COVID-19;
                                                                                           plasma concentrations:     idiopathic pulmonary fibrosis;
                           on




                                                                                           60 min for intravenous;        hereditary angioedema
                                                                                    7 d for subcutaneous administration.
                                                                                              Half-life: 14-20 d
                     N




                                                                                           Clearance: 5.6-9.8 ml/h
Milvexian                    Small molecule                Active-site, reversible             Administration: oral        VTE prevention in surgery;
                                                          inhibitor of human FXIa          Mean time-to-peak plasma              stroke prevention;
                                                        (high affinity and selectivity,       concentrations: 3-4 h       atrial fibrillation; ACS; ESRD
                                                                Ki 0.11 nM)                    Half-life: 8.3-13.8 h
                                                                                              Clearance: 6.9-17.8%
                                                                                            of the administered dose
                                                                                             is excreted within 24 h
Asundexian                   Small molecule                    Direct, potent,                 Administration: oral               Atrial fibrillation;
                                                          reversible FXIa inhibitor            Mean time-to-peak           stroke prevention; AMI; ESRD
                                                                                             plasma concentrations:
                                                                                          2.50 h in fasting, 5.00 h in fed
                                                                                             Half-life: 14.2 to 17.4 h
SHR2285                      Small molecule                  Selective inhibition             Administration: oral          VTE prevention in surgery
                                                               of human FXIa
EP-7041                      Small molecule                    FXIa antagonist             Administration: intravenous              COVID-19
                                                              (highly selective,             Onset-offset of action:
                                                              IC50 of 7.1 nM)                rapidHalf-life: 45 min
F, factor; VTE, venous thromboembolism; ESRD, end stage renal disease; PK, pharmacokinetics; ACS, acute coronary syndrome; AMI, acute myocardial infarction.



                                               Bleeding, Thrombosis and Vascular Biology 2023; 2:76
14                                                         D. Prisco et al.




                                                                       to develop the more potent, second generation anti-FXI ASO
Factor XI and XII inhibitors:                                          fesomersen (also known as IONIS-FXI-LRX, FXI-LICA, BAY-
pharmacological aspects                                                2976217, ION-957943). Fesomersen requires less frequent
                                                                       administration as compared to the unconjugated molecule (once
and clinical indications                                               a month or less, via subcutaneous route), thus reducing the risk
    The knowledge of the X-ray crystal structure of the FXIa           of drug-related reactions and accounting for a better patient
and FXIIa catalytic domains has enabled the rational                   compliance.
development of several pharmacological classes of FXI and                  Concerning FXII, a recent double-blind, placebo-controlled
FXII inhibitors. These include antisense oligonucleotides              phase 1 trial assessed the safety, tolerability, pharmacokinetics,
(ASOs), monoclonal antibodies, small molecules, natural                and pharmacodynamics of the ASO ION547, in single or
inhibitors, and aptamers (Figure 2).                                   multiple doses, in 48 healthy volunteers, but results are not
                                                                       available yet (NCT04934891). Besides single-strand ASO,
Antisense oligonucleotides                                             double-strand oligonucleotides (siRNAs) have also been
                                                                       developed to inhibit the translation of the mRNA encoding FXII.
and double-strand oligonucleotides                                     Among them, one of the leading compounds is ALN-F12, an
    ASOs are single-strand oligonucleotides that bind to a             oligonucleotide conjugated with N-acetylgalactosamine.32,33
complementary mRNA molecule, thus preventing its translation           However, to date no anti-FXII siRNA has reached the clinical
and deregulating the biosynthesis of the encoded protein. The          phases of development.




                                                                                                 ly
benefits of ASO include high specificity, predictable                      It is worth mentioning that ASOs and siRNAs, being




                                                                                          on
pharmacokinetics and long half-life, and the lack of drug-drug         oligonucleotides, cannot be administered orally; moreover,
interactions. To date, two ASOs directed against the mRNA              because of latency for the onset of their pharmacological action,
coding for FXI (IONIS-FXIRX and fesomersen), and one                   they are more likely to be used for chronic rather than acute




                                                                                    e
directed against the mRNA for FXII (ION547) have reached the           therapeutic indications.
clinical phases of development.
    IONIS-FXIRX (also known as FXI-ASO; BAY2306001,
ISIS-416858) is a 2′-O-(2-methoxyethyl) ASO that binds to the
                                                                              us
                                                                       Clinical indications
                                                                       Thromboprophylaxis in the surgical setting
                                                                     al
mRNA for FXI at hepatic level, thus reducing the plasma
concentrations of FXI in a dose-dependent manner, with a peak              Major orthopedic surgery, in particular total knee
                                                       ci

after 3-4 weeks of treatment and prolonged effect for several          arthroplasty (TKA), is a procedure associated with a high risk
weeks after treatment discontinuation.31 The conjugation of the        of postoperative VTE, in particular of asymptomatic DVT,
                                                     er


anti-FXI IONIS-FXIRX with a N-acetyl galactosamine allowed             which can be easily detected with routine venography.34 Thus,
                                                    m
                                           om
                                      -c
                              on
                         N




Figure 2. Factor XI and XII structure and main inhibitors that have reached phases 2 and 3 of clinical development.


                                       Bleeding, Thrombosis and Vascular Biology 2023; 2:76
                                        The new era of anticoagulation: factor XI and XII inhibitors                                    15



this clinical setting is of great interest when studying the efficacy    osocimab) making them suitable also for acute indications. Also,
and safety of new anticoagulant approaches.                              monoclonal antibodies have a relatively long half-life (around
     An open-label phase 2 study assessed the safety and efficacy        25-44 days), allowing monthly administrations or a single
of the anti-FXI ASO IONIS-FXIRX (200 mg or 300 mg,                       administration in the postoperative setting.39,41,43
administered subcutaneously 7 times prior to TKA, and 2 times
after surgery) as compared to enoxaparin (40 mg/day, from the            Clinical indications
evening before or from the day of surgery and for at least eight
days post-surgery) in 300 patients undergoing elective primary           Thromboprophylaxis in the surgical setting
unilateral TKA (NCT01713361). IONIS-FXIRX 300 mg proved
                                                                              In the FOXTROT trial (NCT03276143), 813 patients
superior to enoxaparin in the prevention of VTE events, assessed
                                                                         undergoing TKA were randomized to intravenous the anti-FXI
by mandatory bilateral venography or symptomatic event
                                                                         osocimab at two pre- or post-operative dosages (0.3 or 1.8 mg/kg,
(P<0.001). As for safety, clinically relevant bleeding events
                                                                         administered the day before surgery; or 0.3-1.8 mg/kg, given the
occurred in 3% of patients on IONIS-FXIRX (200 or 300mg)
                                                                         day after surgery), or to subcutaneous enoxaparin (40 mg/day,
and 8% on enoxaparin.35
                                                                         from the night before or 6-8 hours post-surgery) or oral apixaban
                                                                         (2.5 mg twice daily, starting 12-24 hours post-surgery).
Thromboprophylaxis in patients
                                                                         Enoxaparin or apixaban were continued for at least 10 days or
with chronic kidney disease                                              until venography. The trial results demonstrated that osocimab at




                                                                                           ly
    End-stage renal disease (ESRD) is associated with a                  the preoperative dose of 1.8 mg/kg was superior to enoxaparin,
remarkably high risk of cardio- and cerebro-vascular events,36,37        with a risk difference of 15%,44 and with a good safety profile




                                                                                    on
paired by an increased risk of bleeding during anticoagulation.34        (clinically relevant bleeding events occurred in 4.7% of patients
Moreover, hemodialysis might affect the pharmacokinetics of              on osocimab, 5.9% on enoxaparin and 2% on apixaban).44
drugs, impairing their efficacy and safety profile. Double-blind,             Also, the anti-FXI abelacimab was investigated in an open-




                                                                              e
randomized, controlled trials showed that hemodialysis does not          label phase 2 trial (ANT-005 TKA, EudraCT number
affect pharmacokinetics and tolerability of the anti-FXI ASO
IONIS-FXIRX (200 to 300 mg, subcutaneous), which effectively
                                                                        us
                                                                         2019-003756-37) conducted on 412 patients undergoing elective
                                                                         TKA surgery. The trial showed that abelacimab, at doses of 75
reduced blood clot formation at the circuit level in ESRD patients       and 150 mg, was superior to enoxaparin (40 mg/day) for VTE
                                                                   al
on hemodialysis (NCT02553889; NCT03358030 – EMERALD                      prevention (P<0.001),45 with bleeding events occurring in 0-2%
study).38 Also, the ASO fesomersen has just completed a phase 2          of patients on abelacimab and 0% on heparin.45
                                                    ci

study in patients with ESRD receiving hemodialysis (trial RE-
                                                  er


THINc ESRD for fesomersen, NCT04534114).                                 Thromboprophylaxis in patients
                                                                         with chronic kidney disease
                                                 m



Monoclonal antibodies
                                                                              The anti-FXI monoclonal antibodies osocimab, xisomab
                                       om




    To date, four monoclonal antibodies (osocimab, abelacimab,           3G3 and MK-2060 were tested in phase 2 studies in patients
xisomab 3G3 and MK-2060) against FXI and one against FXII                with ESRD receiving hemodialysis (trials CONVERT
(garadacimab) have reached clinical phases of development.               NCT04523220 and NCT03787368 for osocimab; trial MK-
                                 -c




Osocimab (also known as BAY 1213790) and abelacimab (also                2060-007 NCT05027074 for MK-2060; trial NCT03612856 for
known as MAA868) are fully human monoclonal antibodies.                  xisomab 3G3). To date, available results are limited to the latter
                         on




Osocimab binds to a region adjacent to the active site of FXIa,          trial (NCT03612856) on 24 ESRD patients on chronic
causing structural changes that impair its function,39 whereas           hemodialysis randomized to xisomab 3G3 (0.25 or 0.5 mg/kg)
abelacimab binds the catalytic domain of FXI, blocking it in the         or placebo, administered at the start of a normal hemodialysis
                   N




conformation of an inactive zymogen.40 Xisomab 3G3 (also                 procedure. Results in this clinical setting are promising both in
known as AB023) is instead a recombinant humanized antibody              terms of efficacy and of the safety.46
that binds to the apple 2 (A2) domain of FXI and FXIa, blocking
FXIIa-mediated (but not thrombin-mediated) activation of FXI             Stroke prevention in atrial fibrillation
in a dose-dependent manner.41 A fourth monoclonal antibody
(MK-2060), designed to dually block the activation of FXI as                  Patients with atrial fibrillation are at high risk of
well as the downstream activity of the activated protein, is under       cerebrovascular events, and DOACs are now the standard
clinical evaluation.                                                     therapy for the cerebrovascular prophylaxis in this clinical
    As for FXII, garadacimab (also known as CSL312) is a fully           setting.6 However, the use of DOACs in these patients is
human recombinant antibody that specifically inhibits FXIIa. In          hampered by the residual risk of cardio- and cerebrovascular
phase 1 clinical trials in healthy volunteers of various ethnic          events, on one side, and by the small, but not negligible risk of
groups (NCT04580654, NCT05306275 and ACTRN                               severe intra- and extra-cranial bleeding,47-49 paving the way to
12616001438448), garadacimab (3 and 10 mg/kg, intravenous                the advent of new anticoagulant therapies. A first dose range-
or subcutaneous) induced a sustained inhibition of kallikrein            finding phase 2 trial (ANT-004) assessed the efficacy and safety
activity, with a dose-dependent increase in activated partial            of the anti-FXI abelacimab (120 or 180 mg) as compared to
thromboplastin time and without any change in prothrombin                placebo in patients with atrial fibrillation (NCT04213807).40
time, paired by a good safety and tolerability profile.42                Following the results of this study, the phase 2 AZALEA-TIMI
    It is worth specifying that, compared to ASOs, monoclonal            71 trial (NCT04755283) and the phase 3 LILAC-TIMI 76 trial
antibodies have a much faster onset of action (e.g., 1-4 hours for       (NCT05712200) will enroll 1200 patients with atrial fibrillation


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:76
16                                                              D. Prisco et al.




at moderate-to-high risk of stroke and 1900 high-risk patients,             Small molecules
who have been deemed unsuitable for oral anticoagulation,
respectively, to assess the safety and tolerability of this anti-FXI             Differently from ASOs and monoclonal antibodies, synthetic
in this clinical setting.                                                   molecules have a low molecular weight (max 900 Dalton),
                                                                            which confers them a rapid onset/offset of action and makes
Device-associated thrombosis                                                them suitable for enteral administration. Regarding anti-FXI,
                                                                            four small molecules, milvexian (also known as BMS-986177
    Medical devices, such as catheters used for diagnostic or               or JNJ-70033093), asundexian (BAY 2433334), SHR2285 and
therapeutic procedures, left ventricular assist devices or circuits         EP-7041 have reached clinical phase 2 or 3 of development.
for the extracorporeal membrane oxygenation, are known to be                Milvexian and asundexian are reversible, highly selective
pro-thrombotic surfaces.50 Preclinical evidence indicates that              inhibitors of FXIa and can be administered orally.54,55 From a
upstream inhibition of FXIIa-induced intrinsic coagulation                  pharmacokinetic point of view, they display a rapid peak plasma
pathway is promising for device-induced thromboprophylaxis.50,51            concentration (2-4 hours) and a relatively short half-life (8-16
On these bases, a single-arm phase 2 clinical trial is ongoing to           hours).54-56 Notably, the pharmacokinetics of asundexian has
assess the role of the anti-FXI xisomab 3G3 for the prevention of           been characterized also in patients with impaired hepatic or renal
catheter-related thrombosis in oncological patients receiving               function (NCT0541963, NCT03196206).
chemotherapy (NCT04465760).                                                      SHR2285 is suitable for oral administration, similarly to
    Another phase 2 trial (NCT04281524) was meant to assess                 ONO-7684, while two additional small molecules (EP-7041 and




                                                                                                      ly
the efficacy and safety of the anti-FXII garadacimab as                     BMS-962212) have been developed for intravenous




                                                                                               on
prophylactic antithrombotic treatment in cancer patients with               administration. Indeed, the parenteral use ensures a very rapid
peripherally inserted central venous catheter (PICC; trial                  onset of action (about 45 minutes-2 hours), making them
NCT04281524), however this trial was suspended by decision                  promising therapies for acute clinical uses.54




                                                                                         e
of the pharmaceutical company.                                                   Concerning anti-FXII, various small molecules belonging
                                                                            to the classes of N-acetylated 1H-1,2,4-triazol-5-amines and N-
Thromboprophylaxis in the oncological setting
     Thromboprophylaxis is a relevant challenge in the
                                                                                   us
                                                                            acetylated 1H-pyrazol-3-amines have been developed to inhibit
                                                                            FXIIa in the presence of thrombin and other coagulation
                                                                            factors.57 Notably, in vivo studies have shown not only an
                                                                          al
oncological setting: DOACs are progressively replacing low-                 anticoagulant effect, but also a possible role of these molecules
molecular-weight heparin, but the high risk of bleeding,
                                                            ci

                                                                            in the treatment of immune-mediated pathologies, such as
particularly gastrointestinal, observed in these patients still             autoimmune encephalomyelitis (patent no. WO2017123518) or
                                                          er


represents an unmet medical need that can potentially be                    collagen-induced arthritis (patent no. WO2019108565). Among
overcome with FXI inhibitors.52,53 On these bases, two phase 2              the small molecules directed against FXII molecules there are
                                                         m



trials are evaluating the safety and efficacy of the anti-FXI               also peptidomimetics, a series of (S)-piperazin-2-carboxamides
abelacimab as compared to dalteparin (MAGNOLIA trial,                       characterized by various chemical substitutions, which account
                                               om




NCT05171075) and to apixaban (ASTER trial, NCT05171049)                     for different pharmacokinetic and pharmacodynamic profiles.58
for the prevention of cancer related VTE.
                                                                            Clinical indications
                                         -c




Thromboprophylaxis in patients
with severe COVID-19 infection                                              Thromboprophylaxis in the surgical setting
                                 on




    A phase 2 trial has just been completed on the anti-FXII                    In the AXIOMATIC TKR trial (NCT03891524), 1242
garadacimab in combination with standard therapy for                        patients undergoing elective TKA were randomized to one of
                            N




thromboprophylaxis in 124 patients with severe COVID-19                     seven postoperative regimens of the anti-FXI milvexian (25-200
infection. Preliminary results indicate that tracheal intubation or         mg, once or twice daily orally) or enoxaparin (40 mg/day,
death prior to tracheal intubation occurred in 22.2% and 26.2%              subcutaneously). VTE was reported in 21-8% of patients on
of patients on garadacimab and placebo, respectively, whereas               milvexian 25-200 mg twice daily, respectively, and 25-7% of
all-cause mortality occurred in 17.5% and 18.0% of patients,                those on 25-200 mg once daily, compared to 21% of those
respectively (NCT04409509).                                                 randomized to enoxaparin. Clinically relevant bleeding events
                                                                            occurred in 1% and 2% of patients on milvexian and enoxaparin,
Other indications                                                           respectively.59
                                                                                Also, the anti-FXI small molecule SHR2285 is currently
    Various phase 2 trials assessed the anti-FXII garadacimab               undergoing a phase 2 trial which compares multiple oral
in various clinical setting, including idiopathic pulmonary                 administrations of SHR2285 to enoxaparin in 500 patients
fibrosis (NCT05130970) and the prophylaxis of hereditary                    undergoing elective TKA (NCT05203705).
angioedema (HAE) attacks (NCT03712228; NCT04656418;
NCT04739059). To date, only the first of these trials on HAE is             Stroke prevention, particularly in patients
completed, and the preliminary results coming from 44 patients
                                                                            with atrial fibrillation
indicate that the mean time normalized number of HAE attacks
per month during the first period of treatment ranged between                    In the PACIFIC-AF trial (NCT04218266), 753 patients with
0.05 and 0.48 for the different garadacimab dosages, as                     atrial fibrillation (median age 74 years, CHA2DS2-VASc ≥2 for
compared to 4.24 in the placebo group.                                      men and ≥3 for women) were randomized to the anti-FXI


                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:76
                                      The new era of anticoagulation: factor XI and XII inhibitors                                    17



asundexian (20-50 mg/day, orally) or apixaban (5 mg twice              with aspirin and antiplatelet therapy) was associated with a high
daily, with dose reductions where necessary). After 4 weeks of         risk of major intra- or extra-cranial bleeding.64
treatment, asundexian 20-50 mg accounted for 90-94%                         The phase 2 PACIFIC-AMI trial (NCT04304534) assessed
inhibition of FXIa activity at peak concentration. After 12 weeks      the safety and efficacy of the anti-FXI asundexian for the
of therapy, asundexian proved superior to apixaban for the             secondary prevention of acute myocardial infarction (MI) in 1601
primary safety outcome (clinically relevant major or non-major         patients with recent MI (approximately half of them STEMI),
bleeding), with an incidence proportions ratio of 0.33 (0.09-          randomized within 5 days of hospitalization to asundexian 10, 20
0.97) compared with apixaban.60 The OCEANIC-AF trial is                or 50 mg/day or placebo for 6-12 months, in addition to a dual
ongoing on 18000 patients with atrial fibrillation to investigate      antiplatelet therapy with aspirin and a P2Y12 inhibitor. During a
superiority of asundexian (50 mg, orally) as compared to               median follow-up of 368 days the composite efficacy outcome
apixaban for the prevention of both ischemic and bleeding              (cardiovascular death, recurrent MI, ischemic or hemorrhagic
events in this critical clinical setting (NCT05643573).                stroke, and/or stent thrombosis) occurred in 6.8-5.5% of treated
     In another phase 2 trial (PACIFIC Stroke trial,                   patients on asundexian 10-50 mg, respectively, and in 5.5% of
NCT04304508), more than 1800 patients with acute ischemic              patients on placebo. The composite safety outcome (bleeding type
non-cardioembolic stroke were randomized, within 48 hours              2, 3 or 5, according to the Bleeding Academic Research
from the onset, to asundexian (10 mg, 20 mg, or 50 mg/day,             Consortium, BARC classification) was reported in 7.6-10.5% of
orally) or placebo, in combination with routine antiplatelet           patients on asundexian 10-50 mg, respectively, and in 9.0% of
                                                                       patients on placebo.65 These data support future studies of




                                                                                         ly
therapy. At 26 weeks, the composite outcome of recurrent
symptomatic ischemic stroke and/or occult cerebral infarction          asundexian (50 mg/day) for secondary prevention of MI,




                                                                                  on
detected on follow-up MRI occurred in 19-22% of patients on            including the upcoming phase 3 trial OCEANIC-AMI.
asundexian and 19% on placebo (P=0.80). Major and/or                        Also, milvexian is undergoing a phase 3 placebo-controlled
clinically relevant non-major bleeding events occurred in 3-4%         trial in patients with recent ACS (LIBREXIA-ACS,




                                                                            e
of patients on asundexian, and 2% of patients on placebo.61 This       NCT05754957).
trial is followed by the ongoing phase 3 OCEANIC Stroke trial
on more than 9000 patients (NCT05686070).
     Regarding secondary cerebrovascular prevention, the
                                                                     usThromboprophylaxis in patients
                                                                       with chronic kidney disease
                                                                al
randomized, double-blind phase 2 AXIOMATIC SSP trial
                                                                           The anti-FXI small molecules milvexian and asundexian were
(NCT03766581) included 2366 patients with acute non-
                                                  ci

                                                                       also tested in clinical studies on patients with ESRD receiving
cardioembolic ischemic stroke or high-risk transient ischemic
                                                                       hemodialysis (trials NCT03196206, NCT03000673 for
attack (TIA), randomized within 48 hours of the event, to receive
                                                er


                                                                       milvexian; trial NCT04510987 for asundexian). The results
one of 5 doses of the anti-FXI milvexian (200 mg, 100 mg or
                                                                       available for the trial NCT03000673 showed that a single dose of
50 mg twice daily, or 25 mg or 25 daily) or placebo in
                                               m



                                                                       milvexian (60 mg) was safe and well tolerated also in subjects
combination with traditional antiplatelet therapy (single or dual;
                                                                       with moderate or severe renal impairment, and that the half-life
                                     om




clopidogrel 75 mg/day for the first 21 days and aspirin 100
                                                                       increased from 13.8 h in subjects normal renal function to 18.0 h
mg/day).62 The results, presented at the 2022 Congress of the
                                                                       and 17.7 h in those with moderate or severe renal impairment.66
European Society of Cardiology (ESC), indicate that, for the
                               -c




primary efficacy endpoint (the composite of recurrent stroke or
                                                                       Thromboprophylaxis in patients
asymptomatic cerebral infarction on magnetic resonance
                                                                       with severe COVID-19 infection
                       on




imaging), no dose-response relationship was detected for
milvexian. Milvexian was associated with a lower risk of                   The anti-FXI small molecule EP-7041 is under clinical
symptomatic ischemic stroke (but not of asymptomatic cerebral
                  N




                                                                       evaluation as a thromboprophylactic therapy in COVID-19
infarction) by approximately 30% for all doses except the 200          patients admitted to the intensive care unit (NCT05040776).67
mg twice daily dose, for which no benefit was shown. Major
bleeding events occurred in 0.6% of patients on placebo, 0.6%          Natural inhibitors
on milvexian 25 mg and 1.6% on milvexian 100 mg twice daily.
     The encouraging results of this trial paved the way for the           Alongside synthetic molecules, there are also natural
ongoing phase 3 trials on 15500 patients with atrial fibrillation      inhibitors of FXI and FXII derived from nematodes
randomized to milvexian or apixaban (LIBREXIA-AF,                      (acaNAP10), snakes (fasxiator), bats (desmolaris), ticks
NCT05757869), and on 15000 patients randomized to milvexian            (boofilin and the contact phase inhibitor of Ixodes ricinus, Ir-
or placebo after an acute ischemic stroke or high-risk TIA             CPI), Triatoma infestans (like infestin and the synthetic version
(LIBREXIASTROKE trial, NCT05702034).                                   obtained by the fusion with recombinant human albumin, rHA-
                                                                       infestin-4) and Cucurbita Maxima pumpkin seeds (like
Secondary prevention in patients                                       thermostable inhibitors of contact activation 1, TICA1).68
with acute coronary syndrome                                               Ir-CPI is the only natural inhibitor of both FXI and FXII to
                                                                       have reached clinical trials. It is a serine protease inhibitor
    The standard secondary prophylactic therapy for patients           isolated from the salivary glands of the tick Ixodes Ricinus.69 In
with acute coronary syndrome (ACS) is based on the dual                a phase 1, double-blind, placebo-controlled trial, the
antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor.      pharmacokinetic, pharmacodynamic, safety and tolerability
However, the risk of recurrence in these patients remains high,63      profile of Ir-CPI was investigated in healthy male volunteers
while the use of DOACs (namely rivaroxaban in combination              (NCT04653766).69 Not only exogenous or synthetic natural


                                        Bleeding, Thrombosis and Vascular Biology 2023; 2:76
18                                                               D. Prisco et al.




proteins, but also endogenous macromolecules, including serine                8. Shmyr D, Van der Merwe V, Yakiwchuk E, et al. Triple
protease inhibitors are undergoing preclinical investigation as                  antithrombotic therapy for atrial fibrillation and coronary
potential inhibitors of FXIIa.70                                                 stents. Can Fam Physician 2017;63:375-81.
                                                                              9. Eikelboom JW, Connolly SJ, Brueckmann M, et al.
Aptamers                                                                         Dabigatran versus warfarin in patients with mechanical heart
                                                                                 valves. N Engl J Med 2013;369:1206-14.
     Aptamers are short oligonucleotides of single-strand DNA or             10. Dufrost V, Wahl D, Zuily S. Direct oral anticoagulants in
RNA isolated from complex nucleic acid libraries using an                        antiphospholipid syndrome: meta-analysis of randomized
iterative in vitro selection procedure called systematic evolution               controlled trials. Autoimmun Rev 2021;20:102711.
of ligands by exponential enrichment. Among them, Factor                     11. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European
ELeven Inhibitory APtamer, FELIAP, is an single-strand DNA                       Heart Rhythm Association practical guide on the use of non-
aptamer designed to inhibit the activity of FXIa by binding at or                vitamin K antagonist oral anticoagulants in patients with atrial
near its active site with a high affinity,71 and was considered a lead           fibrillation. Eur Heart J 2018;39:1330-93.
compound for the development of other anti-FXIa aptamers,                    12. Weitz JI, Fredenburgh JC. Factors XI and XII as targets for
including two RNA aptamers (11.16 and 12.7).72 Despite the                       new anticoagulants. Front Med (Lausanne) 2017;4:19.
interest in these molecules, the currently existing aptamers have            13. Kluge KE, Seljeflot I, Arnesen H, Jensen T, et al. Coagulation
important pharmacokinetic limitations, and their renal clearance                 factors XI and XII as possible targets for anticoagulant
makes them unattractive for clinical development.73                              therapy. Thromb Res 2022;214:53-62.




                                                                                                        ly
                                                                             14. Donadini MP, Ageno W. Milvexian and other drugs targeting




                                                                                                on
                                                                                 Factor XI: a new era of anticoagulation? Bleed Thromb Vasc
Conclusions                                                                      Biol 2022;1:22.
                                                                             15. Weidmann H, Heikaus L, Long AT, et al. The plasma contact
     Considerable progresses have been made in the field of




                                                                                          e
                                                                                 system, a protease cascade at the nexus of inflammation,
thromboprophylaxis, particularly with the advent of DOACs.
However, the risk of major bleeding associated with their use
remain a clinically relevant challenge, and some therapeutic
settings (e.g., thromboprophylaxis for mechanical heart valves,
                                                                                    us
                                                                                 coagulation and immunity. Biochim Biophys Acta Mol Cell
                                                                                 Res 2017;1864:2118-27.
                                                                             16. Engel R, Brain CM, Paget J, et al. Single-chain factor XII
                                                                           al
severe renal or hepatic function impairment, or extreme body                     exhibits activity when complexed to polyphosphate. J Thromb
weight) represent unsolved medical needs.                                        Haemost 2014;12:1513-22.
                                                             ci

     Inhibition of the contact coagulation pathway at the level of           17. Smith SA, Choi SH, Davis-Harrison R, et al. Polyphosphate
                                                                                 exerts differential effects on blood clotting, depending on
                                                           er


the FXI or FXII is a new concept in the field of anticoagulation,
to uncouple thrombosis and hemostasis. To date, several phase                    polymer size. Blood 2010;116:4353-9.
                                                                             18. Oehmcke S, Morgelin M, Herwald H. Activation of the
                                                          m



2 and 3 clinical trials have been conducted or initiated on FXI
and (to a lesser extent) FXII inhibitors, possibly paving the way                human contact system on neutrophil extracellular traps. J
                                                om




for their use as primary or secondary thromboprophylactic                        Innate Immun 2009;1:225-30.
treatments in different challenging therapeutic contexts.                    19. Jaffer IH, Fredenburgh JC, Hirsh J, Weitz JI. Medical device-
                                                                                 induced thrombosis: what causes it and how can we prevent
                                                                                 it? J Thromb Haemost 2015;13:S72-81.
                                          -c




                                                                             20. Karthikeyan G, Connolly SJ, Ntsekhe M, et al. The
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                                                                          al
                                                            ci
                                                          er
                                                         m
                                               om
                                         -c
                                  on
                             N




                                          Bleeding, Thrombosis and Vascular Biology 2023; 2:76
