Investigational anticoagulants

INTRODUCTION — Anticoagulants in clinical use have advantages and disadvantages related to their efficacy profile, safety, route of administration, drug interactions, and cost. All available anticoagulants increase bleeding to some degree. Strategies for developing safer and more effective anticoagulants continue to be pursued.

Development of new anticoagulants often starts with dose-finding studies in patients undergoing elective knee arthroplasty; efficacy can be objectively and efficiently assessed in such patients using venography to determine the rate of deep vein thrombosis after surgery. Such information can then be used to inform dosing for other therapeutic indications.

This topic discusses anticoagulants at later stages of development for clinical use. Approved anticoagulants are discussed in separate topic reviews.

●Parenteral

•Heparins – (See "Heparin and LMW heparin: Dosing and adverse effects".)

•Fondaparinux – (See "Fondaparinux: Dosing and adverse effects".)

•Argatroban and bivalirudin – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Parenteral direct thrombin inhibitors'.)

●Oral

•Vitamin K antagonists – (See "Warfarin and other VKAs: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control".)

•Dabigatran – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Dabigatran'.)

•Factor Xa inhibitors – (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors'.)

INHIBITORS OF FACTOR XI OR FACTOR XIa — Factor XI is part of the intrinsic pathway of the clotting cascade; the activated form (factor XIa) participates in the amplification of thrombin generation (figure 1). (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Individuals with hereditary factor XI deficiency have a lower risk of venous thromboembolism (VTE) or ischemic stroke than individuals with normal factor XI levels but rarely have spontaneous bleeding. (See "Factor XI (eleven) deficiency".)

It has been hypothesized that inhibition of factor XI/XIa, by blocking the amplification of thrombin generation, might uncouple thrombosis prevention from normal hemostasis, allowing maximal anticoagulation without incurring more bleeding risk.

Milvexian — Milvexian is an orally active, potent and specific small molecule inhibitor of factor XIa [1,2]. In a trial that randomly assigned 1242 individuals ≥50 years who were undergoing knee arthroplasty to receive one of several doses/schedules of milvexian versus low molecular weight (LMW) heparin (enoxaparin 40 mg once daily) for 10 to 14 days postoperatively, participants assigned to milvexian had lower rates of VTE [3]. All participants underwent mandatory unilateral venography on the operated leg 10 to 14 days after surgery.

●Efficacy – There was a dose-dependent reduction in postoperative VTE rates with once or twice daily milvexian:

•Milvexian, 25 mg once daily – 25 percent

•Milvexian, 25 mg twice daily – 21 percent

•Milvexian, 50 mg twice daily – 11 percent

•Milvexian, 100 mg twice daily – 9 percent

•Milvexian, 200 mg once daily – 7 percent

•Milvexian, 200 mg twice daily – 8 percent

•Enoxaparin, 40 mg once daily – 21 percent

●Safety – Bleeding rates (a composite of major, clinically relevant nonmajor, and minor bleeding) were similar (4 percent with milvexian and 4 percent with enoxaparin). Major bleeding occurred in one individual in the enoxaparin arm and none in the milvexian arm. Rates of clinically relevant bleeding (a composite of major and clinically relevant nonmajor bleeding) were 0.8 percent with milvexian and 1.7 percent with enoxaparin. There was no dose-dependent increase in the rate of clinically relevant bleeding over a 16-fold range of milvexian doses.

Asundexian — Asundexian is an orally active, potent, and specific small molecule inhibitor of factor XIa [4-6]. In a trial that randomly assigned 753 individuals with atrial fibrillation (mean age, 74 years; nearly one-third had chronic kidney disease) to receive asundexian (20 or 50 mg once daily) or the factor Xa inhibitor apixaban (5 mg twice daily) for 12 weeks, participants assigned to asundexian had similar or lower rates of clinical bleeding compared with those assigned to apixaban [7].

●Efficacy – Efficacy for stroke prevention was not a primary endpoint during this short observation period. Rates of a composite endpoint of cardiovascular death, myocardial infarction, stroke, or embolism were:

•Asundexian 20 mg once daily – 0.8 percent

•Asundexian 50 mg once daily – 1.5 percent

•Apixaban 5 mg twice daily – 1.2 percent

●Safety – There were no episodes of major bleeding. Clinically relevant nonmajor bleeding rates were as follows:

•Asundexian 20 mg once daily – 1.2 percent

•Asundexian 50 mg once daily – 0.4 percent

•Apixaban 5 mg twice daily – 2.4 percent

A randomized trial of asundexian 20 or 50 mg in 1601 individuals with acute myocardial infarction assigned to secondary prevention with asundexian or placebo found similar rates of stroke, cardiovascular events, and stent thrombosis with asundexian and placebo and no increase in bleeding with asundexian [8]. Nearly all participants underwent percutaneous intervention and all received dual antiplatelet therapy. A randomized trial of asundexian in 1808 individuals with prior ischemic (non-embolic) stroke showed no difference in stroke incidence or bleeding (risk of covert brain infarct or recurrent stroke in approximately 19 percent of individuals assigned to asundexian and placebo [9]).

Abelacimab — Abelacimab (MAA868) is a monoclonal antibody that binds to factor XI (the inactive precursor) and locks it in the inactive state, preventing it from being activated by factor XIIa or thrombin. A trial involving 412 individuals undergoing knee arthroplasty evaluated three doses of abelacimab (30, 75, or 150 mg) administered postoperatively as a single intravenous infusion versus subcutaneous enoxaparin, 40 mg once daily [10]. Patients could receive a single preoperative dose of enoxaparin. All participants underwent postoperative venography for VTE evaluation. There was a lower rate of VTE with all doses of abelacimab than with enoxaparin.

●Efficacy – Postoperative VTE rates were as follows:

•Abelacimab, 30 mg – 13 percent

•Abelacimab, 75 mg – 5 percent

•Abelacimab, 150 mg – 4 percent

•Enoxaparin, 40 mg – 22 percent

●Safety – The risk of clinically relevant bleeding (the composite of major and clinically relevant nonmajor bleeding) was low (2, 2, and 0 percent of patients in the 30, 75, and 150 mg abelacimab cohorts, and in 0 percent of those treated with enoxaparin).

Osocimab — Osocimab (BAY 1213790) is a monoclonal antibody that binds adjacent to the active site of factor XIa and prevents it from activating factor IX (allosteric inhibition) [11]. The half-life of osocimab is 30 to 44 days, allowing single-dose administration for surgical prophylaxis. It is administered as an intravenous infusion over one hour.

A trial evaluated dose-finding, timing of administration, and comparison with other anticoagulants (enoxaparin and apixaban) in 813 adults undergoing elective knee arthroplasty [12]. Individuals were randomly assigned to receive one of several weight-based doses of osocimab, some preoperatively and some postoperatively, or to receive enoxaparin (40 mg subcutaneously twice daily started the evening before surgery or 12 to 24 hours postoperatively) or apixaban (2.5 mg orally twice per day starting 12 to 24 hours postoperatively).

●Efficacy – The risk of VTE (symptomatic or identified by mandatory screening venography) was lowest in individuals who received the highest osocimab dose (1.8 mg/kg), given preoperatively (11.3 percent), followed by apixaban (14.5 percent). VTE rates were 26.3 percent with enoxaparin and 15.7 to 17.9 with various doses of osocimab given postoperatively. In all the arms, most of the VTE events were asymptomatic; symptomatic VTE occurred in 0 to 2 percent of participants.

●Safety – The risk of major bleeding was 1 to 5 percent with osocimab (depending on dose and timing), 6 percent with enoxaparin, and 2 percent with apixaban. All bleeding events were surgical site bleeding; there were no instances of intracranial or other critical sites of bleeding. Thrombocytopenia was seen in 6 percent of the osocimab and enoxaparin-treated patients and 2 percent of the apixaban-treated patients.

Fesomersen — Fesomersen is a ligand conjugated factor XI antisense oligonucleotide (ASO) that blocks synthesis of factor XI in the liver, thereby reducing the circulating levels of factor XI [13].

In an open-label trial, 300 patients undergoing elective knee replacement were randomly assigned to receive the first generation, nonligand conjugated ASO at one of two doses (200 or 300 mg) or enoxaparin (40 mg) once daily [14]. The rate of VTE, assessed by venography in all patients, was reduced in those receiving the higher dose of ASO (3 of 71 patients; 4 percent), compared with the lower dose of ASO (27 percent) or enoxaparin (30 percent). Bleeding was not increased with the higher ASO dose (3 percent), versus 3 percent for ASO 200 mg and 8 percent for enoxaparin (figure 1).

There are caveats for this strategy including the extended half-life of the antisense therapy (up to three months), injection site reactions, and potential cost [15]. Fesomersen, the second-generation ligand-conjugated antisense oligonucleotide, has increased potency, thereby reducing the required volume of injection and the risk of injection site reactions, and likely decreasing cost.

AB023 — ABO23 is a monoclonal antibody that binds to factor XI and prevents its activation by factor XIIa, thus acting as a factor XIIa inhibitor [16]. By leaving intact the activation of factor XI by thrombin, this agent may allow better separation of thrombosis from hemostasis.

Sulfated chiro-inositol — Sulfated chiro-inositol (SCI) is a synthetic heparin-like molecule that binds to factor XIa and alters its conformation, thereby reducing its enzymatic activity (allosteric inhibition) [17]. Preclinical testing suggests that this molecule could be effective as an anticoagulant and could be reversed by protamine sulfate.

INHIBITORS OF OTHER CLOTTING PROTEINS — Other coagulation proteins involved in thrombosis are amenable to inhibition. (See "Overview of hemostasis".)

Although many agents have been investigated, none have moved forward into advanced stages of development.

TF/factor VIIa inhibitors — Vascular injury causes exposure of tissue factor (TF). TF binds activated factor VII (factor VIIa) and promote activation of factor X; this is the extrinsic pathway of the clotting cascade. (See "Overview of hemostasis", section on 'Extrinsic pathway'.)

Inhibitors of the TF pathway could potentially be developed as anticoagulants.

Conversely, natural inhibitors of the TF pathway, such as tissue factor pathway inhibitor (TFPI), antithrombin, and activated protein C, could potentially render the TF pathway more active. Approaches that take advantage of these steps in the clotting cascade are under investigation as "rebalancing therapies" to reduce bleeding risk in people with hemophilia. (See "Overview of hemostasis", section on 'Control mechanisms and termination of clotting' and "Gene therapy and other investigational approaches for hemophilia", section on 'Reducing natural anticoagulants'.)

Recombinant TFPI and anti-TF antibodies — Tissue factor pathway inhibitor (TFPI) is the physiologic inhibitor of the TF-FVIIa complex. Recombinant TFPI, anti-TF monoclonal antibodies, and peptide inhibitors of TF were investigated as anticoagulants, but development of these agents has stopped [18,19].

Nematode anticoagulant peptide-2 (NAPc2) — NAPc2 is a peptide produced by a hookworm nematode; it blocks the TF-factor VIIa complex. Recombinant NAPc2 is a potential anticoagulant [20-22].

Factor VIII inhibitor — Factor VIIIa acts as a nonenzymatic cofactor for factor IXa in activating factor X (the "intrinsic tenase" complex). (See "Overview of hemostasis", section on 'Multicomponent complexes'.)

TB-402 is a human IgG4 monoclonal antibody that partially inhibits factor VIII. The long half-life (approximately three weeks) suggested that the therapy might be effective as a single dose.

In a randomized phase II trial in patients after total knee replacement, a single postoperative intravenous dose of TB-402 was more effective than the low molecular weight (LMW) heparin enoxaparin (40 mg/day for at least 10 days) in preventing postoperative venous thromboembolism (VTE) [23]. However, bleeding rates with TB-402 were higher than with enoxaparin (major or clinically relevant nonmajor bleeding, 4.0, 5.4, and 8.0 percent with 0.3, 0.6, and 1.2 mg/kg of TB-402 compared with 3.8 percent with enoxaparin). Consequently, further development of TB-402 was halted.

Thrombomodulin — Thrombomodulin is a membrane protein that acts as a cofactor for thrombin in activating protein C [24].

A recombinant form of the extracellular domain of thrombomodulin was developed as an anticoagulant (ART-123) and has been approved in Japan for treatment of disseminated intravascular coagulation (DIC). It has a half-life of two to three days after a subcutaneous injection, such that it can be given once every five to six days with maintenance of anticoagulant activity [25]. In a phase II trial, ART-123 was effective for VTE prophylaxis following total hip replacement [26]. However, ART-123 has not progressed further for prevention or treatment of VTE.

Factor IXa inhibitor — REG1 consists of pegnivacogin (RB006), an injectable ribonucleic acid (RNA) aptamer that specifically binds and inhibits factor IXa, and anivamersen (RB007), the complementary oligonucleotide that neutralizes its anti-IXa activity when needed (ie, as an antidote).

Initial tests of this agent combined with antiplatelet therapy in patients with coronary artery disease appeared promising [27,28]. However, a randomized trial comparing REG1 with bivalirudin in patients undergoing percutaneous coronary intervention (PCI) was terminated early due to severe allergic reactions (including fatal reactions) with REG1 in 10 of 1616 patients (1 percent), compared with 1 of 1616 patients (0.1 percent) given bivalirudin [29]. Consequently, further development of REG1 was halted.

Factor XIIa inhibitor — Factor XIIa is the initial enzyme in the intrinsic pathway of the coagulation cascade. (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Infestin-4 is a factor XIIa inhibitor produced by a blood-feeding insect. Recombinant Infestin-4 fused to albumin (rHA-Infestin-4) is highly active as an anticoagulant in preclinical studies (human plasma and animal models) [30]. rHA-Infestin-4 is being considered for prevention and treatment of acute ischemic cardiovascular and cerebrovascular events.

Protein disulfide isomerase inhibitors — Protein disulfide isomerase (PDI) is an oxidoreductase enzyme that catalyzes redox protein folding in newly synthesized proteins in the endoplasmic reticulum, including coagulation factor XI and tissue factor. PDI is expressed on the surface of several cell types, including platelets, where it promotes platelet aggregation via integrin activation [31]. (See "Overview of hemostasis", section on 'Platelet secretion'.)

PDI inhibitors have the potential to attenuate thrombin generation and platelet activation. Several molecules inhibit PDI, including quercetins, which are found in certain plant-based foods. Preclinical studies using a peptide inhibitor of PDI have demonstrated antiplatelet activity in vitro [32]. In a phase 2 trial in patients with cancer who were at risk for VTE, isoquercetin (1000 mg daily, but not 500 mg) decreased plasma D-dimer levels by 22 percent [33].

Polyphosphate inhibitors — Polyphosphate (released from platelets upon their activation or from a microbial source) may initiate and/or accelerate coagulation via the intrinsic pathway. Compounds that inhibit polyphosphate and reduce thrombosis in preclinical models are under investigation [34].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY

●Factor XI/XIa inhibitors – Factor XI is part of the intrinsic pathway of the clotting cascade; activated factor XI (factor XIa) participates in amplifying thrombin generation (figure 1). It has been hypothesized that inhibition of factor XI/XIa might uncouple thrombosis prevention from normal hemostasis, allowing maximal anticoagulation without increasing bleeding risk. (See "Overview of hemostasis", section on 'Intrinsic or contact activation pathway'.)

Several factor XI or XIa inhibitors are under development, including small molecules (ending in "xian") and monoclonal antibodies (ending in "mab") and an antisense oligonucleotide (fesomersen):

•Milvexian – (See 'Milvexian' above.)

•Asundexian – (See 'Asundexian' above.)

•Abelacimab – (See 'Abelacimab' above.)

•Osocimab – (See 'Osocimab' above.)

•Fesomersen – (See 'Fesomersen' above.)

●TF-factor VIIa inhibitors – Vascular injury causes tissue factor (TF) exposure. TF binds activated factor VII (factor VIIa) and promotes activation of factor X; this is the extrinsic pathway of the clotting cascade. (See "Overview of hemostasis", section on 'Extrinsic pathway'.)

Inhibitors of the TF-factor VIIa pathway are being explored, including recombinant tissue factor pathway inhibitor (TFPI) and peptides derived from nematodes:

•Recombinant TFPI – (See 'Recombinant TFPI and anti-TF antibodies' above.)

•Nematode anticoagulant peptide-2 (NAPc2) – (See 'Nematode anticoagulant peptide-2 (NAPc2)' above.)

●Earlier stages of development – Inhibitors of thrombomodulin, factor XIIa, and protein disulfide isomerase (PDI) are under development. (See 'Thrombomodulin' above and 'Factor XIIa inhibitor' above and 'Protein disulfide isomerase inhibitors' above.)

●Development halted – Development of some anticoagulants has been halted due to increased bleeding (factor VIII inhibitor) or excessive adverse effects (anaphylaxis with factor IXa inhibitor REG1). (See 'Factor VIII inhibitor' above and 'Factor IXa inhibitor' above.)