Pharmacology and Clinical Development of Factor XI Inhibitors.

Therapeutic anticoagulation is indicated for a variety of circumstances and conditions in several fields of medicine to prevent or treat venous and arterial thromboembolism. According to the different mechanisms of action, the available parenteral and oral anticoagulant drugs share the common principle of hampering or blocking key steps of the coagulation cascade, which unavoidably comes at the price of an increased propensity to bleed. Hemorrhagic complications affect patient prognosis both directly and indirectly (ie, by preventing the adoption of an effective antithrombotic strategy). Inhibition of factor XI (FXI) has emerged as a strategy with the potential to uncouple the pharmacological effect and the adverse events of anticoagulant therapy. This observation is based on the differential contribution of FXI to thrombus amplification, in which it plays a major role, and hemostasis, in which it plays an ancillary role in final clot consolidation. Several agents were developed to inhibit FXI at different stages (ie, suppressing biosynthesis, preventing zymogen activation, or impeding the biological action of the active form), including antisense oligonucleotides, monoclonal antibodies, small synthetic molecules, natural peptides, and aptamers. Phase 2 studies of different classes of FXI inhibitors in orthopedic surgery suggested that dose-dependent reductions in thrombotic complications are not paralleled by dose-dependent increases in bleeding compared with low-molecular-weight heparin. Likewise, the FXI inhibitor asundexian was associated with lower rates of bleeding compared with the activated factor X inhibitor apixaban in patients with atrial fibrillation, although no evidence of a therapeutic effect on stroke prevention is available so far. FXI inhibition could also be appealing for patients with other conditions, including end-stage renal disease, noncardioembolic stroke, or acute myocardial infarction, for which other phase 2 studies have been conducted. The balance between thromboprophylaxis and bleeding achieved by FXI inhibitors needs confirmation in large-scale phase 3 clinical trials powered for clinical end points. Several of such trials are ongoing or planned to define the role of FXI inhibitors in clinical practice and to clarify which FXI inhibitor may be most suited for each clinical indication. This article reviews the rationale, pharmacology, results of medium or small phase 2 studies, and future perspectives of drugs inhibiting FXI.

Coagulation factors XI and XII as possible targets for anticoagulant therapy.

In this review, we give an overview over observational and experimental studies supporting factors XI and XII as targets for anticoagulant therapy. The majority of observational studies on FXI report low concentrations of FXI to be protective against ischemic stroke and venous thrombosis. There is also extensive evidence from experimental and animal studies supporting FXI inhibition as a target for anticoagulant therapy, alone or in combination with other antithrombotic treatments. Four Phase 2 clinical trials on patients undergoing total knee arthroplasty showed non-inferiority or superiority of FXI inhibition compared to enoxaparin for the primary outcome, which was incidence of venous thromboembolism. One Phase 2 trial reported that FXI inhibition is associated with fewer bleeding events than apixaban. The results from observational studies on FXII are more conflicting. Some show that low FXII concentrations confer protection against thrombosis, while others have found it to be deleterious. Results from experimental studies are inconclusive, but suggest that FXII inhibition might be useful in preventing thrombosis caused by foreign objects like catheters or mechanical heart valves. One Phase 2 study not conducted on thrombosis has reported FXII inhibition as safe. In conclusion, FXI seems to be a promising target for antithrombotic therapy, both alone and in combination with existing therapies, while the potential of targeting FXII is still unclear.

Abelacimab for Prevention of Venous Thromboembolism.

BACKGROUND: The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation. METHODS: In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery. RESULTS: Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group. CONCLUSIONS: This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding. (Funded by Anthos Therapeutics; ANT-005 TKA EudraCT number, 2019-003756-37.).

The rebirth of the contact pathway: a new therapeutic target.

PURPOSE OF REVIEW: Anticoagulation with vitamin-K antagonists or direct oral anticoagulants is associated with a significant risk of bleeding. There is a major effort underway to develop antithrombotic drugs that have a smaller impact on hemostasis. The plasma contact proteins factor XI (FXI) and factor XII (FXII) have drawn considerable interest because they contribute to thrombosis but have limited roles in hemostasis. Here, we discuss results of preclinical and clinical trials supporting the hypothesis that the contact system contributes to thromboembolic disease. RECENT FINDINGS: Numerous compounds targeting FXI or FXII have shown antithrombotic properties in preclinical studies. In phase 2 studies, drugs-targeting FXI or its protease form FXIa compared favorably with standard care for venous thrombosis prophylaxis in patients undergoing knee replacement. While less work has been done with FXII inhibitors, they may be particularly useful for limiting thrombosis in situations where blood comes into contact with artificial surfaces of medical devices. SUMMARY: Inhibitors of contact activation, and particularly of FXI, are showing promise for prevention of thromboembolic disease. Larger studies are required to establish their efficacy, and to establish that they are safer than current therapy from a bleeding standpoint.