Pharmacology and Clinical Development of Factor XI Inhibitors

Abstract

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.

Factor XI Inhibition With Heparin Reduces Clot Formation in Simulated Pediatric Extracorporeal Membrane Oxygenation

“…30 Several phase 2 studies of different classes of FXI inhibitors in orthopedic surgery and atrial fibrillation suggested that dose-dependent reductions in thrombotic complications are not accompanied with increases in bleeding compared with low-molecular-weight heparin. 31 This is especially important compared to previous anticoagulants on ECMO that have had complications with cerebral bleeding. 32 In a murine sepsis model, knocking out or pharmacological targeting of FXI produced a strong anti-inflammatory response and limited overwhelming coagulation factor consumption, also known as disseminated intravascular coagulation.…”

Factor XI as a therapeutic target in neuroinflammatory disease

“…Yet, although mechanistically promising, the translation of direct inhibition of thrombin or FXa generation as a treatment option for multiple sclerosis is hampered by the bleeding side effects of these targets [50]. By way of reducing feedback activation of FXI or activity of FXIIa, FXI inhibitors have emerged as a promising strategy to reduce the propagation of thrombin generation and inflammation without compromising hemostasis [51 ▪▪ ,52]. Based on the success of several small to medium phase 2 clinical studies [53], FXI inhibitors may represent a useful strategy for treatment of thromboinflammatory and neurocoagulant diseases, including multiple sclerosis.…”

Atrial fibrillation: mechanism and clinical management

“…[48] In recent years, there has been promising research on Factor XI inhibitors, which have the potential to reduce bleeding risks and enhance the safety of current OACs. [49] These drugs are anticipated to accumulate more clinical data, become available on the market soon, and offer a higher quality and more efficient treatment option for AF patients. Some patients are unable to use anticoagulants due to contraindications.…”