Factor XI antagonists: the discovery of the philosopher's stone?

The widely held belief that thrombosis and bleeding are the opposite sides of the same coin has been challenged by research on factor XI ( FXI) inhibition. The role of FXI within the coagulation pathway is primarily supportive: it is responsible for thrombus growth and stabilization by amplifying thrombin formation and enhancing clot resistance to fibrinolysis, but it is not essential for clot formation in response to tissue injury ( Fig. 1 ) . Inhibition of FXI may thus prevent pathological thrombus propagation without interfering with normal haemostasis. Several oral and parenteral FXI/XIa inhibitors have completed phase 2 studies in different settings and fulfilled the promise of low bleeding complications ( Table 1 ) . Phase 3 trials in cancer-associated thrombosis ( NCT05171049, NCT05171075) and stroke ( NCT0586070) are on-going. One phase 3 trial in atrial fibrillation ( AF) was interrupted prematurely for inferior efficacy versus apixaban [1 ]. A drug that could effectively reduce the rate of thrombotic events without simultaneously increasing the risk of bleeding would be particularly useful in patients with end-stage kidney disease ( ESKD) , a population characterized by a high burden of cardiovascular disease as well as a severely elevated bleeding risk. The CONVERT trial is a multinational phase 2b randomized, double-blind

The widely held belief that thrombosis and bleeding are the opposite sides of the same coin has been challenged by research on factor XI ( FXI) inhibition.The role of FXI within the coagulation pathway is primarily supportive: it is responsible for thrombus growth and stabilization by amplifying thrombin formation and enhancing clot resistance to fibrinolysis, but it is not essential for clot formation in response to tissue injury ( Fig. 1 ) .Inhibition of FXI may thus prevent pathological thrombus propagation without interfering with normal haemostasis.Several oral and parenteral FXI/XIa inhibitors have completed phase 2 studies in different settings and fulfilled the promise of low bleeding complications ( Table 1 ) .Phase 3 trials in cancer-associated thrombosis ( NCT05171049, NCT05171075) and stroke ( NCT0586070) are ongoing.One phase 3 trial in atrial fibrillation ( AF) was interrupted prematurely for inferior efficacy versus apixaban [1 ].
A drug that could effectively reduce the rate of thrombotic events without simultaneously increasing the risk of bleeding would be particularly useful in patients with end-stage kidney disease ( ESKD) , a population characterized by a high burden of cardiovascular disease as well as a severely elevated bleeding risk.The CONVERT trial is a multinational phase 2b randomized, double-blind, placebo-controlled trial examining the inhibitory FXIa antibody osocimab in 704 patients with kidney failure undergoing haemodialysis ( HD) [2 ].While patients with a pre-existing high bleeding risk were excluded, the incidence of clinically relevant bleeding was comparable in the lower-and higher-dose osocimab and placebo groups [2 ].Another phase 2 study of the FXI inhibitor fesomersen also revealed a bleeding risk similar to that of placebo [3 ], thus confirming the safety profile of FXI inhibition in ESKD.However, the challenge remains to demonstrate that FXI inhibition can fulfil the unmet needs in HD, including prevention of stroke in AF, reduction of adverse cardiovascular events and inhibition of clotting induced by foreign surfaces.
The conundrum of oral anticoagulation for stroke prevention in HD remains largely unresolved [4 ].While non-vitamin K antagonist anticoagulants ( NOACs) have a superior benefitrisk profile compared with vitamin K antagonists, their bleeding complication rate remains undeniably high and superior efficacy versus no anticoagulation has not been unequivocally Figure 1: FXI is part of the intrinsic/contact pathway of coagulation and is activated by FXIIa.Its activation is enhanced by thrombin ( FIIa) , as part of a feedback loop.There are three main types of FXI inhibitors: antisense oligonucleotides that bind to FXI mRNA and catalyse its degradation, thus reducing the synthesis of FXI in the liver; monoclonal antibodies that bind to FXI and block its activation by FXIIa; and monoclonal antibodies or small molecules that bind and inhibit FXIa.*Abelacimab inhibits both FXI and FXIa.**Ir-CPI ( Ixodes ricinus contact phase inhibitor) inhibits both FXIa and FXIIa.demonstrated in ESKD.The CONVERT trial included patients with AF who were not considered candidates for therapeutic anticoagulation by their treating physician but was not designed to test the ability of osocimab to reduce the risk of thromboembolic events in AF.
An increasing body of evidence supports a role of NOACs in the prevention of cardiovascular disease beyond their anticoagulant properties [5 ].The ongoing TRACK trial ( NCT03969953) is investigating whether low-dose rivaroxaban may prevent cardiovascular events in patients with advanced CKD.Whether FXI inhibitors attenuate the inflammatory processes involved in atherosclerosis progression is unclear.In the CONVERT trial, the incidence of major adverse vascular events, a prespecified exploratory outcome, was too low to draw meaningful conclusions.Likewise, the rate of arteriovenous fistula or graft thrombosis was low and not significantly different between the groups.However, osocimab significantly reduced dialysis circuit clotting compared with placebo [2 ].Similarly, another FXI inhibitor, AB023, reduced dialyzer clotting during heparin-free HD [6 ].
Taken together, the CONVERT trial demonstrates that FXI inhibition is a promising strategy to provide safe anticoagulation in ESKD.Other phase 2 trials are currently ongoing ( Table 1 ) .However, before we call out the discovery of the philosopher's stone with the power to cure all ailments in ESKD, large efficacy trials need to be conducted in this notoriously difficult population.