The contact activation inhibitor AB023 in heparin-free hemodialysis: results of a randomized phase 2 clinical trial

Abstract

End-stage renal disease (ESRD) patients on chronic hemodialysis have repeated blood exposure to artificial surfaces that can trigger clot formation within the hemodialysis circuit. Dialyzer clotting can lead to anemia despite erythropoietin and iron supplementation. Unfractionated heparin prevents clotting during hemodialysis, but it is not tolerated by all patients. Although heparin-free dialysis is performed, intradialytic blood entrapment can be problematic. To address this issue, we performed a randomized, double-blind, phase 2 study comparing AB023, a unique antibody that binds factor (F) XI and blocks its activation by factor XIIa but not by thrombin, to placebo in 24 patients with ESRD undergoing heparin-free hemodialysis (www.clinicaltrials.gov #NCT03612856). Patients were randomized to receive a single pre-dialysis dose of AB023 (0.25 or 0.5 mg/kg) or placebo in a 2:1 ratio and safety and preliminary efficacy were compared to placebo and to observations made prior to dosing within each treatment arm. AB023 administration was not associated with impaired hemostasis or other drug-related adverse events. Occlusive events requiring hemodialysis circuit exchange were less frequent and levels of thrombin-antithrombin complexes and C-reactive protein were lower after AB023 administration compared with data collected prior to dosing. AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer.

A proposal for managing bleeding in patients on therapeutic factor XI(a) inhibitors

“…Indeed, IONIS-FXI Rx and osocimab administered preoperatively did not produce an obvious detrimental effect on hemostasis during or after TKA. 16,17 AB023 was given to patients with end-stage kidney disease on chronic hemodialysis 47 and reduced clot formation on dialyzer membranes without increasing bleeding.…”

“…Several compounds that reduce FXI activity for days to weeks have been tested in phase 2 trials (Table 2). They include an antisense oligonucleotide (IONIS‐FXI Rx or BAY2306001) that decreases plasma FXI protein by specifically reducing FXI synthesis in the liver, 16 antibodies (AB023 47 and abelacimab 18 ) that bind zymogen FXI and interfere with its activation and activity, and an antibody (osocimab) that inhibits the FXIa active site 17 . IONIS‐FXI Rx , osocimab, and abelacimab were comparable or superior to standard‐dose enoxaparin for preventing deep vein thrombosis in patients undergoing TKA.…”

Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence

“…Four of these studies on FXI inhibition have already been completed, in which clinically relevant bleeding was determined as the primary safety endpoint by combining major bleeding and clinically relevant non-major bleeding ( 85 – 88 ). The second type of FXI inhibitor studies focused on patients with end-stage kidney disease on hemodialysis ( 89 , 90 ). High risk of bleeding and thrombosis provoked by the extracorporeal device makes them the prime target for potentially safer anticoagulants inhibiting the intrinsic pathway.…”

“…This phenomenon of a short half-life at lower doses is likely due to the rapid binding of a large proportion of free xisomab 3G3 to FXI ( 93 ). Xisomab 3G3 was tested in a randomized controlled trial of 24 patients with end-stage kidney disease in need of heparin-free hemodialysis ( 90 ). Patients were randomized to 0.25, 0.5 mg/kg xisomab 3G3, or placebo injected as a single bolus into the dialysis line proximal to the dialyzer at the start of hemodialysis.…”

Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis

“…23 The human analog of 14E11, 3G3/AB023, has been shown to provide efficacy in reducing incidence of device-associated thrombosis in patients undergoing chronic hemodialysis. 5 Importantly, in humans and non-human primates, the mechanism of action of 3G3/AB023 appears to be inhibition of FXI activation by FXIIa as opposed to depletion or reduction of FXI levels. Therefore, the results presented in this study may be more mechanistically related to clinical trials investigating the FXI antisense oligonucleotide ISIS 416858, whose mechanism of action is reduction of FXI levels.…”