Isis Pharmaceuticals has announced final data from its phase II comparator-controlled study evaluating the incidence of venous thromboembolic events in patients treated with ISIS-FXI(Rx) undergoing total knee arthroplasty. ISIS-FXI(Rx) is designed to reduce the production of Factor XI, a coagulation factor that plays a key role in thrombosis. The data were published in The New England Journal of Medicine and will be presented at the 56th American Society of Hematology meeting as a late-breaking oral presentation on 9 December 2014.
“Thrombosis is the leading cause of morbidity and mortality worldwide. Although warfarin and oral Factor Xa and thrombin inhibitors are effective, they have limitations that restrict or prevent their use in several indications. Furthermore, despite the benefit of existing anticoagulants, there is a risk of bleeding when they are administered in therapeutic doses,” said Jeffrey Weitz, professor of medicine and biochemistry, McMaster University, Ontario, Canada.
“Because Factor XI is involved in the propagation of clots, but not in their initiation, we hypothesised that reducing Factor XI activity would decrease the risk of deep vein thrombosis after knee replacement surgery without increasing the risk of bleeding. This concept is supported by evidence from patients with congenital Factor XI deficiency; such patients are at reduced risk for venous thrombosis and do not suffer from spontaneous bleeding. The results of this study are important for two reasons. First, these results support the important biological role that Factor XI plays in the development of blood clots after surgery. Second, the results showed that lowering the levels of Factor XI with ISIS-FXI(Rx) was associated with a reduction in clotting without increasing the risk of bleeding. Therefore, for the first time, we have results that dissociate the antithrombotic effect from bleeding risk.”
In the paper and presentation titled: “Factor XI antisense oligonucleotide for prevention of venous thrombosis”, the authors report that ISIS-FXI(Rx)-treated patients experienced a dose-dependent decrease in venous thromboembolic events. Patients treated with 300mg of ISIS-FXI(Rx) experienced a seven-fold lower rate of venous thromboembolic events as compared with those treated with enoxaparin (4.2% and 30.4%, respectively; p<0.001). Patients treated with 200mg of ISIS-FXI(Rx) had a rate of venous thromboembolic events comparable to that in patients treated with enoxaparin (26.9% and 30.4%, respectively). The rate of venous thromboembolic events in patients given enoxaparin is within the range documented in previous studies in this therapeutic setting. ISIS-FXI(Rx) treatment was associated with a dose-dependent and sustained reduction in Factor XI activity that correlated with the lower rate of venous thromboembolic events. The rate of bleeding was low with ISIS-FXI(Rx) and enoxaparin.
“These data show that ISIS-FXI(Rx) significantly lowered the risk of venous thromboembolism following a highly thromboembolic event, elective knee replacement surgery. The rate of venous thromboembolic events with ISIS-FXI(Rx) in this phase II study is lower than that observed in the previous studies with the new oral anticoagulants in this surgical setting,” said Harry Buller, professor of medicine, department of vascular medicine academic medical centre in Amsterdam, Netherlands.
“By evaluating our drug in this therapeutic setting, we were able to directly compare ISIS-FXI(Rx) with enoxaparin, a commonly prescribed anticoagulant. In this study, the lower incidence of thromboembolic events with ISIS-FXI(Rx) compared with enoxaparin, combined with the low rate of bleeding, support the concept that ISIS-FXI(Rx) has the potential to provide a breakthrough therapeutic opportunity for the treatment of thrombosis. By reducing Factor XI activity, we believe that ISIS-FXI(Rx) could be used to prevent thrombosis in many different therapeutic settings,” said Sanjay Bhanot, vice president, clinical development and translational medicine at Isis Pharmaceuticals.