Final data from a phase 2 comparator-controlled study evaluating the incidence of venous thromboembolic events ( VTE ) in patients treated with ISIS-FXI Rx undergoing total knee replacement surgery, or total knee arthroplasty ( TKA ) were published in The New England Journal of Medicine ( NEJM ) and were presented at the 56th American Society of Hematology meeting.
ISIS-FXI Rx is designed to reduce the production of Factor XI, a coagulation factor that plays a key role in thrombosis.
Although Warfarin ( Coumadin ) 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. Consequently, there remains a significant unmet need for safer and more effective anticoagulants.
Because Factor XI is involved in the propagation of clots, but not in their initiation, researchers at McMaster University ( Ontario, Canada ) have hypothesized 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.
In the study, researchers have reported that ISIS-FXI Rx-treated patients experienced a dose-dependent decrease in venous thromboembolic events. Patients treated with 300 mg of ISIS-FXI Rx experienced a seven-fold lower rate of venous thromboembolism as compared with those treated with Enoxaparin ( Clexane, Lovenox ) ( 4.2% and 30.4%, respectively; p less than 0.001 ).
Patients treated with 200 mg of ISIS-FXI Rx had a rate of venous thromboembolism comparable to that in patients treated with Enoxaparin ( 26.9% and 30.4%, respectively ). The rate of venous thromboembolism in patients given Enoxaparin was 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 thromboembolism.
The rate of bleeding was low with ISIS-FXI Rx and Enoxaparin.
This study is the first to evaluate a Factor XI lowering therapeutic strategy in patients and the results validate Factor XI as a novel target for antithrombotic therapy.
These data have shown that ISIS-FXIRx significantly lowered the risk of venous thromboembolism following a highly thromboembolic event, elective knee replacement surgery. The rate of venous thromboembolism with ISIS-FXI Rx in this phase 2 study is lower than that observed in the previous studies with the new oral anticoagulants in this surgical setting.
These data suggest that ISIS-FXI Rx could be useful in many different therapeutic settings, including patients at high-risk for thrombosis and high risk of bleeding.
The phase 2 study of ISIS-FXI Rx in 293 patients undergoing TKA was a global, multicenter, open-label, comparator-controlled study comparing ISIS-FXI Rx with Enoxaparin.
Patients in the ISIS-FXI Rx-treated groups received either 200 mg or 300 mg of ISIS-FXI Rx for six weeks prior to TKA surgery and six hours and three days after surgery.
Patients in the Enoxaparin group received 40 mg of Enoxaparin the evening before surgery, and once daily thereafter for at least eight days.
All patients underwent mandatory bilateral venography to detect deep vein thrombosis.
In this study, ISIS-FXI Rx was well tolerated. There were no observed differences in safety outcomes compared with Enoxaparin. In particular, there were no flu-like symptoms, and injection site reactions were infrequent and mild.
There have been no drug-related serious adverse events reported to date. ( Xagena )
Source: Isis Pharmaceuticals, 2014