Isis Pharmaceuticals, announced final data from its phase 2 comparator-controlled study evaluating the incidence of venous thromboembolic events (VTE) in patients treated with ISIS-FXIRx undergoing total knee replacement surgery, or total knee arthroplasty (TKA).  ISIS-FXIRx is designed to reduce the production of Factor XI, a coagulation factor that plays a key role in thrombosis.  These data were published in The New England Journal of Medicine and will be presented at the 56th American Society of Hematology (ASH) meeting as a late-breaking oral presentation on December 9, 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.  Consequently, there remains a significant unmet need for safer and more effective anticoagulants," said Jeffrey Weitz, MD, 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 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-FXIRx 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-FXIRx-treated patients experienced a dose-dependent decrease in venous thromboembolic events.  Patients treated with 300 mg of ISIS-FXIRx experienced a seven-fold lower rate of VTE as compared with those treated with enoxaparin (4.2 per cent and 30.4 per cent, respectively; p<0.001).  Patients treated with 200 mg of ISIS-FXIRx had a rate  of VTE comparable to that in patients treated with enoxaparin (26.9 per cent and 30.4 per cent, respectively).  The rate of VTE in patients given enoxaparin is within the range documented in previous studies in this therapeutic setting.  ISIS-FXIRx treatment was associated with a dose-dependent and sustained reduction in Factor XI activity that correlated with the lower rate of VTE.  The rate of bleeding was low with ISIS-FXIRx 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 show that ISIS-FXIRx significantly lowered the risk of venous thromboembolism following a highly thromboembolic event, elective knee replacement surgery.  The rate of VTE with ISIS-FXIRx 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-FXIRx has the potential to be a best-in-class antithrombotic drug and could be useful in many different therapeutic settings, including patients at high-risk for thrombosis and high risk of bleeding" said Harry Buller, MDprofessor of medicine, department of vascular medicine academic medical centre in Amsterdam, Netherlands.

"TKA is associated with a high incidence of postoperative VTE.  By evaluating our drug in this therapeutic setting, we were able to directly compare ISIS-FXIRx with enoxaparin, a commonly prescribed anticoagulant.  In this study, the lower incidence of thromboembolic events with ISIS-FXIRx compared with enoxaparin, combined with the low rate of bleeding, support the concept that ISIS-FXIRx has the potential to provide a breakthrough therapeutic opportunity for the treatment of thrombosis.  By reducing Factor XI activity, we believe that ISIS-FXIRx could be used to prevent thrombosis in many different therapeutic settings" said Sanjay Bhanot, MD.vice president, clinical development and translational medicine at Isis Pharmaceuticals.  "Given the limitations of currently prescribed anticoagulants, there are many patients who need a safer anticoagulant.  We plan to conduct additional phase 2 studies in patients with the greatest unmet needs, including patients with atrial fibrillation who also have end-stage renal disease.  These patients are at the highest risk of stroke, but because the risk of bleeding in these patients is so high, they are rarely prescribed anticoagulants. ISIS-FXIRx has the potential to change this."

"Our plan is to bring in a partner for later-stage development and commercialisation of this programme. We have already had considerable interest from potential partners," said Lynne Parshall, chief operating officer at Isis Pharmaceuticals. "Our goal is to identify a partner who has experience with development and commercialisation of drugs in this therapeutic area; one who can help us optimise the opportunities this drug represents."

The phase 2 study of ISIS-FXIRx in 293 patients undergoing TKA was a global, multi-centre, open-label, comparator-controlled study comparing ISIS-FXIRx with enoxaparin.  Patients in the ISIS-FXIRx-treated groups received either 200 mg or 300 mg of ISIS-FXIRx 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. Venograms and suspected bleeding events were evaluated by a blinded independent adjudication committee.

In this study, ISIS-FXIRx 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.

The phase 2 study was published ahead of print and on-line in The New England Journal of Medicine on Sunday, December 7, 2014.