Isis commences ISIS-FXIRx Phase 2 study in knee replacement surgery patients

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Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced the initiation of a Phase 2 comparator-controlled study evaluating ISIS-FXIRx in patients undergoing knee replacement surgery, also referred to as total knee arthroplasty (TKA).  ISIS-FXIRx inhibits the production of Factor XI, a coagulation factor produced in the liver that is involved in the formation of clots.  In this study, Isis will evaluate the effectiveness of ISIS-FXIRx in reducing the number of thrombotic events in patients after TKA without increasing bleeding.  The combination of robust anti-thrombotic activity with an improved safety profile to currently available anticoagulants could be broadly useful in many therapeutic settings where thrombosis is a serious problem. 

"Although there are a number of anti-coagulants on the market today that are considered standard-of-care in multiple therapeutic settings, complications of bleeding associated with these medications remain high and can lead to fatal outcomes," said Harry Buller, Ph.D., M.D., professor of medicine at Academic Medical Center in Netherlands.  "Factor XI is an exciting target because it plays a key role in the formation of clots but inhibiting it does not cause bleeding.  Humans who are deficient in Factor XI tend to have a lower incidence of stroke and venous thrombosis with no evidence of spontaneous bleeding episodes."

The Phase 2 study is a global, multi-center, open-label, comparator-controlled study in up to 400 patients who are undergoing TKA.  The study will compare ISIS-FXIRx safety and activity to enoxaparin, a commonly used anti-coagulant.  In a Phase 1 study in healthy volunteers, ISIS-FXIRx produced robust dose-dependent, statistically significant reduction of greater than 80 percent in Factor XI activity with no bleeding events observed. 

"ISIS-FXIRx is one of many maturing drugs in our pipeline and represents the broad applicability of our technology to develop novel drugs for many different diseases.  We believe that the safety profile observed thus far coupled with the robust activity we have seen for ISIS-FXIRx in both our Phase 1 study and preclinically, suggest that this drug could have a significant benefit for patients at risk of a thrombotic event.  Given the mechanism of Factor XI inhibition, we believe that the drug could be used broadly to prevent deep vein thrombosis or pulmonary embolism in many different therapeutic settings, including stroke, myocardial infarction and with surgeries such as knee or hip replacement, where additional safe and effective anti-thrombotic drugs are needed.  Our earlier work suggests that ISIS-FXIRx could be used in combination with existing therapies," said Sanjay Bhanot, M.D., Ph.D., vice president, clinical development and translational medicine at Isis. 

"TKA is one of the leading surgeries performed worldwide each year and is associated with a high incidence of venous thromboembolism," said Brett Monia, Ph.D., senior vice president, antisense drug discovery at Isis.  "By evaluating our drug in these patients, we will be able to directly compare the activity and safety of ISIS-FXIRx to a commonly prescribed anti-coagulant, enoxaparin.  With this proof-of-value data in hand, we believe that we will have a robust and comprehensive data package representing a significant licensing opportunity for us."

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