Biotech Values

[iwfal]

ISIS anti-VTE: knocks the ball out of the park in ph ii (but I'd still want to see the details - e.g. bleeds data - before declaring victory. See bottom of post for comments):

Isis Pharmaceuticals Reports Positive Phase 2 Data for ISIS-FXI Rx in the Prevention of Venous Thrombosis in Patients Undergoing Total Knee Replacement Surgery
Seven-fold lower incidence of VTEs in patients treated with ISIS-FXIRx compared to enoxaparin
CARLSBAD, Calif., May 22, 2014 /PRNewswire/ -- Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today positive top-line data from a Phase 2 comparator-controlled study evaluating the incidence of venous thrombolic events (VTE) in patients treated with ISIS-FXIRx undergoing total knee replacement surgery, or total knee arthroplasty (TKA). ISIS-FXIRx inhibits the production of Factor XI, a coagulation factor that plays a key role in thrombosis. In this study with a data cutoff of May 7, 2014, ISIS-FXIRx-treated patients experienced a dose-dependent decrease in VTEs. Patients treated with 300 mg of ISIS-FXIRx experienced a seven-fold (p<0.0001) lower incidence of VTEs compared to patients treated with enoxaparin. Patients treated with 200 mg of ISIS-FXIRx had comparable incidence of VTEs compared to patients treated with enoxaparin. Patients treated with ISIS-FXIRx and enoxaparin experienced a very low rate of bleeding with ISIS-FXIRx-treated patients experiencing numerically fewer bleeding events compared to patients treated with enoxaparin. (Note: this is awkwardly phrased - they did NOT have a combo arm (although I wish they did) so this is just attempting to explain that both enox and FXIRx had very low rate of bleeding by the definition they used) Isis plans to report the full data at an upcoming scientific meeting.

Isis Pharmaceuticals, Inc.
"Thrombosis is the leading cause of morbidity and mortality worldwide. Although warfarin and oral Factor Xa and thrombin inhibitors are effective, there are limitations that preclude their use in a number of indications. In addition, bleeding remains a concern because there are no specific antidotes for the new oral anticoagulants. As such, there remains a significant unmet need for safer and more effective anticoagulants," said Jeffrey Weitz, M.D., professor of medicine and biochemistry, McMaster University, Ontario, Canada. "This study is the first to evaluate a Factor XI lowering strategy in humans and the results validate Factor XI as a novel target for effective antithrombotic therapy. The data show that compared with enoxaparin, ISIS-FXIRx can significantly lower the risk of venous thromboembolism after elective knee replacement surgery. The incidence of venous thromboembolism with ISIS-FXIRx are numerically lower than those observed with new oral anticoagulants in this setting. Therefore, ISIS-FXIRx has the potential to be a best-in-class antithrombotic drug and could be useful in many different therapeutic settings."

"Genetic and preclinical studies clearly suggest that reducing Factor XI should be a more effective means of reducing thrombogenic events than reducing other coagulation factors, and could be associated with very low bleeding risk. In fact, in head-to-head comparisons in animal models, we have shown that inhibiting Factor XI was more effective and produced less bleeding than achieved with warfarin or Factor Xa inhibitors. The results from this Phase 2 study support this attractive profile," said Brett Monia, Ph.D., senior vice president, antisense drug discovery at Isis. "TKA results in a high incidence of VTEs. By evaluating our drug in this therapeutic setting, we have been able to directly compare the activity and safety of ISIS-FXIRx to enoxaparin, a commonly prescribed anticoagulant. These data suggest that ISIS-FXIRx has a low bleeding risk and is a more effective antithrombotic agent than enoxaparin. Given the mechanism of Factor XI inhibition, we believe that this drug could be used broadly to prevent VTE in many different therapeutic settings as well as other therapeutic indications requiring safe and effective thromboprophylaxis. We believe based on this robust data package that ISIS-FXIRx represents a significant licensing opportunity."

The Phase 2 study of ISIS-FXIRx in approximately 300 patients was a global, multi-center, open-label, comparator-controlled study in patients undergoing TKA. The study compared the safety and activity of ISIS-FXIRx to enoxaparin. Patients in the ISIS-FXIRx-treated cohorts received either 200 mg or 300 mg of ISIS-FXIRx for six weeks prior to TKA surgery and a dose six hours and three days after surgery. Patients in the enoxaparin cohort received 40 mg of enoxaparin the evening before TKA surgery, six to eight hours after surgery and daily for at least eight days after surgery. VTEs and bleeding events were evaluated by a blinded independent adjudicated committee.

ISIS-FXIRx was well tolerated in the study. There were no observed differences in safety compared to the enoxaparin group. 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.

Comments:

1) Did they define bleeds oddly that they got such low bleed rate? What were the lesser-bleeds data?

2) With such a strong efficacy they may not need a partner to get to approval. The caveat is the bleeds data above - do the more minor bleeds data also favor drug (vs enox). Do they favor it strongly enough to keep small trials?