Factor XI Data by ISIS Pharmaceuticals Revolutionizes Anti-Clotting Field

Yesterday, ISIS Pharmaceuticals disclosed in-depth data from their phase II anti-clotting study in about 300 patients undergoing total knee arthroplasty (TKA).  This took place at the American Society of Hematology (ASH) meeting alongside a publication in the New England Journal of Medicine (Bueller et al. 2014).  The data for the first time provide striking evidence that it is possible to dissociate anti-clotting activity from a commensurate increase in the risk of bleeding.

Accordingly, while the 200mg per week dose (moderate 59% FXI knockdown) achieved a rate of venous thromboembolism (VTE) similar to the enoxaparin standard-of-care comparator in the trial (27% and 30%, respectively), at the 300mg per week dose (much more robust 78% FXI knockdown) the VTE rate dropped by 7-fold to just 4%.  

At the same time, bleeding risk remained the same, if not better for ISIS-FXIRx vs enoxaparin: 3% bleeding events for both FXI cohorts vs 8% for enoxaparin, albeit this was not a statistically significant difference.

In terms of safety and tolerability, ISIS-FXIRx resulted in mild local skin reactions in 6.6% of the injections, but leading to no discontinuations.  Moreoever, no flu-like symptoms were recorded.  This is a stark departure from ISIS’ legacy drug mipomersen which suffered from frequent flu-like symptoms and injection site reactions resulting in relatively frequent drug discontinuations.

Challenging the paradigm

Until now, it has been widely thought that whenever you develop a new, more powerful anticoagulant, you will pay the price of more bleeding.  This has meant not only much development money wasted, but also created important market needs such as in patients which require anticoagulants with lower bleeding risks.

It is these markets, including patients with end-stage renal disease and atrial fibrillation, that ISIS Pharmaceuticals will address first as it seeks a partner more familiar with the complexities of the anti-clotting market.

What seems to underlie the surprising results is that with Factor XI you are targeting the intrinsic branch of the clotting cascade which prevents the formation of large clots that may travel around the body often with fatal consequences, but without impeding the ability to form small clots when healing tissue damage following trauma caused by external factors. 

By contrast, conventional anticoagulants such as enoxaparin (a heparin derivative), Factor Xa and thrombin inhibitors interfere with both processes.

Challenging the establishment

The strategy of addressing niches of high unmet need in the anticlotting market first is not only explained by potentially faster orphan-type development timelines, but also by the fact that by presenting such disruptive data in a multi-billion market, ISIS can be expected to encounter stiff resistance from the anti-clotting establishment.  This refers not only to competing pharmaceutical companies, but also their associated key opinion leaders from academia that enjoy a gate-keeper function partly due to the regulators commonly seeking their advice.   

So given that the efficacy results are undoubtedly impressive, expect over the coming days, months, if not years to hear the message that the ISIS-FXIRx data ‘might’ be a proof-of-principle for dissociating clotting from bleeding for anticoagulant therapy, but that this 300-patient study needs to be replicated in a larger population and that there are ‘concerns’ around the tolerability and convenience of ISIS-FXIRx, all the while the same groups are busy catching up developing antibody- and small molecule-based versions of anti-Factor XI drugs.