Will OCEANIC-AF Sink Factor XI Inhibitors?

Cardiologists Michelle O'Donoghue and Manesh Patel discuss the disappointing findings for the factor XIa inhibitor asundexian from the OCEANIC-AF trial presented at ESC.
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-- TRANSCRIPT --
Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. I'm here at the European Society of Cardiology (ESC) Congress in London, and one of the more hotly anticipated presentations is that of OCEANIC-AF. This is a trial of factor XI inhibition in patients with atrial fibrillation.
Joining me to discuss the results is Dr Manesh Patel. He is division chief at Duke Department of Medicine. Thanks for joining me, Manesh.
Manesh R. Patel, MD: Thanks for having me.
The Holy Grail of Anticoagulation
O'Donoghue: Let's start by talking about the theory behind factor XI inhibition.
Patel: Our hope always is the holy grail of trying to get to stopping clots and not bleeding, or what we've discussed as uncoupling thrombosis from hemostasis.
The history of our practice here in the coagulation cascade is for conditions like atrial fibrillation; we used warfarin, which affected many spots along the coagulation cascade. The good news is it certainly stopped clots, but there's a lot of bleeding. There were significant advances, I'll say, with direct thrombin or factor X inhibitors, like edoxaban, rivaroxaban, and apixaban, that inhibited that and improved it.
There are a few types of factor XI inhibitors. OCEANIC-AF used something called asundexian, a small molecule affecting factor XIa inhibition - so activated factor XI. What happens in the coagulation cascade is you have a common pathway, and then you have a contact pathway, which is thrombin amplification.
The idea is that if you inhibit factor XI, you might still have some normal hemostasis and clot formation that you need to stop bleeding, but you would stop the propagation of thrombus to get to that pathologic thrombus. That was the biologic concept. I often say it's our understanding of the current cartoon of thrombosis and hemostasis, but it's an important biologic process. That was the hope.
O'Donoghue: As you say, in many ways, this has been the holy grail because the direct-acting oral anticoagulants (DOACs) were, of course, a big advance in the field of atrial fibrillation, anticoagulation management, and anticoagulation in general. Bleeding is still a significant concern, and certainly gastrointestinal (GI) bleeding has been one of those.
The appeal of this class has been that idea that potentially you could have your cake and eat it too - that you could prevent clot formation without having the excess in bleeding.
Patel: Yeah, that's right. That's the way almost all of our antithrombotic steps forward have been. If warfarin was leading to more bleeding, then the DOACs actually beat warfarin by leading to fewer strokes in atrial fibrillation, but much of it was hemorrhagic stroke and less bleeding.
The concept for factor XIa inhibition with asundexian was first done in healthy volunteers, but then it was studied in some phase 2 studies to get ready for the atrial fibrillation study.
The phase 2 studies included PACIFIC-AF, where we aimed to understand how it looked in relation to apixaban in patients with atrial fibrillation. PACIFIC-AF was a short-term study looking at bleeding with two doses of asundexian, 20 mg and 50 mg, and looking at a factor XI activity assay to say, did you inhibit factor XI activity as you intended a nd then was there a difference in bleeding compared with apixaban?
What was previously presented and published with PACIFIC-AF showed that at trough, about 92% of factor XI activity was inhibited with the 50-mg dose, and a little less with the 20-mg dose. Overall, bleeding was significantly less than with apixaban. The 50-mg dose was chosen to go into a large phase 3 study that we have to do to see if we can reduce stroke, systemic embolism, and the combination of that benefit for bleeding.
O'Donoghue: I think you're highlighting the real challenge, which is about dose selection, ultimately, for a pathway that is not yet tested in terms of knowing its clinical efficacy.
As you said, you had the factor XIa activity data, suggesting 92% inhibition of XIa at trough, as well as 94% at peak?
Patel: Yeah. The thinking is that we've got a reasonably high inhibition. There wasn't a huge amount of difference, and then the idea that there's significantly less bleeding. Not only is dose selection important, we were trying to do it in a population that we would be testing against a comparator that we thought we would be using in phase 3.
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