WSC 2025 | An update on studies investigating Factor XIa inhibitors for secondary stroke prevention

This was a general overview of the current status of ongoing randomized trials testing Factor XIa inhibitors for stroke prevention in patients with non-cardioembolic ischemic stroke or high-risk TIA. This really comes on the heels of a lot of work that over a decade that has led us to this critical junction where we’re soon to see some of the results of these trials. Really, the initial observation that got people excited about Factor XI as a target for stroke prevention was that in patients who have inherent Factor XI deficiency or hemophilia C, the rates of ischemic stroke and venous thromboembolism are much less than what we see in the general population. And at the same time, we do not see an excess risk of spontaneous major bleeding in this population. And these kind of early clinical observations in this rare type of hemophilia have led to subsequent studies testing this concept of our ability to potentially uncouple pathologic thrombus formation versus hemostasis and that are we able to reduce ischemic events without increasing major bleeding. Through animal studies which were demonstrating consistent results and then subsequent Mendelian randomization studies looking at genetic polymorphisms that affect Factor XI levels and their association with ischemic events and major bleeding events, again replicating kind of the initial experiment of nature, which was hemophilia C. So now there’s several molecules that are being tested in various disease conditions. Those include antisense oligonucleotides, monoclonal antibodies, and then there’s two oral direct Factor XIa inhibitors that are being tested, and that’s asundexian and milvexian. And both of those are being tested now for secondary stroke prevention in patients with non-cardioembolic ischemic stroke or high-risk TIA. There was two phase 2 studies that were dose-finding trials or phase 2B trials that led us to this point. One was PACIFIC-Stroke that I led with my colleagues Bob Hart and Stuart Connolly and then the AXIOMATIC-SSP study that tested milvexian. That was led by my other colleague Mike Sharma. And the overall kind of results of those trials were also very consistent in that both studies, their primary endpoint was covert brain infarction and symptomatic ischemic stroke as a composite. These Factor XIa inhibitors did not seem to have an effect on the covert brain infarction component of that primary endpoint. Covert brain infarction being infarcts that you just see on imaging that don’t have any associated symptoms. Yet when you look at symptomatic events, ischemic stroke, there does seem to be a trend for dose-dependent reduction with these agents. And in our study, PACIFIC-Stroke, when we looked at the exploratory endpoint of ischemic stroke and TIA as a composite, we did find dose-dependent reductions that were significant. And the highest effect size was in patients that had some degree of atherosclerosis on vascular imaging. It didn’t have to be stenotic atherosclerotic disease. It didn’t have to be symptomatic atherosclerotic disease, but just some degree of atherosclerotic disease in their vessels. And that population, the effect size that was significant with the highest dose of asundexian, 50 milligrams daily versus placebo, was a 60% relative risk reduction, which is quite robust. Importantly, these drugs were being tested against placebo on top of background antiplatelet treatment, and we did not see any excess risk of major bleeding in this population, right? So again, kind of supporting the hypothesis of our ability to uncouple pathologic thrombus formation from hemostasis. Now, of course, these were phase two studies. These were some suggestive findings that now need to be validated, and this is where the ongoing phase three trials come into play, and that’s OCEANIC-STROKE. I’m leading with Mike Sharma as co-PI and that’s at McMaster University and then our colleagues Graeme Hankey and Clay Johnston are leading the LIBREXIA-STROK trial. These trials are testing either asundexian 50 milligrams daily or milvexian 25 milligrams twice daily versus placebo on top of background antiplatelet therapy in patients who have non-cardioembolic ischemic stroke or high-risk TIA. And there are some enrichment criteria towards having some degree of atherosclerotic disease in a majority of patients that get into the trial. Again, that should not be confused with only those with large artery atherosclerosis who have stenotic symptomatic disease, but rather some degree of atherosclerosis in their vessels throughout the body. And OCEANIC-STROKE, we’re very happy to say that we were able to complete enrollment of 12,300 patients. We’re just over that. A large global initiative, a massive thanks to all our investigators around the world. This study occurred at 38 countries, over 700 sites, representation from all the way from East Asia to Europe and the Americas. And we have a really large global representative population of patients with non-cardioembolic ischemic stroke and high-risk TIA, to which we could then validate, hopefully, what we saw in phase two. And we’re hoping to share those results at the end of this year and present them formally at a major conference next year.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.