WSC 2025 | The existing evidence for Factor XIa inhibition in secondary stroke prevention: Phase II trials

So, you know, I’ve talked about the genetic deficiency syndrome in the background. Mendelian randomization studies also correlate Factor XI levels with the risk of stroke. The higher the level, the higher the risk of stroke. And again, we don’t see severe bleeding with lower levels. In animals, when you inhibit Factor XI, the thrombi that are generated are smaller, more fragile, less likely to occlude blood vessels. And this happens in spite of no change in the bleeding time in animals or in people. This happens with Factor XI inhibitors on top of antiplatelet agents. We are currently at a time point where we have a number of Phase II dose-finding and early safety trials in Factor XI. In stroke specifically, there are two. There is AXIOMATIC with milvexian, which is a small molecule inhibitor of activated Factor XI, and PACIFIC-STROKE with asundexian, also a small molecule inhibitor. Now, the two designs were complementary. In AXIOMATIC, the patients that were randomized all had atherosclerosis. Even though it was mild, it had to be ipsilateral. There, the primary endpoint was a combination of MRI-defined infarcts and symptomatic stroke. We did not see a dose response with milvexian for that combined endpoint because the MRI-defined infarcts were not affected by treatment. What we did see was a signal of efficacy. Every dose in milvexian was associated with fewer symptomatic strokes than placebo, with the exception of the highest dose. In PACIFIC-STROKE, which used asundexian as a treatment, again, with a composite endpoint, no effect on the MRI infarct. However, with a 50 milligram dose, a signal of efficacy for symptomatic stroke, which seemed to be augmented in patients who had atherosclerosis. Now in that trial, I have to emphasize that the atherosclerosis just had to be present. It didn’t have to be severe or causative. In fact, it didn’t even have to be on the same side as the stroke. It just had to be present. So those studies really led to the development of the Phase III trials which we’re now conducting, LIBREXIA with milvexian and OCEANIC-STROKE with asundexian. OCEANIC-STROKE, we presented the design and baseline data this morning, so they’re now publicly available, and that trial we expect to have a closed locked data set before the end of the year.

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