Two new factor XI inhibitors (FXI) developed for the secondary prevention of stroke have «yielded somewhat disappointing results» in recent studies, according to Prof. Matthias Endres from the Department of Neurology at the Charité Hospital in Berlin at Neurowoche 2022.
Background
Inhibition of blood clotting with FXI as a promising target for secondary prevention of Stroke.People who produce less FXI due to their genetic make-up are less likely to suffer a stroke. However, intracranial hemorrhages are not more frequently observed under such FXI deficiency. New data are now available for the substances milvexian and asundexian, both of which start early in the intrinsic pathway of the blood coagulation cascade and should thus have similar effects as congenital FXI poverty.
Results
- In a cohort of more than 500 stroke patients at Charité, there was a significantly lower risk of recurrence for the>75 percentile compared to patients with higher factor XI activity.
- Milvexian is a small and specific inhibitor of FXIa that is rapidly absorbed orally and has limited potential for drug side effects. It is being evaluated in addition to and at escalating doses in the double-blind, randomized, placebo-controlled AXIOMATIC-SSP study, which will continue until the end of 2022 and included 2366 stroke patients with evidence of atherothrombosis.The primary endpoint was the combination of visible cerebral infarctions and re-cerebral infarctions detected by MRI up to day 90. However, there was no difference between placebo (16.6%) and doses between 25 mg and 200 mg (14.1 – 18.5%). «If you just look at symptomatic ischemic strokes, you get the impression that the rate with Milvexian is lower up to 100 mg. Quite surprisingly, however, this effect is not comprehensible at the highest dose,» says Endres. Simple bleeding («not actionable») was less common under the medication, in severe and fatal bleeding there were no differences.
- Results for another FXI – Asundexian – were published recently published. In a very similar design, the double-blind, randomized, placebo-controlled Phase 2b PACIFIC-Stroke study included patients with lacunar cerebral infarction. Again, there were no differences in the primary (combined) endpoint, but there was a trend towards better outcomes under medication when ischemic stroke was considered alone.The risk of bleeding was slightly higher than in the AXIOMATIC study, but the difference (possibly due to small numbers of cases) was also not significant.
- Both Milvexian and Asundexian will now enter longer-term Phase 3 trials. Their results are expected around 2027.
Funding: Bristol Myers Squibb and Janssen Research & Development, LLC.; Bavarian.
Conflicts of interest: Prof. Endres is a member of the steering committee of the AXIOMATIC-SSP study.
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Source — https://www.univadis.de/viewarticle/neurowoche-2022—faktor-xi-inhibition-zur-schlaganfall-sekundarpravention-etwas-enttauschend