Key Points
- Selective XIa inhibitor Milvexian may innovate the field of oral anticoagulation by uncoupling hemostasis from thrombosis and potentially providing protection from ischemic events with reduced bleeding risk among patients with acute non-lacunar stroke.
- The Phase 2 AXIOMATIC-SSP trial (n=2,366) compared 5 doses of Milvexian (25 mg once daily, or 25, 50, 100, 200 mg twice daily) against placebo daily for 90 days among patients within 48 hours from acute non-lacunar stroke or TIA. Milvexian was not found to have a statistically significant dose-response in the reduction of the primary outcome (clinical ischemic stroke during treatment or infarct identified on brain MRI at 90 days), though Milvexian at the doses of 50 mg and 100 mg twice daily did result in numerically lower event rates, compared to placebo. BARC 3 or 5 rates were similar to placebo with most doses of Milvexian compared to placebo, with numerically higher bleeding rates with Milvexian 200 mg twice daily.
During the 2022 European Society of Cardiology Conference in Barcelona, novel factor XIa inhibitors took center stage as a series of Phase 2 randomized trials explored their safety and efficacy in very common ischemic conditions, ranging from acute myocardial infarction to acute stroke. Two of these agents, Milvexian and Asundexian, have emerged from promising Phase I trials and have now both been tested among patients with acute ischemic strokes. This represent a population with high risk of ischemic events, as their risk of stroke recurrence is >5% per year with current guideline-recommended antiplatelet therapy – which also introduces a risk of bleeding and hemorrhagic stroke conversion. No anticoagulants are currently approved for non-cardioembolic stroke prevention in this population, and therefore it would be particularly beneficial to identify a targeted way to provide additional ischemic protection to these patients.
Selective factor XIa inhibition is an innovative principle that acts in a more targeted fashion compared to the other DOACs that are already available on the market. Specifically, DOAC-mediated Factor Xa inhibition prevents the formation of pathological thrombi, but also blocks the tissue factor pathway, which in turns may prevent the formation of thrombin-mediated “beneficial clots” that are needed in routine homeostasis of blood vessels around the body. This status quo, however, could be revolutionized with selective Factor XIa inhibition, which would be capable of preventing the formation of pathological thrombi while still allowing activation of the tissue factor pathway and thus the formation of “beneficial clots”.
As such, during the 2022 European Society of Cardiology Conference in Barcelona, Dr. Mukul Sharma presented the results of the AXIOMATIC-SSP trial (NCT03766581). This multicenter, prospective, randomized, placebo-controlled, double-blind, study is the largest dose-finding trial of an anticoagulant in a stroke population to date, as it randomized 2,366 patients within 48 hours from acute non-lacunar stroke (or TIA with high risk of subsequent stroke, defined by ABCD2 score ≥6) with documented evidence of atherosclerosis in the vessel feeding the affected brain area (per baseline MRI). Patients were randomized them to one of five doses of Milvexian (25 mg once daily, or 25, 50, 100, 200 mg twice daily) or placebo daily for 90 days. Importantly, in every arm this was on top of dual antiplatelet therapy with aspirin and clopidogrel for 21 days, followed by aspirin alone from day 21-90. Patients were elderly (mean age 71 years), with ~35% female. Notably, patients had to have NIHSS score <7 to be eligible to enroll in the trial, as this was used as a surrogate to indicate a small-moderate size infarction; patients were given the first dose of the study drug within an average of 35 hours from index event.
The primary efficacy endpoint was a composite of clinical ischemic stroke during treatment or infarct identified on brain MRI at 90 days. In the intention-to-treat population, Milvexian was not found to have a statistically significant dose-response in the reduction of the primary outcome, compared to placebo, though Milvexian at the doses of 50 mg and 100 mg twice daily did result in numerically lower event rates compared to placebo (16.2% with 25 mg once daily, 18.5% with 25 mg twice daily, 16.4% with 200 mg twice daily, and 16.6% with placebo, versus 14.1% with 100 mg twice daily and 14.7% with 100 mg twice daily). Similarly, most doses of Milvexian (except 200 mg twice daily) were found to cause numerically lower rates of clinical ischemic stroke, with an approximate 30% relative risk reduction compared to placebo (namely, 4.6% with 25 mg once daily, 3.8% with 25 mg twice daily, 4.0% with 50 mg twice daily, and 3.5% 100 mg twice daily versus 5.5% on placebo, while 200 mg twice daily had a higher stroke event rate of 7.7%).
The primary safety endpoint was BARC type 3 or 5 bleeding, which was similar to placebo with lower doses of Milvexian (25 mg once daily and 25 mg twice daily), while it was higher than placebo in higher doses like 50 mg twice daily and above, though no dose-response in the bleeding risk was established. Reassuringly, the majority of the bleeds were gastrointestinal, with no increase in severe, intracranial or fatal bleeding. Other serious adverse events were similar to placebo, again with some numerically higher events in the Milvexian 200 mg twice a day dosing.
During the same Hotline session in Barcelona, results from the Phase 2 PACIFIC-STROKE trial were also presented, where the other factor XIa inhibitor Asundexian was compared to placebo (on top of antiplatelet therapy) among patients suffering from acute non-cardioembolic stroke (n=1,808). Overall, the three doses of Asundexian that were tested in this trial (10 mg, 20 mg and 50 mg) appeared safe as with non-statistically different rates of major and clinically-meaningful non-major ISTH bleeding compared to placebo. At the same time, however, even the highest dose of Asundexian did not achieve a statistically significant reduction in the primary ischemic outcome, namely reducing the incidence of symptomatic ischemic stroke or covert brain infarct (detected by MRI) at 6 months from the index event (which were around 20% in all arms – including placebo). Nonetheless, secondary exploratory analyses of Asundexian 50 mg suggested a dose-dependent reduction in the risk of recurrent symptomatic ischemic strokes and TIAs, compared to placebo (compared to placebo (5.4% vs 8.3%, HR 0.64, 90% CI 0.41-0.98).
In conclusion, the Factor XIa inhibitors Milvexian and Asundexian are promising new entries in the field of oral anticoagulation, given their potential to selectively prevent the formation of pathological thrombi while still preventing the formation of “beneficial clots”. This could have powerful implications for patients at high recurrent ischemic risk, such as those with ischemic strokes. The Phase 2, dose-finding studies of these agents among patients with stroke suggest the two agents are overall safe, though more definitive Phase 3 studies are now needed to understand whether these agents can deliver the projected reduction in ischemic events.