After positive effects were seen with the factor XIa inhibitor, milvexian, in patients undergoing knee arthroplasty in the phase 2 AXIOMATIC-TKR trial,1 the large phase 2 study, AXIOMATIC-SPP, was conducted to assess its effects on stroke occurrence and bleeding in patients at high risk of recurrent stroke.
As described by Doctor Mukul Sharma (McMaster University - Ontario, Canada) in a Hot Line session yesterday, AXIOMATIC-SPP included patients aged over 40 years who had had a mild-to-moderate acute non-lacunar ischaemic stroke (National Institutes of Health Stroke Scale score ≤7) or a high-risk transient ischaemic attack (ABCD2 score ≥6). All patients had to have atherosclerotic plaque proximal to the affected brain area. Within 48 hours of symptom onset, patients were randomised to one of five doses of milvexian (25 mg, 50 mg, 100 mg, 200 mg twice daily or 25 mg once daily) or placebo daily for 90 days. Background antiplatelet therapy consisted of open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin from day 22 to 90. Assessed at 90 days, the primary efficacy endpoint was a composite of ischaemic stroke during treatment or incident infarct on brain magnetic resonance imaging. The median age of the 2,366 participants was 71 years and 64% were men.
The primary efficacy endpoint occurred in 16.2% of patients with milvexian 25 mg once daily, 18.5% with 25 mg twice daily, 14.1% with 50 mg twice daily, 14.7% with 100 mg twice daily, 16.4% with 200 mg twice daily and 16.6% with placebo, indicating no apparent dose-response with milvexian.
Milvexian numerically reduced the risk of clinical ischaemic stroke (excluding covert brain infarction) in the intention-to-treat population at all doses except 200 mg twice daily, with doses from 25 to 100 mg twice daily showing an approximately 30% relative risk reduction versus placebo (4.6% with 25 mg once daily, 3.8% with 25 mg twice daily, 4.0% with 50 mg twice daily, 3.5% with 100 mg twice daily, 7.7% with 200 mg twice daily versus 5.5% with placebo).
The incidence of the main safety endpoint, major bleeding (BARC type 3 or 5 bleeding), was low overall: 0.6% with 25 mg once daily, 0.6% with 25 mg twice daily, 1.5% with 50 mg twice daily, 1.6% with 100 mg twice daily, 1.5% with 200 mg twice daily and 0.6% with placebo. The rate of major bleeding with milvexian 25 mg once daily and twice-daily doses was similar to placebo. A moderate increase was observed with doses of 50 mg twice daily and above – the majority of which were gastrointestinal bleeds – with no apparent dose-response. No increase in severe bleeding (BARC type 3c or symptomatic intracranial haemorrhage) versus placebo was reported and there was no fatal bleeding in any of the study arms.
Regarding next steps, Dr. Sharma comments, “Based on the observed efficacy signal for ischaemic stroke, the bleeding profile, and the overall safety and tolerability, milvexian will be further studied in a phase 3 trial in a similar stroke population.”