AXIOMATIC-SSP Trial Evaluates Milvexian to Reduce Risk of Ischemic Stroke

August 28, 2022—Findings from the phase 2 AXIOMATIC-SSP trial of the anticoagulant milvexian (Bristol Myers Squibb in collaboration with Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson) in patients with a previous ischemic stroke or high-risk transient ischemic attack (TIA) indicate that milvexian should be further investigated for its ability to reduce the risk of ischemic stroke without a clinically important increase in bleeding, announced the European Society of Cardiology (ESC).

“Based on the observed efficacy signal for ischemic 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,” commented Mukul Sharma, MD, in the ESC press release. Dr. Sharma is the AXIOMATIC-SSP Principal Investigator and is with McMaster University in Hamilton, Canada.

The late-breaking research was presented in a Hot Line session at the 2022 ESC Congress held August 26-29 in Barcelona, Spain.

As summarized in the ESC press release, the study’s background is that the risk of ischemic stroke in patients with a previous ischemic stroke or TIA is approximately 5% to 10% in the first few months. Efforts to reduce the early risk of recurrent stroke have focused on antiplatelets. Improvements in outcome have been observed with novel antiplatelet strategies, but a significant residual risk of ischemic stroke and the potential for major bleeding have limited the effectiveness of these options. No anticoagulants are currently approved for noncardioembolic ischemic stroke prevention in the early phase. Furthermore, factor XIa is a driver of thrombus growth, and genetic studies have found that higher levels are associated with a greater risk of ischemic stroke.

The phase 2 AXIOMATIC-TKR trial indicated that in patients undergoing knee arthroplasty, factor XIa inhibition with milvexian could prevent venous thromboembolism with a low risk of bleeding (Weitz et al. N Engl J Med. 2021;385:2161-2172).

According to ESC, AXIOMATIC-SSP is the largest dose-finding trial of an anticoagulant in a stroke population. The study estimated the dose-response relationship of milvexian on stroke occurrence and bleeding in patients with a high risk of recurrent stroke and associated disability.

Eligible patients were aged > 40 years, had a mild-to-moderate acute nonlacunar ischemic stroke (National Institutes of Health Stroke Scale score ≤ 7) or high-risk TIA (ABCD² score ≥ 6) with evidence of arterial atherosclerosis, and could be randomized within 48 hours of symptom onset. All participants had visible atherosclerotic plaque in a vessel supplying the affected brain region.

The study included 2,366 patients from 367 sites in 27 countries. The median age was 71 years, and 64% were men. Patients were randomly assigned to one of five doses of milvexian (25, 50, 100, 200 mg twice daily, 25 mg once daily) or placebo daily for 90 days. All patients received background treatment with open-label aspirin and clopidogrel for 21 days, followed by open-label aspirin from day 22 to 90. MRI was performed at baseline and 90 days.

The primary efficacy endpoint was a composite of ischemic stroke during treatment or incident infarct on brain MRI at 90 days. The main safety endpoint was major bleeding, defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding.

The ESC press release reported the following results from AXIOMATIC-SSP:

• The rate of the primary efficacy endpoint was numerically lower at the 50 and 100 mg twice daily doses. However, the investigators found there was no apparent dose-response: placebo, 16.6%; 25 mg once daily, 16.2%; 25 mg twice daily, 18.5%; 50 mg twice daily, 14.1%; 100 mg twice daily, 14.7%; and 200 mg twice daily; 16.4%).
• Milvexian numerically reduced the risk of clinical ischemic stroke (excluding covert brain infarction) in the intention-to-treat population at all doses except 200 mg twice daily. Doses from 25 to 100 mg twice daily showed an approximately 30% relative risk reduction versus placebo: placebo, 5.5%; 25 mg once daily, 4.6%; 25 mg twice daily, 3.8%; 50 mg twice daily, 4.0%; 100 mg twice daily, 3.5%; and 200 mg twice daily, 7.7%.
• The incidence of major bleeding was low overall: placebo, 0.6%; 25 mg once daily, 0.6%; 25 mg twice daily, 0.6%; 50 mg twice daily, 1.5%; 100 mg twice daily, 1.6%; and 200 mg twice daily, 1.5%.
• The rate of major bleeding for the milvexian 25 mg once daily and twice daily doses were similar to placebo. A moderate increase was observed in the milvexian dose arms of 50 mg twice daily and above (the majority of which were gastrointestinal bleeds), with no apparent dose response.
• The investigators found no increase in severe bleeding (BARC type 3c or symptomatic intracranial hemorrhage) versus placebo, and there was no fatal bleeding in any arm of the study, stated ESC.

A detailed summary of the findings was also provided in an announcement from Bristol Myers Squibb.