Factor XIa inhibitor milvexian did not provide meaningful secondary prevention over dual antiplatelet therapy for stroke survivors, the phase II trial AXIOMATIC-SSP found.
In patients with recent ischemic stroke or transient ischemic attack (TIA), randomization to any one of five doses of milvexian did not significantly reduce the combined incidence of ischemic stroke or covert brain infarct on MRI at 90 days (range from 15.3% for 200 mg twice daily to 16.7% for 25 mg once daily) compared with placebo (16.8%), reported Mukul Sharma, MD, of McMaster University in Hamilton, Ontario, and co-authors.
No significant dose-response was observed for the primary efficacy outcome, nor was one observed for major bleeding, the investigators reported in Lancet Neurology.
Paradoxically, a prior analysis showed that milvexian numerically lowered the risk of clinical ischemic strokes, not counting covert brain infarctions, in the four lower dose groups but not in the highest dose group.
Milvexian’s promise as an antithrombotic rests on evidence that people with factor XI deficiency have lower rates of ischemic stroke than the general population and infrequent spontaneous bleeding, the authors noted. Milvexian is an oral inhibitor of activated factor XIa and is rapidly absorbed after oral administration, with a half-life of approximately 12 hours. The hope is that it would carry a lower risk of complications compared with available anticoagulants.
Previous phase II trials had supported milvexian as an effective anticoagulant with a good safety profile. In another phase II trial, milvexian showed a dose-response relationship with prevention of venous thromboembolism after elective knee arthroplasty alongside low bleeding.
However, in AXIOMATIC-SSP, the highest dose of milvexian was associated with renal adverse events and subsequent study discontinuation, Pooja Khatri, MD, of the University of Cincinnati, pointed out in an accompanying editorial.
“As expected, most of the primary outcome events within the trial were covert brain infarcts and, disappointingly, the results showed that milvexian had no dose-response effect,” she wrote.
Another dose-finding study, PACIFIC-Stroke, showed similarly disappointing efficacy results for another factor XIa inhibitor, asundexian, over placebo.
“Together, the results of these trials suggest that factor XI and factor XIa inhibitors might not prevent noncardioembolic stroke. This possibility becomes more likely if covert brain infarcts are considered as part of the same biological spectrum as symptomatic cerebral ischaemia, but smaller or in less eloquent areas of the brain,” Khatri suggested.
Hints of efficacy in these trials may have been “spurious,” she noted, though phase III trials may “tip the balance towards benefiting patients with non-cardioembolic cerebral ischaemia.”
Milvexian is now under investigation in the phase III LIBREXIA-STROKE trial that is testing the 25-mg twice-daily dose against placebo in a targeted population of 15,000 stroke or TIA patients.
AXIOMATIC-SSP was conducted from 2019 to 2021 in 367 hospitals in 27 countries. Enrollees were adults ages 40 and older, with acute ischemic stroke or high-risk TIA, seen within 48 hours of symptom onset. Participants had imaging evidence of interior or exterior atherosclerosis in a feeding artery and a premorbid modified Rankin scale score of 3 or lower.
Sharma and colleagues ultimately had 2,366 individuals in the study cohort. Their median age was 71 years, 36% were women, and 80% were white.
Patients were randomized to one of five doses of milvexian, or placebo, for 90 days. All participants also received clopidogrel (Plavix) 75 mg daily for the first 21 days and aspirin 100 mg daily for 90 days.
An MRI scan was performed at baseline and at 90 days.
The researchers were limited by a study completion rate of 75% due to adverse events and COVID-19 pandemic-related difficulties. Another limitation was the low representation of women in the trial population.
Sharma’s group also acknowledged the trial’s reliance on covert brain infarcts as a surrogate for clinical ischemic stroke in the composite primary outcome, as these infarcts contributed most of the primary outcome events. The validity of this surrogate marker is still unclear, the authors wrote.
Funding for the trial came from Bristol Myers Squibb and Janssen.
Sharma disclosed relationships with Janssen, HLS Therapeutics, Bayer, and the Canadian Stroke Consortium.
Study co-authors had multiple relationships with industry, including several as employees of Bristol Myers Squibb.
Khatri disclosed relationships with Bayer, Cerenovus, the National Institutes of Health, UpToDate, Basking Biosciences, Lumosa, and Shionogi.
Source Reference: Sharma M, et al “Safety and efficacy of factor XIa inhibition with milvexian for secondary stroke prevention (AXIOMATIC-SSP): a phase 2, international, randomised, double-blind, placebo-controlled, dose-finding trial” Lancet Neurol. 2023; DOI: 10.1016/S1474-4422(23)00403-9.
Source Reference: Khatri P, “Anticoagulants to prevent recurrent non-cardioembolic stroke” Lancet Neurol. 2023; DOI: 10.1016/S1474-4422(23)00464-7.