Study Evaluates Use of Milvexian in Secondary Stroke Prevention

Stroke rests as the leading cause of disability in the US and around 25% of individuals are impacted by a secondary stroke within 5 years. Additionally, therapies to treat stroke, like direct oral anticoagulants, are not indicated for secondary stroke prevention (SSP) and stroke prevalence has increased among younger individuals. To improve this lack of care options, Bristol Myers Squibb and Johnson & Johnson partnered to assess milvexian, an investigational oral Factor XIa inhibitor, and its role in reducing hypercoagulability in patients with stroke and transient ischaemic attack (TIA).^1,2

“Patients with non-cardioembolic ischaemic stroke still have an unacceptably high rate of recurrent ischemic stroke (of at least 5% at 3 months), despite current standard care dual, followed by single, antiplatelet therapy. There is an unmet need for improved secondary stroke prevention,” said Graeme J. Hankey, MBBS, MD, FRCP, FRCPE, FRACP, FAHA, Perron Institute Chair in Stroke Research at The University of Western Australia, Phase 3 Program Co-Chair, SSP, in an interview with Pharmacy Times.

In addition to assessment of milvexian, the researchers assessed clinical outcomes by stroke severity using the National Institute of Health Stroke Scale (NIHSS) score among hospitalized individuals with ischameic stroke (IS) or TIA.^1,2

A total of 54,381 individuals with ischemic stroke (IS) and/or TIA were included in the study if they did not have an atrial fibrillation-related stroke or previous oral anticoagulant use. The National Institutes of Health Stroke Score (NIHSS) categories were divided as 0 to 7, 8 to 15 and 16 to 42; 0 to 7 represents a less severe stroke whereas 16 to 42 is the most severe.²

The results showed that 40,805 patients had a score of 0 to 7; 14.3%(n=7,788) had a score of 8 to 15; and 10.6% (n=5,788) had scores of 16 to 42, according to study authors. However, during a follow up, the researchers found that individuals in the 0 to 7 category represented the largest number of patients who experienced recurrent stroke (73.1%), major bleeding (77%), and death (67%).²

“Among US-hospitalised patients with non-cardioembolic IS and TIA, patients with an NIHSS score of 0 to 7 (consistent with the inclusion criteria of the Librexia Stroke trial) represented the largest proportion (75%) of all IS and TIA patients, with rates per 100 person-years of 6.7 for recurrent stroke; 2.9 for major bleeding; and 9.6 for death,” Hankey said.

These findings highlighted the need for further clinically effective therapies to aid impacts following a stroke, according to study authors.²

Together, Bristol Myers Squibb and Johnson & Johnson conducted the AXIOMATIC-SSP phase 2b trial (NCT0376658) and assessed oral milvexian versus a placebo.¹ The study was designed to emphasize the differences between Factor XIa inhibition and direct oral anticoagulants regarding their use in secondary stroke prevention.

“Factor XIa inhibition is more selective and limited to 1 factor (XIa) upstream in 1 pathway of coagulation—the intrinsic (contact) pathway. The intrinsic pathway (and FXIa) is important for thrombosis, an intravascular process, whether triggered by activation of FXII (intrinsic pathway) or by exposure of low concentrations of subendothelial tissue factor (extrinsic pathway), because thrombus expansion/growth following activation of the tissue factor pathway requires thrombin-mediated activation of FXI. In contrast, haemostasis is a predominantly extravascular process triggered by exposure of large quantities of tissue factor surrounding blood vessels to Factor VII in the blood. This triggers such explosive generation of thrombin by the extrinsic pathway (and haemostatic thrombus formation/clotting) that any further thrombin-mediated activation of FXI, or direct activation of FXI (by FXII in the intrinsic pathway) is rendered mostly redundant for haemostasis. So, inhibition FXIa is hypothesised to uncouple/dissociate thrombosis (inhibition) from haemostasis (preservation),” said Hankey.

The study authors noted that the individuals were randomly assigned to receive 1 of the 5 does of milvexian or the placebo and were treated for 90 days with antiplatelet therapy. Throughout the 90 days, plasma samples were collected on day 1, day 21, and day 90 to analyze activated partial thromboplastin time (aPTT), prothrombin time (PT) and D-dimer at the central laboratory, according to study authors.²

The results showed that individuals treated with milvexian displayed a prolonged aPTT in a dose-dependent manner with limited effects of PT. The study authors noted that this displayed consistent pharmacodynamic effects with milvexian ability as a selective inhibitor of FXla.²

“By adding a new, complementary treatment paradigm to a broad range of patients with non-cardioembolic ischaemic stroke (large artery, small artery, embolic stroke of undetermined source and other cryptogenic ischaemic stroke) which could further reduce their risk of recurrent ischaemic stroke with an acceptable safety profile,” said Hankey, in an interview.3

Further results found that milvexian had a better outcome in decreasing D-dimer levels compared to the placebo, which could reduce hypercoagulability in individuals with IS/TIA.²

Hankey said that for the future drug developers and researchers can “continue current ongoing large phase III clinical trials of FXIa inhibitors (vs placebo, on top of standard care, in patients with ischaemic stroke, and patients with acute coronary syndrome; and vs standard care with a direct oral anticoagulant in patients with atrial fibrillation).”

Disclaimer: Milvexian is an investigational product and is not approved by the FDA. Dr. Hankey responded to these questions with that understanding.

References

1. Priyanka Gaitonde. Jenny Jiang. Meg Crighton. Merena Henderson. Clincal Outcomes By Stroke Severity Using National Institute of Health Stroke Scale (NIHSS) Score Among Patients with IS or TIA. Presented at: European Stroke Organization Conference / ESOC 2024. May 15, 2024. Basel, Switzerland.

2. Wang Z. HE A, Anderson W. Kahl A. Abelian G. Endres M. Donovan M. LI D. Gailani d. Sharma M. Effects ff Factor Xla Inhibition by Milvexian on Coagulation Biomarkers in Patients with Acute IS or TIA in the AXIOMATIC-SSP Trial. Presented at: European Stroke Organization Conference / ESOC 2024. May 15, 2024. Basel, Switzerland.