Findings from a phase 2 study with FXIa inhibitor in non-cardioembolic ischemic stroke

PACIFIC-STROKE – Phase 2 Program of AntiCoagulation via Inhibition of FXIa by the oral Compound BAY 2433334 – non-cardioembolic STROKE study

Presented at the ESC congress 2022 by: Ashkan Shoamanesh – Hamilton, Canada

Introduction and methods

The PACIFIC-STROKE trial was a prospective, randomized, double-blind, placebo-controlled, phase 2, dose-ranging study. Patients with non-cardioembolic ischemic stroke presenting within 48 hours from symptom onset (with high recurrent risk of stroke and who were intended to be treated with antiplatelet therapy) were randomized to asundexian (10, 20 or 50 mg daily) or placebo. Patients underwent MRI at baseline and at 6-12 months or at end of treatment. In total 1808 patients were enrolled at 196 sites in 23 countries.

Main results

• There was no dose-response relationship for asundexian and the primary efficacy outcome (ischemic stroke or covert infarct at 6 months) (events occurred in 19.1% in patients on placebo; 18,9% with asundexian 10 mg; 22.0% with asundexian 20 mg; and 20.1% with asundexian 50). There was a numerical reduction of ischemic stroke with 50 mg asundexian compared to placebo.
• In an exploratory post hoc analysis, there was a suggestion of dose-dependent reduction of the composite endpoint of ischemic stroke or TIA with asundexian at the total median follow-up of 10.6 months (events occurred in 8.3% of patients on placebo; 7.7% with asundexian 10 mg; 6.2% with asundexian 20 mg; 5.4% with asundexian 50 mg translating into the following HRs: 0.92 [95%CI:0.63-1.35] for asundexian 10 mg; 0.74 [95%CI:0.49-1.12] for asundexian 20 mg; 0.64 [95%CI:0.41-0.98] for asundexian 50 mg).
• In an exploratory post-hoc subgroup analysis, patients with large artery stroke and patients with any extra-/intracranial atherosclerosis (detected by vascular imaging) appeared to benefit on the outcome of recurrent stroke and TIA from asundexian 50 mg compared to placebo (HR 0.56, 95%CI:0.26-1.19 and HR 0.39, 95%CI: 0.18-0.85, respectively).
• There was no increase in major or clinically-relevant non-major bleeding (ISTH criteria) (3.9% for the pooled asundexian group vs. 2.4% in the placebo group) nor for all bleeding (9.97% for the pooled asundexian group vs. 9.73% in the placebo group). There was no sign of increase in hemorrhagic transformation in patients receiving asundexian relative to placebo.

Conclusion

The findings of this phase 2 trial were that inhibition of factor XIa with asundexian did not reduce the primary outcome – a composite of covert brain infarction or ischemic stroke – in patients with acute, non-cardioembolic ischemic stroke. A dosing of 50 mg asundexian did however reduce recurrent symptomatic ischemic strokes and TIAs, particularly in patients with atherosclerosis. There was no significant increase in risk of major or intracranial bleeding.

*Discussion*

In response to a question about the lack of dose-response relationships, Ashkan Shoamanesh answered that as opposed to MI, ischemic stroke has multiple underlying pathologies. In this study, non-cardioembolic ischemic stroke was targeted, which is a grouping of three types of strokes, including small vessel disease, large atherosclerotic disease either in aorta, carotid or brain, and cryptogenic strokes. He said that there are suggestions that patients with cerebral small vessel disease do not benefit from factor XI inhibition and small vessel infarcts accounted for almost 75% of the primary outcome in this trial. There was a suggestion of a dose-response when looking at the composite endpoint of ischemic stroke and TIA. TIA is a vascular event that is overrepresented in people with atherosclerotic disease and when looking at subgroup analyses, the largest effect size of asundexian was seen in people with atherosclerotic disease. Shoamanseh said: “The take-home message is that addition of a factor XI inhibitor to background antiplatelet therapy seems to benefit patients with atherosclerotic disease when looking at a non-cardio embolic and non-AF population.”

Another question was about why was there a dichotomy between the effect of asundexian on MI and stroke? Ashkan Shoamanesh answered that plaque rupture and artery to artery thrombotic embolism is much more significant in ischemic stroke and that is where the combination of dual pathway inhibition may be having its greatest effect. Whereas in coronary arteries, it is a combination of vaso-occlusive disease and due to the smaller vessels, plaque rupture will occlude the vessels immediately. John Alexander added that background antiplatelet therapy and procedural therapies in the studies were different; almost all patients in PACIFIC-AMI were stented prior to randomization and everybody was on DAPT.

• Our reporting is based on the information provided at the ESC Congress -