Phase 2 trial with novel factor XIa inhibitor after acute MI

Efficacy and safety of the oral factor XIa inhibitor, asundexian, added to dual antiplatelet therapy after an acute myocardial infarction – Main results of PACIFIC-AMI

Presented at the ESC congress 2022 by: Professor John Alexander, MD, MHS - Durham, NC, USA

Introduction and methods

Following acute MI, dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is considered standard of care. Oral anticoagulation (OAC) has been shown to prevent recurrent ischemic events in post-MI patients and those with chronic vascular disease. However, use of OAC after MI is limited by the risk of bleeding. Factor XIa inhibition may offer a safer but still effective OAC option.

In PACIFIC-AMI, a prospective, randomized, double blind, placebo-controlled, dose-ranging, phase 2 trial, 1601 acute MI patients treated with DAPT were randomized to receive the oral factor XIa inhibitor asundexian (10, 20, or 50 mg) or placebo for 6–12 months. Endpoints included quantification of factor XIa inhibition, safety outcomes (significant bleeding (Bleeding Academic Research Consortium type 2, 3, or 5) and any bleeding), and an efficacy outcome (CV death, MI, stroke, or stent thrombosis).

Main results

• At 4 weeks, factor XIa inhibition by asundexian was as follows: >70% for 10 mg, >80% for 20 mg, and >90% for 50 mg.
• The risk of significant bleeding was 7.6% for asundexian 10 mg, 8.1% for asundexian 20 mg, 10.5% for asundexian 50 mg, and 9.0% for placebo (hazard ratio (HR) for all asundexian arms vs. placebo: 0.98; 90%CI: 0.71–1.35; HR for asundexian 50 mg vs. placebo: 1.20; 90%CI: 0.83–1.75). There was no fatal bleeding.
• With regard to the risk of any bleeding, there were also no significant differences across the asundexian arms or between asundexian and placebo.
• The efficacy outcome event rate was 6.8% (asundexian 10 mg), 6.0% (20 mg), 5.5% (50 mg), and 5.5% for placebo (HR for asundexian 20 and 50 mg vs. placebo: 1.05; 90%CI: 0.69–1.61; HR for asundexian 50 mg vs. placebo: 1.01; 90%CI: 0.61–1.66).
• The frequency of other adverse events was similar across the study arms.

Conclusion

In this placebo-controlled phase 2 trial with a small-molecule factor XIa inhibitor in addition to DAPT in patients following acute MI, asundexian 50 mg resulted in near complete (>90%) inhibition of factor XIa activity. There was no increase in significant or any bleeding with any asundexian dose compared with placebo. Nor was there a reduction in ischemic events, although the numbers were small and, therefore, the CIs were wide, Professor Alexander added.

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

The results of this study were simultaneously published in Circulation.