A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction

Abstract

Background: Oral factor XIa (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without significantly increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6–2 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on factor XIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% were women, 51% had ST-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10, 20, 50 mg, and placebo (pooled asundexian vs. placebo: HR 0.98, 90% CI 0.71–1.35). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10, 20, 50 mg, and placebo (pooled asundexian 20 and 50 mg vs. placebo: HR 1.05, 90% CI 0.69–1.61). Conclusions: : In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients following acute MI.

Pharmacological targets of Asundexian relevant to its therapeutic efficacy in treating cardiovascular diseases.

“…Asundexian (BAY-2433334) is reported to be a selective and reversible factor XIa inhibitor which when used together with aspirin and P2Y12 inhibitor was recently reported to be well tolerated among patients with recent acute myocardial infarction. [4] In this study asundexian was reported to dose dependently inhibit factor Xia and as anticipated did not cause any signi cant increase in bleeding. In addition the incidence of any adverse ischemic events were low among patients receiving asundexian.…”

“…Based on the observations from this study, several such targets may account for the cardiovascular bene ts of asundexian. [4] One such target of interest was factor XII. Factor XI is reported to be contact activated by factor XII and also involving ampli cation loop by thrombin.…”

“…In addition the incidence of any adverse ischemic events were low among patients receiving asundexian. [4] Although asundexian is reported to selectively inhibit human factor XIa with high potency (IC 50 of 1 nM), [3] it is likely that other off targets may potentially be involved in its cardiovascular bene ts. To evaluate the potential off targets of asundexian, this study looked at the Insilco approach to identify all possible targets asundexian can interact with in humans.…”

Clinical Pharmacology of Factor XI Inhibitors: New Therapeutic Approaches for Prevention of Venous and Arterial Thrombotic Disorders

“…In a very recent multicenter trial, 1601 patients with recent (within 5 days) acute myocardial infarction (MI) were randomized to oral asundexian at the dosages of 10, 20, or 50 mg or placebo once daily for 6–2 months. Patients received also dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor [ 31 ]. The main safety outcome was bleeding, while the efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses vs. placebo.…”

Properdin (factor P) as a new target cleaved by factor XIa: Intrinsic coagulation at the crossroads with inflammation

“…In a phase 2 dose‐finding clinical trial for the indication stroke prevention in atrial fibrillation, asundexian at doses of 20 mg and 50 mg once daily resulted in near‐complete in vivo FXIa inhibition and in lower rates of bleeding compared with standard dosing of the active comparator, the FXa inhibitor apixaban. 9 Two more phase 2 clinical trials investigating asundexian in acute MI or noncardioembolic stroke are completed: PACIFIC AMI 10 and PACIFIC Stroke, 11 both demonstrating no significant increase in bleeding when added to antiplatelet therapy.…”