• Phase 2 Results Demonstrate Safety and Efficacy for FXIa Inhibitor Asundexian

    Treatment with the Factor XI activity inhibitor asundexian results in significantly lower rates of bleeding compared with apixaban and is well-tolerated, according to new data from the Phase 2 dose-finding PACIFIC-AF trial.

    Data from the trial were reported Sunday at the American College of Cardiology’s 71st Annual Scientific Session in Washington, D.C., and simultaneously published online in The Lancet, where researchers noted that patients with atrial fibrillation are known to have an increased risk of stroke due to a predisposition to the development of atrial thrombi.

    The authors, led by Jonathan P Piccini, MD, from the Duke University School of Medicine, noted that current treatment guidelines recommend the use of oral anticoagulant therapy in patients with atrial fibrillation – preferably with direct-acting oral anticoagulants due to their improved safety and efficacy over vitamin K antagonists.

    “Based on the results of preclinical testing, observational data from patients with inherited factor XI deficiency, and Phase 1 data, we hypothesised that treatment with asundexian would lead to less bleeding compared with apixaban,” they said, noting that the Phase 2 dose-finding trial was funded by Bayer who make the drug.

    “The FXIa inhibitor asundexian at 20 mg and 50 mg resulted in lower rates of bleeding compared with apixaban, with near-complete in-vivo FXIa inhibition,” revealed the authors. “These findings add to increasing evidence around FXIa as a therapeutic target, and specifically provide rationale for larger clinical outcome studies with asundexian.”

    Trial design

    In the randomized, double-blind, phase 2 dose-finding study, Piccini and colleagues compared asundexian at a dose of 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk.

    The study was conducted at 93 sites in 14 countries – 12 European countries, Canada, and Japan – with 755 participants randomly assigned (1:1:1) to a treatment group using an interactive web response system. The randomization was stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start.

    The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication.

    The team noted that at baseline, the average age of participants was 73.7 years, 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3.9.

    Study results

    The trial showed that asundexian at a dose of 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations, while asundexian at a 50-mg dose resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations.

    “Asundexian at 20 mg and 50 mg doses led to similar reliable suppression of FXIa with once daily dosing,” noted the team, noting that asundexian treatment resulted in significantly lower rates of bleeding compared with apixaban.

    According to Piccini and colleagues, the ratios of incidence proportions for the primary endpoint for asundexian were 0.50 (90% confidence interval [CI] 0.14–1.68) at 20 mg (three events), 0.16 (95% CI 0.01–0.99) for asundexian 50 mg (one event), and 0.33 (95% CI 0.09–0.97) for pooled asundexian (four events) versus apixaban (six events).

    Furthermore, they noted that similar to apixaban, asundexian is well-tolerated, with only 1 in 20 participants discontinuing the drug due to an adverse event

    “The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban,” said the authors.

    They concluded that at doses of 20 mg and 50 mg once daily, the FXIa inhibitor asundexian resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in vivo FXIa inhibition, in patients with atrial fibrillation.

    “Taken together, these findings add to increasing evidence around FXIa as a therapeutic target, and specifically provide rationale for larger clinical outcome studies with asundexian,” said Piccini and colleagues.


    Piccini JP, Caso V, Connolly SJ, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): A multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. The Lancet. 2022 Apr 3. doi: 10.1016/S0140-6736(22)00456-1 [Article in press]

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