Factor XIa inhibitor lowers bleeding rate compared with NOAC in AF patients

Multicenter, Randomized, Active, Comparator-Controlled, Double-Blind, Double-Dummy, Parallel Group, Dose-Finding Phase 2 Study Comparing the Safety of the Oral FXIa Inhibitor Asundexian with Apixaban in Patients with Atrial Fibrillation: PACIFIC-AF

Presented at ACC.22 by Manesh Patel, MD (Durham, NC, USA)

Introduction and methods

The hypothesis for potential therapy with factor XI inhibition is to uncouple hemostasis from thrombosis: when a factor XI inhibitor is used, thrombin amplification is inhibited, thereby preventing the formation of pathological thrombi; at the same time, the tissue factor pathway is preserved and still produces thrombin, which allows beneficial blood clots to form.

The current evidence that supports FXI inhibition as target includes findings with animals models and inhered FXI deficiency.

Asundexian is an oral FXIa inhibitor with a half life between 14 and 17 hours and 15% renal elimination. It was well tolerated in phase I trials and inhibits FXIa dose-dependently.

In the phase 2 PACIFIC-AF trial, the comparative bleeding rate of asundexian vs. apixaban was evaluated in patients with AF. PACIFIC-AF was a prospective, randomized, double-blind, active-comparator study. 755 Patients with AF at risk of stroke were randomized in 1:1:1 ratio to asundexian 50 mg, asundexian 20 mg, or apixaban for a period of 12 weeks with a 2 weeks post study drug observation period.

Primary safety endpoint was bleeding (ISTH major and non-major clinically relevant bleeding).

Results

• There was near complete inhibition of factor XIa activity with asundexian 20 and 50 mg observed at trough and peak levels.
• Proportion of participants with bleeding event was less in the pooled asundexian group compared to the apixaban group (incidence ration of 0.33, 95%CI:0.09-0.97).
• A similar pattern was observed for non-major clinically relevant bleeding, ISTH minor bleeding, all bleeding, and BARC and TIMI bleeding definitions.
• Asundexian was well tolerated. Percentage adverse events was fairly similar as with apixaban.

Conclusion

In this phase 2 trial of patients with AF, the small oral FXIa inhibitor asundexian resulted in lower bleeding rates compared to apixaban and asundexian was well tolerated.

Manesh Patel concluded: “Factor XI inhibition is a promising strategy to prevent pathologic thrombi while minimizing bleeding risk in AF patients and of course, a phase 3 trial is required”.

– Our coverage of ACC.22 is based on the information provided during the congress –

The findings of this study were simultaneously published in The Lancet