PACIFIC-AF: Low bleeding rates for asundexian in atrial fibrillation

The oral factor XIa inhibitor asundexian showed a favourable safety profile in a phase 2 study that investigated 755 patients with atrial fibrillation (AF). In addition, lower bleeding rates were reported for patients who were randomised to asundexian than for those who received apixaban. Thus, factor XI is a promising target to prevent thrombosis in patients with AF, while minimising the risk of bleeding.

Factor XI inhibition is hypothesised to reduce the risk of the development of pathological thrombi. In addition, since thrombin can still be formed with factor XI inhibition, it is expected that beneficial blood clots can be formed to prevent bleeding. In contrast, factor Xa inhibitors reduce the risk for pathological thrombi but also hamper thrombin production. The phase 2 PACIFIC-AF trial (NCT04218266) is part of the larger phase 2 PACIFIC programme, which aims to assess asundexian, a small, orally administered factor XI inhibitor [1]. The safety results were published a few days after the presentation in the Lancet [2].

In the PACIFIC-AF trial, 755 patients with AF were randomised 1:1:1 to 50 mg asundexian, 20 mg asundexian, or the factor Xa inhibitor apixaban. The primary safety endpoint was ISTH major and clinically relevant non-major (CRNM) bleeding after 12 weeks. Prof. Manesh Patel (Duke University School of Medicine, NC, USA) presented the results.

After 12 weeks, the risk of ISTH major bleeding or CRNM bleeding was lower in the pooled asundexian arms than in the apixaban arm (ratio of incidence proportion 0.33; 90% CI 0.09–0.97). The corresponding ratios of incidence proportion in the 20 mg arm and 50 mg arm were 0.50 (90% CI 0.14–1.68) and 0.16 (90% CI 0.01–0.99), respectively. Notably, no major bleedings had occurred in any treatment arm, meaning that the incidence of CRNM bleedings drove the primary safety outcome of this study. Furthermore, ISTH minor bleedings occurred more frequently in patients on apixaban than in patients on asundexian (0.42; 90% CI 0.26–0.67).

Asundexian was well tolerated in this population and no notable safety differences were reported between the 2 asundexian arms (see Figure). The rate of any adverse events (AEs) was similar for patients on asundexian (47.3%) and apixaban (48.8%) and the rates of AEs leading to discontinuation were 6.2% and 5.2% for patients receiving asundexian and apixaban, respectively. In an exploratory efficacy analysis, 0 patients in any group experienced systemic embolism. Ischaemic strokes were observed in 2 patients (0.8%) and 1 patient (0.39%) in the asundexian 20 mg and 50 mg groups, respectively, versus 0 in the apixaban arm. No conclusion can be drawn from these data at this time.

Figure: Primary safety outcome for PACIFIC-AF suggested that there was less bleeding in the arms treated with asundexian versus apixaban [1]



ISTH, International Society on Thrombosis and Haemostasis.

 

Asundexian is a promising agent that may provide thromboembolic protection with a more favourable safety profile relative to existing anticoagulants; however, phase 3 trials are needed to validate the findings of this study and provide data on the efficacy of asundexian.

1. 
   
   1. Patel MR, et al. Multicenter, Randomized, Active Comparator-Controlled, Double-Blind, Double-Dummy, Parallel Group, Dose-Finding Phase 2 Study Comparing the Safety of the Oral FXI1 Inhibitor Asundexian with Apixaban in Patients with Atrial Fibrillation: PACIFIC-AF. Abstract 407–08, ACC 2022, 2–4 April, Washington DC, USA.
   2. Piccini JP, et al. Lancet. 2022;399(10333):1383–1390.

 

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Posted on 15 June 202229 February 2024