ESC24: Bayer outlines asundexian failure in atrial fibrillation trial

Bayer's oral factor XIa inhibitor, asundexian, did not meet expectations in the OCEANIC-AF study when compared to the leading factor Xa inhibitor, Eliquis (apixaban), in the prevention of strokes and systemic embolism in patients with atrial fibrillation (AF). The findings were presented at the European Society of Cardiology (ESC) Congress.

The Phase III study, which was halted prematurely last year on the advice of an independent data monitoring committee due to the "inferior efficacy" of asundexian, significantly affected Bayer's market standing, leading to a 20% drop in its shares when the announcement was made in November.

The challenge in preventing strokes in AF patients with direct-acting oral anticoagulants often lies in the associated risk of bleeding. There was hope that asundexian, targeting the XIa clotting factor, might reduce stroke risk while causing less bleeding. The OCEANIC-AF trial involved 14,810 high-risk AF patients who were randomized to receive either 50 mg of asundexian daily or the standard dose of Eliquis. According to detailed results, stroke or systemic embolism occurred in 98 patients (1.3%) on asundexian, compared to just 26 patients (0.4%) on Eliquis.

Cardiovascular deaths were nearly equivalent between the two groups, with 48 (0.6%) patients on asundexian and 44 (0.6%) on Eliquis. Deaths from any cause were slightly lower in the asundexian group, occurring in 60 (0.8%) patients, compared to 71 (1.0%) in the Eliquis group.

Interestingly, asundexian showed a lower risk of major bleeding. Seventeen (0.2%) patients on asundexian experienced major bleeding during the trial, versus 53 (0.7%) on Eliquis. 

"Our results show that the dose of asundexian tested was inferior for stroke or systemic embolism compared with apixaban," noted principal investigator Manesh Patel. "We could speculate that near-total factor XIa suppression may be needed to prevent thrombus formation." Analysts from Jefferies had also suggested that the dose of asundexian used in the trial might have been insufficient to achieve the necessary levels of factor XIa inhibition.

Researchers in the NEJM paper on OCEANIC-AF referenced an earlier trial, PACIFIC-AF, where a similar dose of asundexian resulted in a 94% reduction in factor XI activity at peak concentrations. "However, to effectively prevent thrombus formation, complete or near complete (>99%) suppression of factor XIa may be required," the authors wrote.

The failure of asundexian in the OCEANIC-AF trial marked a significant setback for Bayer, particularly as analysts had previously suggested that the AF indication could represent approximately €4 billion ($4.4 billion) of the €5.5 billion ($6.1 billion) peak sales estimate for the drug. The late-stage program also includes the OCEANIC-STROKE trial, which is testing asundexian for preventing stroke caused by a clot in people after an acute ischemic stroke or high-risk transient ischemic attack, a so-called mini-stroke. This study is expected to conclude in October of the following year.

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