Bayer suspended the phase 3 trial for its factor XIa inhibitor asundexian late last year after the drug showed “inferior efficacy” at preventing strokes in patients with atrial fibrillation compared to Bristol Myers Squibb and Pfizer’s Eliquis. The full picture of what that “inferior efficacy” looks like has now come into focus: Patients receiving asundexian actually suffered strokes or systemic embolisms at a higher rate than those receiving Eliquis.
In a 14,810-patient study, dubbed OCEANIC-AF, 98 patients receiving Bayer’s drug suffered strokes or systemic embolisms, compared to 26 patients receiving Eliquis, at the time the trial was called off prematurely because of the concerning trend, according to trial results published Sept. 1 in The New England Journal of Medicine. Preventing stroke was the trial’s primary efficacy endpoint.
Adverse event incidence was similar between asundexian and Eliquis, but 147 patients discontinued Bayer's drug due to adverse events compared to 118 discontinuations for patients on Eliquis. About twice as many patients (155) receiving asundexian died of heart attack, stroke or another cardiovascular event compared to 77 in the Eliquis group.
Atrial fibrillation is an irregular, often rapid heartbeat that increases the risk of stroke and heart failure. Eliquis targets factor Xa, the activated form of an enzyme that is critical for initiating the coagulation process, when blood cells bunch together and form clots. Preventing coagulation reduces the chance that blood clots form and travel to the brain, triggering a stroke, but also increases the risk of dangerous bleeding because the body is less able to stop the flow of blood.
Bayer sought to circumvent the bleeding risk by going after a target further down the coagulation pathway, known as factor XIa. Asundexian was successful in this regard, as only 17 patients who received asundexian had major bleeding compared to 53 who received Eliquis, hitting the trial’s primary safety endpoint. But this improved safety, the data show, came at the loss of efficacy.
Investigators have proposed some theories as to why asundexian has failed despite the promise of the factor XIa mechanism. They suggest the asundexian dose tested, at 50 mg daily, may have been too low to achieve high enough levels of factor XIa inhibition. In a previous trial, PACIFIC-AF, this dosage reduced factor XIa activity by 94% at peak concentrations; preventing harmful blood clot formation may take close to 100% activity reduction, the authors suggest.
The trial was designed to end once 350 patients had experienced strokes or embolisms and was just over a third of the way there when Bayer pulled the plug at the recommendation of the independent data monitoring committee. The trial started enrolling patients Dec. 5, 2022, and ended on Nov. 19 of the following year.
Asundexian has struggled in other indications as well; the drug failed to reduce the rate of covert brain infarction or ischemic strokes in a phase 2 trial in 2022. In 2023, Bayer outlined expectations that the blood thinner could bring in $5.5 billion per year as a potential treatment for thrombosis and stroke prevention.
The German pharma giant is reevaluating its plans for another trial, OCEANIC-AFINA, meant for a subset of atrial fibrillation patients with a high risk for stroke or systemic embolism who are ineligible for oral anticoagulation treatment. Another late-stage trial examining how asundexian stacks up against standard-of-care antiplatelets in ischemic stroke prevention, called OCEANIC-STROKE, is ongoing. That trial is expected to enroll 12,300 patients and finish in October 2025.
Bayer's rivals in the race to inhibit factor XIa have also struggled. BMS and Johnson & Johnson's milvexian failed a phase 2 trial, but the pharma is still pursuing a phase 3.