The AZALEA-TIMI 71 randomized trial evaluated the safety and tolerability of 2 blinded doses of the novel factor XI inhibitor abelacimab compared with open-label rivaroxaban.
Anticoagulation for the prevention of cardioembolic stroke remains the cornerstone of treatment for patients with atrial fibrillation, explained Christian T. Ruff, MD, MPH, director of general cardiology in the Cardiovascular Division at Brigham and Women’s Hospital and associate professor of medicine at Harvard Medical School in Boston, Massachusetts, during a session at the American Heart Association (AHA) Scientific Sessions 2023 in Philadelphia, Pennsylvania.
Ruff explained further that previously, phase 3 trials had investigated direct oral anticoagulants (DOACs) vs warfarin. These trials, which Ruff had been involved in, led to the approval of several DOACs over a decade ago.
“Meta analyses of those trials demonstrate that DOACs are as effective in reducing ischemic stroke, but markedly safer with respect to intracranial hemorrhage, reducing rates by 50%,” Ruff said. “It is this substantial reduction in serious bleeding that drove the 10% mortality benefit of DOACs over warfarin.”
However, Ruff noted that the ability of DOACs to reduce less serious types of bleeding was not as evident from these trial data.
“While they tend to reduce major bleeding, they're associated with a significant 25% increase in gastrointestinal [GI] bleeding,” Ruff said. “We know that bleeding or even the fear of bleeding drives substantial undertreatment of our patients, and so we are still on our quest for an even safer anticoagulant.”
Factor XI inhibitors have emerged as a potentially attractive target to uncouple pathological thrombosis from physiological hemostasis, offering the potential for hemostasis-sparing anticoagulation. According to Ruff, factor XI is unique because it is required to drive thrombus growth and propagation in thrombosis, but it appears to have a minor role in vascular hemostasis.
Recently, abelacimab (MAA868; Anthos Therapeutics) came to the fore as an attractive factor XI inhibitor because it is a highly selective, fully human monoclonal antibody that binds to factor XI and locks it in the inactive state, which prevents the formation of activated factor XI.
“That brings us to the AZALEA-TIMI 71 trial [NCT04755283], where our objective was to investigate the bleeding profile of abelacimab compared to rivaroxaban [Xarelto; Janssen Pharmaceuticals] in [patients with] atrial fibrillation at moderate to high risk of ischemic stroke,” Ruff said during the session.
During the trial, the investigators randomly assigned 1287 patients (median age 74 yrs, 44% women, median CHADS-VASc score 5) to receive either abelacimab 150 mg subcutaneous monthly, abelacimab 90 mg subcutaneous monthly, or rivaroxaban 20 mg daily with appropriate dose adjustment in selected patients. The abelacimab dose was blinded to subjects and investigators, but the trial was open label with respect to abelacimab vs rivaroxaban. Ruff explained that this was an event-driven study targeting 166 major or clinically relevant non-major bleeds.
“We were alerted earlier this year in September that the Data Monitoring Committee had recommended termination of the trial due to an overwhelmingly substantial and highly significant reduction in both abelacimab doses for major and clinically relevant non-major bleeding compared to rivaroxaban, with a net clinical benefit that favored abelacimab,” Ruff said. “Based on their recommendation, we proceeded with quarterly close out of the trial, which is still ongoing.”
Data from the last Data Monitoring Committee snapshot showed that abelacimab provided potent factor XI inhibition at greater than 95% inhibition in both doses, Ruff explained. The 150 mg dose of abelacimab had achieved 99% inhibition of factor XI, with a very tight interquartile range. The 90 mg dose had achieved 97% inhibition with a broader range.
“All abelacimab doses were associated with substantial and highly significant reductions: a 67% reduction for abelacimab at 150 mg and a 77% reduction for the 90 mg dose,” Ruff said. “If we look at major bleeding in general, there was a 74% reduction with the 150 mg dose and an 81% reduction with the 90 mg dose.”
Additionally, GI bleeding, which was the most common bleeding observed with DOAC therapy, was almost eliminated with both abelacimab doses, achieving 93% reduction. Further, Ruff explained that intracranial hemorrhage was uncommon across all treatment arms, with clinically relevant non-major bleeding reduced by 61% to 75% in the abelacimab arms.
“Abelacimab provides a potent inhibition of factor XI, with greater than 95% inhibition of both doses over the dosing interval,” Ruff said. “There was substantial reduction in bleeding in the 150 milligram dose compared with rivaroxaban—and that is the dose that is being investigated in phase 3 trials—with a 67% reduction in major or clinically relevant non-major bleeding, a 74% reduction in major bleeding alone, and a 93% reduction in major GI bleeding.”
Ruff CT. AHA Scientific Sessions 2023 Late-Breaking Science. Presented at: AHA Scientific Sessions 2023; November 11, 2023.