Trial Halted for Bleeding Reduction With Abelacimab in AF

A phase 2 trial of the investigational factor XI inhibitor, abelacimab, in patients with atrial fibrillation (AF) who are at moderate to high risk for stroke has been stopped early due to “an overwhelming reduction” in the primary endpoint — major and clinically relevant nonmajor bleeding — in patients taking abelacimab vs those on rivaroxaban.

The announcement of topline results of the AZALEA-TIMI 71 trial was made by Anthos Therapeutics, the company developing abelacimab.

“The AZALEA-TIMI 71 study is the largest and longest head-to-head study of a Factor XI inhibitor to provide definitive evidence of a highly significant reduction in bleeding as compared to the standard-of-care anticoagulant,” Marc Sabatine, MD, chair of cardiovascular medicine at Brigham and Women’s Hospital, and chair of the TIMI study group, stated in the Anthos press release.

“With a median of 21 months of follow-up, spanning more than 2,000 patient years, AZALEA-TIMI 71 represents a landmark study confirming the promise of Factor XI inhibition as causing substantially less bleeding than a current standard-of-care,” Sabatine added.

Abelacimab is a novel, highly selective, fully human monoclonal antibody with dual inhibitory activity against factor XI and its active form, factor XIa. At the 150-mg dose given subcutaneously once monthly, the drug maintains around 98% inhibition of factor XI, in line with the benign bleeding profile of patients with genetic factor XI deficiency, the company notes.

The AZALEA-TIMI 71 study is an event-driven, randomized study comparing two blinded doses of abelacimab (90 mg or 150 mg given by subcutaneous injection once-monthly) with rivaroxaban 20 mg daily in 1287 patients with AF who are at moderate to high risk for stroke. Full results of the study will be presented at an upcoming scientific congress.

Patients in the rivaroxaban arm can transition to abelacimab in an extension study.

In a previous proof-of-concept study published in The New England Journal of Medicine in 2021, a single IV dose of abelacimab achieved a large reduction in venous thromboembolism (VTE) vs enoxaparin in patients undergoing knee surgery.

A phase 3 trial in AF patients is now planned. The LILAC-TIMI 76 study is an event-driven, randomized trial to evaluate the efficacy and safety of abelacimab relative to placebo on the rate of ischemic stroke or systemic embolism in AF patients who have been deemed to be unsuitable for currently available anticoagulation therapy. Patients will be randomized to receive abelacimab 150 mg subcutaneously or matching placebo once monthly. The researchers aim to enroll approximately 1900 patients from North America, Europe, Latin America, the Middle East, and Asia.

Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said that, “Abelacimab embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions.”

It is estimated that 12.1 million people in the United States will have AF by 2030, but 40%-60% of patients with AF are not prescribed anticoagulants today, one of the main reasons being concerns about bleeding, the company notes.

“Abelacimab has the potential to provide a game-changing treatment option for all those patients who live with the daily fear of bleeding while taking current anticoagulants,” said Leslie Lake, president of the National Blood Clot Alliance, in a quote.

Abelacimab has been granted a fast-track designation by the US Food and Drug Administration for the prevention of stroke and systemic embolism in patients with atrial fibrillation.

Several other Factor XI inhibitors are in development and have also shown promising results in terms of a more benign bleeding profile than current standard-of-care anticoagulants.

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