The AZALEA-TIMI 71 trial was stopped early due to an "overwhelming reduction" in a composite endpoint of major bleeding events compared to rivaroxaban standard of care.
Abelacimab, a novel investigational factor XI/XIa inhibitor in development by Anthos Therapeutics, was “overwhelmingly” superior to rivaroxaban in reducing a primary composite endpoint of major and clinically relevant nonmajor bleeding in patients with atrial fibrillation at moderate-to-high risk of stroke.1
The dramatic results, topline findings from the AZALEA-TIMI 71 phase 2 trial, prompted the study’s Data Monitoring Committee to stop the study early, according to a September 18 news release from Anthos.1
The company stated also that the highly selective, fully human monoclonal antibody, which exerts dual inhibitory activity against factor XI and its active form, factor XIa, is the first factor XI inhibitor to show an “unprecedented” reduction in major bleeding compared to a direct oral anticoagulant (DOAC) in use as standard of care.
“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. With a median of 21 months of follow-up, spanning more than 2000 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,” said Marc S Sabatine, MD, MPH, the Lewis Dexter, MD, distinguished chair in cardiovascular medicine at Brigham and Women’s Hospital and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.1
Abelacimab dosed at 150 mg mimics the “benign bleeding profile” of individuals with genetic factor XI deficiency, maintaining ~98% inhibition over the dosing interval, according to Anthos. Intravenous infusion of the agent “almost immediately reduces the functional factor XI level in a dose-dependent manner,” wrote investigators in a previous phase 2 trial of abelacimab, published in the New England Journal of Medicine in 2021.2 In that study, a single dose of abelacimab 150 mg administered following total knee arthroplasty was associated with a ~80% reduction in venous thromboembolism at post-surgical day 10 compared with enoxaparin.
The event-driven phase 2b AZALEA-TIMI 71 trial completed enrollment in December 2021, with 1287 participants across 95 global study sites. Participants were aged 55 years or older, had a history of atrial fibrillation or atrial flutter on chronic anticoagulation and a CHA2DS2-VASc score of at least 3.
The study assessed the effects of 2 blinded doses of abelacimab vs open-label treatment with rivaroxaban on the composite of the rate of major or clinically relevant nonmajor bleeding events and, in a secondary endpoint, on the rate of major bleeding events alone. Sabatine and colleagues randomized participants in a 1:1:1 ratio to receive abelacimab 150 mg once monthly, abelacimab 90 mg once monthly, or rivaroxaban 20 mg daily.
When taken together, the “overwhelming reduction” in bleeding seen in AZALEA-TIMI 71 and the significant reduction in thrombosis seen in the 2021 VTE study, suggest abelacimab “embodies its promise as a hemostasis-sparing anticoagulant and represents a paradigm shift in the prevention of stroke and other thrombotic conditions,” said Dan Bloomfield, MD, Anthos Therapeutics chief medical officer. “If approved, more patients with atrial fibrillation could be treated effectively and safely, with a much lower risk of bleeding with abelacimab as compared to a DOAC.”
AZALEA-TIMI 71 participants in the rivaroxaban arm will be given the option to transition to an extension study to be treated with abelacimab, the company said. Full results of the study will be presented at a future scientific congress.