AZALEA-TIMI 71 Trial Shows Abelacimab Significantly Reduces Bleeding Events vs. Xarelto in AFib Patients

Results of the Phase IIb AZALEA-TIMI 71 trial published in The New England Journal of Medicine show that abelacimab produced a significant decrease in factor XI levels and bleeding events compared to Xarelto (rivaroxaban) in patients with atrial fibrillation at moderate-to-high risk for stroke.^1,2 Abelacimab is an investigational, highly selective, fully human monoclonal antibody. The medication was designed to attach to factor XI and stop it from activating and preventing it from generating its activated form.

“Many doctors are put in the unfortunate position of having to weigh the risk of stroke against the risk of bleeding for their patients with AFib,” AZALEA-TIMI 71 principal investigator Christian T. Ruff, MD, MPH, director of General Cardiology at Brigham and Women’s Hospital, associate professor of Medicine at Harvard Medical School, said in a press release. “This study reinforces the promise of abelacimab as a potentially safer alternative to current anticoagulants to address the risk of bleeding.”³

The study authors noted that current guidelines favor the use of direct-acting oral anticoagulants (DOACs) instead of vitamin K antagonists for atrial fibrillation due to DOACs having similar efficacy to vitamin K antagonists in lower the risk of ischemic stroke with less of a risk for intracranial hemorrhage. However, bleeding is a significant adverse effect (AE) associated with DOACs, raising the need for safer anticoagulants.

“Factor XI has emerged as a target for anticoagulants that have the potential to be safer than currently available agents because there is mounting evidence that factor XI is essential for thrombosis but nonessential in most cases for hemostasis,” the study authors wrote. “Persons with genetically mediated factor XI deficiency have fewer embolic events without an appreciable increase in the occurrence of spontaneous bleeding. Therefore, factor XI inhibitors have the potential to uncouple thrombosis from hemostasis.”¹

Trial Design

The multinational, parallel-group, partially blind, randomized, active-controlled AZALEA–TIMI 71 trial was conducted at 95 centers in seven countries. Investigators enrolled 1287 patients with atrial fibrillation and a moderate-to-high risk of stroke, who were randomly assigned in a 1:1:1 ratio to receive either subcutaneous abelacimab at a dose of 150 mg or 90 mg once per month, or oral rivaroxaban at a dose of 20 mg once daily administered in an open-label fashion. The trial’s primary endpoint was major or clinically relevant nonmajor bleeding, with secondary endpoints that included major bleeding and any bleeding event, all of which were evaluated in a time-to-event analysis.

The results show that after three months, median decrease in free factor XI levels among patients administered abelacimab at the 150 mg dose range was 99% (interquartile range, 98 to 99) and 97% at the 90 mg dose range (interquartile range, 51 to 99). An independent data monitoring committee recommended stopping the trial early because of the greater-than-anticipated decrease in bleeding events with abelacimab.

Major or clinically relevant nonmajor bleeding events had an incidence rate of 3.2 events per 100 person-years in the 150 mg abelacimab dose range and 2.6 events per 100 person-years in the 90 mg dose range compared to 8.4 events per 100 person-years in the rivaroxaban cohort (hazard ratio for 150-mg abelacimab vs. rivaroxaban, 0.38 [95% confidence interval {CI}, 0.24 to 0.60]; hazard ratio for 90-mg abelacimab vs. rivaroxaban, 0.31 [95% CI, 0.19 to 0.51]; P<0.001 for both comparisons).

“The incidence of major gastrointestinal bleeding with abelacimab was very low (two events of bleeding in each abelacimab group vs. 18 events in the rivaroxaban group),” the study authors wrote. “This finding is of interest for two reasons. First, the gastrointestinal tract is the most common site of bleeding with DOAC treatment, and gastrointestinal bleeding is the one type of bleeding in which DOACs do not have a better risk profile than warfarin. Second, the lower risk of gastrointestinal bleeding with a parenteral anticoagulant raises the possibility that local exposure of the gastrointestinal tract to a direct-acting oral anticoagulant contributes to the risk of bleeding.”¹

In terms of safety, AE incidence and severity were similar among all three cohorts. Injection site reactions were reported in 2.8% of the patients in the 150 mg dose cohort and 1.6% in the 90 mg dose cohort.

The study authors noted that the efficacy of abelacimab in preventing ischemic stroke and systemic embolization among high-risk patients with atrial fibrillation who are not able to take currently available anticoagulation medications is currently under investigation in the Phase III LILAC–TIMI 76 trial (NCT05712200).

“Building on the overwhelmingly positive data from the AZALEA study, data on the safety of abelacimab in patients undergoing surgical procedures as well as data in patients taking antiplatelet therapy further reinforce the fundamental premise of the promise of Factor XI inhibition – the potential to prevent thrombotic events without affecting normal hemostasis,” Dan Bloomfield, MD, chief medical officer of Anthos Therapeutics, said in the release. “Even when the risk of bleeding is highest, during surgery or invasive procedures or when using antiplatelet therapy, patients treated with abelacimab have a very low rate of bleeding, despite near complete inhibition of Factor XI. The growing body of safety data on abelacimab elevates its promise for patients and, if approved, its potential to be a very attractive therapeutic option for those seeking a safer, more convenient anticoagulant.”³

References

1. Ruff C., et al. Abelacimab versus Rivaroxaban in Patients with Atrial Fibrillation. N Engl J Med 2025;392:361-371. DOI: 10.1056/NEJMoa2406674. VOL. 392 NO. 4.

2. Safety and Tolerability of Abelacimab (MAA868) Vs. Rivaroxaban in Patients with Atrial Fibrillation (AZALEA-TIMI 71). ClinicalTrials.gov. Updated January 23, 2025. Accessed January 29, 2025. https://clinicaltrials.gov/study/NCT04755283

3. Data Published Today in the New England Journal of Medicine Demonstrates Anthos Therapeutics’ novel Factor XI inhibitor, Abelacimab 150mg, Reduced Major or Clinically Relevant Non-Major Bleeding by 62% Compared to Rivaroxaban (Xarelto) in Patients with Atrial Fibrillation. News release. Anthos Therapeutics. Published January 23, 2025. Accessed January 29, 2025. https://anthostherapeutics.com/press-release/anthos_2025-01-22_release/