AZALEA – Abelacimab, a Novel Factor XI/XIa Inhibitor, vs Rivaroxaban in Patients with Atrial Fibrillation: Primary Results of the AZALEA-TIMI 71 Ran

Presented at the AHA Scientific Sessions 2023 by: Christian Ruff, MD- Boston, MA, US

Introduction and methods

A meta-analysis of trials (ARISTOTLE, ENGAGE AF-TIMI 48, ROCKET-AF, RE-LY) examining a DOAC vs. warfarin for stroke prevention in patients with atrial fibrillation (AF) showed that DOACs are as effective as warfarin in reducing ischemic stroke, but with improved efficacy for hemorrhagic stroke prevention and substantial reduction in serious bleeding that drove the mortality benefit with DOACs over warfarin. However, the ability of DOACs to reduce less serious types of bleeding was not as evident. DOACs are associated with an increase in gastrointestinal bleeding. Bleeding or fear of bleeding drives undertreatment of patients.

Factor XI inhibitors have emerged as a new potential target to uncouple hemostasis from thrombosis. Factor XI is required to drive thrombus growth and propagation of thrombosis but appears unnecessary or plays a minor role in vascular hemostasis, suggesting that inhibition of FXI could be a hemostasis sparing anticoagulant.

Abelacimab is a highly selective, fully human monoclonal antibody. It binds to factor XI and locks it in the inactive state thereby preventing the formation of activated factor XI (FXIa).

In the phase 2 AZALEA-TIMI 71 trial, 1287 patients with AF at moderate-to-high risk of ischemic stroke were randomized in a 1:1:1 ratio to abelicamab 150 mg SC monthly, abelacimab 90 mg SC monthly or rivaroxaban 20 mg daily. The randomization to abelacimab or rivaroxaban was open label and the abelicamab dose was blinded to subjects and investigators. This was an event driven study targeting 166 major or clinically relevant non-major bleeds. Due to overwhelming efficacy of both abelicamab doses, the trial was terminated early based on recommendations of the Data Safety Monitoring Committee. Here, data from the last data monitoring committee snapshot are presented.

The primary (safety) endpoint was major or clinically relevant non-major bleeding.

Main results

• The median change in FXI from baseline to 3 months was -97% (IQR: -50 to -99) in the 90 mg group and -99% (IQR: -98 to -99) in the 150 mg group.
• The primary endpoint was reduced in the abelacimab 150 mg group (2.7 per 100 Pt-years) compared with the rivaroxaban group (8.1 per 100 Pt-year) (HR 0.33, 95%CI: 0.19-0.56, P<0.0001) and in the abelacimab 90 mg group (1.9 per 100 Pt-years) compared with the rivaroxaban group (HR 0.23, 95%CI:0.13-0.42, P<0.0001). This was based on data of the on-treatment population.
• Other endpoints of major bleeding, GI bleeding and clinically relevant non-major bleeding (but not intracranial hemorrhage) were also significantly reduced in the abelacimab groups compared with the rivaroxaban group. The incidence rate of gastrointestinal bleeding was 0.1 in the abelacimab 150 mg group, 0.1 in the 90 mg abelacimab 90 mg group and 2.1 in the rivaroxaban group (HR 0.07, 95%CI: 0.01-0.50 and HR 0.07, 95%CI: 0.01-0.51, respectively).

Conclusion

The results of the AZALEA-TIMI 71 trial showed potent inhibition of FXI with both doses of abelacimab (90 and 150 mg) in patients with AF at moderate-to-high-risk of stroke. Moreover, the primary (safety) endpoint of major or clinically relevant non-major bleeding was largely reduced with both doses of abelacimab compared with the DOAC rivaroxaban.

The dose of 150 mg of abelacimab is currently being investigated in phase 3 trials.

- Our reporting is based on the information provided at the AHA Scientific Session 2023-