麻豆传媒

For people with atrial fibrillation (Afib), investigational abelacimab proved to be a potent dual factor XI/XIa inhibitor with much lower safety risks compared with a direct oral anticoagulant (DOAC), according to the AZALEA-TIMI 71 trial.

Testing two once-monthly doses of abelacimab against rivaroxaban (Xarelto), researchers found that abelacimab significantly reduced major or clinically relevant nonmajor bleeding at both the 90-mg (2.6 events per 100 person-years, HR 0.31, 95% CI 0.19-0.51) and the 150-mg doses (3.2 events per 100 person-years, HR 0.38, 95% CI 0.24-0.60).

Notably, there was a "very low" 0.5% incidence of major gastrointestinal bleeding with both doses of abelacimab, as compared with 4.2% in the rivaroxaban group, reported the study authors led by Christian Ruff, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston.

That's significant because the GI tract is the most common site of bleeding with DOACs, and this type of bleeding is the only one for which DOACs do not have a better risk profile than warfarin. Also, the researchers noted in their paper, "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."

As the trial had been stopped early because of the unexpectedly large reduction in bleeds with abelacimab, the report covers the complete AZALEA-TIMI 71 dataset with the full cohort accounted for at a median 2.1 years of follow-up. Preliminary results, previously at the American Heart Association meeting in late 2023, had extended out to 1.8 years.

Abelacimab is a fully human monoclonal antibody that binds to the inactive form of factor XI and blocks its activation, which is hoped to uncouple thrombosis from hemostasis and result in a safer anticoagulant.

"As a monoclonal antibody, abelacimab is not metabolized by the cytochrome P-450 system and is not a substrate for P-glycoprotein, so the risk of drug-drug interactions is reduced. There is no need to adjust the dose on the basis of age or of renal or hepatic status," added Dominick Angiolillo, MD, PhD, of University of Florida College of Medicine, Jacksonville, and Davide Capodanno, MD, PhD, of Azienda Ospedaliero Universitaria Policlinico G. Rodolico-San Marco and the University of Catania, Italy, in an .

Angiolillo and Capodanno cited other approaches now being developed to inhibit factor XI, factor XIa, or both, including the monoclonal antibodies osocimab and gruticibart, antisense oligonucleotides such as fesomersen, small interfering RNAs, and oral asundexian and milvexian.

In AZALEA-TIMI 71, both of the tested doses nearly eliminated free factor XI in Afib patients at moderate-to-high risk for stroke. At 3 months, abelacimab's reduction in free factor XI levels was 99% at the 150-mg dose and 97% with the 90-mg dose.

Whether the antibody can show clinical efficacy is unknown, however, as the present trial was not large enough to study that. Ruff and colleagues found no significant differences in stroke across assigned treatments, though stroke rates trended numerically higher with abelacimab (1.21 and 1.36 per 100 person-years with 150 mg and 90, respectively, vs 0.83 per 100 person-years with rivaroxaban).

Ruff and colleagues acknowledged the need for a larger study to evaluate abelacimab's clinical efficacy. To that end, the investigators have moved on to the phase III that is currently investigating abelacimab (at 150 mg) for prevention of ischemic stroke and systemic embolization in high-risk Afib patients with bleeding risk factors.

Separately, abelacimab has also reached phase III study for prevention of venous thromboembolism in patients with cancer, in the ASTER and MAGNOLIA trials.

AZALEA-TIMI 71 was a phase IIb study among Afib patients with a moderate-to-high risk of stroke, defined as a CHA₂DS₂-VASc score of 4 or higher or a CHA₂DS₂-VASc score of 3 with either planned concomitant use of antiplatelet medications or an estimated creatinine clearance ≤50 mL/min.

Ruff's group randomly assigned 1,287 individuals to abelacimab injections (150 mg or 90 mg once monthly, blinded assignments) or oral rivaroxaban (20 mg once daily, open-label).

The cohort had a median age of 74 years, with 44% being women and about 95% white. The baseline median CHA₂DS₂-VASc score was 5 and HAS-BLED score 2 or 3. Overall, 92% of participants had previously received an anticoagulant for at least 60 days, with 66% of those having taken a DOAC.

The incidence and severity of safety events came out similar among the three treatment groups.

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