Can Abelacimab Attenuate the Risk of Bleeding in Patients With Atrial Fibrillation?

STUDY TITLE: Study to Evaluate the Efficacy and Safety of Abelacimab in High-Risk Patients With Atrial Fibrillation Who Have Been Deemed Unsuitable for Oral Anticoagulation (LILAC-TIMI 76)

CLINICALTRIALS.GOV IDENTIFIER: NCT05712200

PARTICIPATING CENTERS: 451 locations distributed across the following countries: United States, Argentina, Brazil, Bulgaria, Canada, Chile, China, Czechia, Estonia, Germany, Hungary, India, Israel, Italy, Japan, Latvia, Mexico, Poland, Romania, South Africa, Spain, United Kingdom

SPONSOR: Anthos Therapeutics, Inc.

ACCRUAL GOAL: 1,900 patients

STUDY DESIGN: This phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study is designed to compare the effect of abelacimab to placebo in patients with atrial fibrillation (AF) who have been deemed unsuitable for oral anticoagulant therapy. Eligible patients must be at high risk for stroke (age 65-74 with a CHA2DS2-VASc score ≥4 or age >75 with a CHA₂DS₂ VASc score ≥3); be deemed unsuitable for oral anticoagulation (risks outweigh benefits) either by the responsible physician or patient; have at least one bleeding risk factor; and be deemed unsuitable for a left atrial appendage closure or occlusion device. Exclusion criteria include AF from an acute reversible cause; receipt of anticoagulation within 60 days prior to randomization; intracranial or intraocular bleed in the past three months; any stroke within 14 days prior to randomization or transient ischemic attack within three days prior to randomization; a mechanical heart valve or the expectation of requiring mechanical valve intervention in the course of the study; and patients on dialysis.

Patients are randomized 1:1 to receive 150 mg of abelacimab subcutaneously or a matching placebo once monthly. The primary outcome measures are efficacy (time to first event of ischemic stroke or systemic embolism) and safety (time to first occurrence of Bleeding Academic Research Consortium type 3c/5 bleeding). Patients will be followed up to 30 months. The trial is still actively recruiting participants.

RATIONALE: Patients with AF have an increased risk of stroke, and current clinical practice guidelines recommend anticoagulation to reduce this danger in those with an estimated annual thromboembolic risk of greater than 2% per year.¹  Direct oral anticoagulants (DOACs) are recommended over warfarin in patients without moderate to severe rheumatic mitral stenosis or a mechanical heart valve due to the lower risk of bleeding associated with these agents compared to warfarin.¹  However, the annual rate of serious bleeding in patients taking DOACs for stroke prevention in AF is 3%, providing an impetus to find alternative therapies that reduce this risk even further.² 

Early preclinical studies of factor XI (FXI) biology and effects of FXI inhibition (in baboons and rodents) suggested that inhibition of FXI could have antithrombotic benefit without the same degree of impairment of hemostasis induced by other anticoagulants.³  Further observations spurring interest in FXI as a therapeutic target included a lower rate of venous thromboembolism (VTE) and ischemic stroke in individuals with FXI deficiency, correlations between FXI levels and incidences of VTE, myocardial infarction, and ischemic stroke.³ 

Abelacimab is a monoclonal immunoglobulin G antibody that binds to the catalytic domain of FXI to inhibit its activation and activity. It is administered as either a subcutaneous injection or intravenously, and it has a very long elimination half-life of 25 to 30 days.³  Abelacimab has been established as effective at preventing VTE in patients who have undergone total knee arthroplasty, with a low rate of bleeding, showing similar results as other drugs that target FXI.^3,4 

The AZALEA-TIMI 71 trial, which compared abelacimab at a dose of 150 mg or 90 mg once monthly to rivaroxaban at a standard dose of 20 mg orally daily, demonstrated a marked reduction in the rate of major or clinically relevant non-major bleeding in patients taking both doses of abelacimab compared to rivaroxaban (hazard ratio [HR] = 0.38 for the 150 mg abelacimab dose and 0.31 for the 90 mg abelacimab dose compared to rivaroxaban).⁵  However, more ischemic strokes were observed in both abelacimab groups compared to the rivaroxaban group. The OCEANIC-AF trial, which compared asundexian (a small molecular FXIa inhibitor) to apixaban in patients with AF for prevention of stroke, also showed a higher incidence of stroke or systemic embolism in the asundexian group (HR=3.79), leading to premature stopping of the trial;⁶  however, less bleeding was seen (HR= 0.32). The PACIFIC-AF trial, which compared asundexian to apixaban for patients with atrial fibrillation and increased bleeding risk, also showed a lower rate of bleeding compared to the standard dose of apixaban of 5 mg twice daily.^6,7 

Taken together, the results of these studies show that while FXI inhibition as a therapeutic strategy is likely inferior to anti-factor Xa DOACs at preventing stroke in patients with atrial fibrillation, it appears to result in a substantial reduction in bleeding risk. FXI inhibition may therefore be a therapeutic alternative for patients in whom oral anticoagulation is deemed too high of a risk from a bleeding perspective, providing the impetus for this trial.

COMMENT: This trial aims to address an important unmet need in the management of AF: the treatment of the patient who is at high risk for stroke but unable or unwilling to receive oral anticoagulant therapy. Too often, patients who have contraindications to anticoagulation are forced to live in fear of suffering a devastating stroke. An alternative treatment that provides some protection against this outcome with a safer bleeding risk profile would therefore be a welcome addition to the therapeutic armamentarium. As outlined above, the superiority of abelacimab and other agents targeting FXI from a bleeding risk perspective already seems clear. The key outcome of this trial will therefore be the efficacy outcome, as at least some benefit compared to placebo in terms of stroke reduction will be needed to justify prescribing this therapy.

I anticipate that the results of this study will prompt much discussion and debate regarding appropriate patient selection for this treatment, particularly when other strategies such as the use of reduced-dose DOACs have been shown to have some promise.⁸  Another important clinical challenge will be the management of bleeding that does occur on abelacimab, particularly given the 30-day elimination half-life.