A New Breakthrough In Anticoagulation

Most patients with atrial fibrillation require life-long anticoagulation to prevent stroke, which exposes them to a significant cumulative risk for major hemorrhage. While most of the bleeding episodes that these patients experience are nuisance, a small but significant number can be catastrophic and fatal. While the DOACs were a significant improvement over warfarin in terms of reducing the risk of major hemorrhage, a significant number of patients on DOACs still bleed.

The currently available anticoagulants work downstream in the coagulation cascade on factors like II and X. Abelacimab is a fully human monoclonal antibody that binds to the catalytic domain of factor XI and locks it in the zymogen (inactive precursor) conformation, thereby preventing its activation by factor XIIa or thrombin. The idea to target factor XI came from observations that patients with inherited deficiencies of this protein have reduced rates of thromboembolism but rarely do they spontaneously bleed. Therefore, pharmacologic targeting of factor XI may finally create a drug that can divorce bleeding from thrombosis prevention in patients at risk for stroke or DVT.

Point 1: Potential Blockbuster Trial Competed

The AZALEA-TIMI 71 study was a phase 2 randomized study comparing two doses of abelacimab (90 mg or 150 mg) given by subcutaneous injection once-monthly with rivaroxaban 20 mg daily in over 1,200 atrial fibrillation patients.

Earlier this week, the company published a press release which reported that with a median of 21 months of follow-up, spanning more than 2,000 patient years, the AZALEA-TIMI 71 trial found “overwhelming reduction in bleeding.”

Unfortunately more details of the trial will not be available until they are presented at an upcoming medical conference.

Point 2: More Work Is Needed

The company has already planned a phase 3 trial named The LILAC-TIMI 76 study, which will evaluate the efficacy and safety of abelacimab relative to placebo on rates of thromboembolic complications in patients with atrial fibrillation who are not candidates for oral anticoagulation. There is also data published from a prior study which demonstrated significant reductions in rates of venous thromboembolism in patients after orthopedic surgery.

If the results of the phase 3 trial confirm the finding of AZALEA-TIMI 71, abelacimab would represent a sea change in managing atrial fibrillation. I would be hard pressed to imagine that this drug wouldn’t completely take over the market for stroke prevention in atrial fibrillation, even with the limitations related to parenteral administration.