BREAKING NEWS: Wall Street Journal article puts spotlight on the potential of new anticoagulants taking fresh aim at one of cardiology’s toughest challenges.

Factor XI inhibitor for AF drastically reduces bleeding vs. rivaroxaban in phase 2 trial

Factor XI inhibitor for AF drastically reduces bleeding vs. rivaroxaban in phase 2 trial

Key takeaways:

  • In patients with AF requiring anticoagulation, the factor XI inhibitor abelacimab greatly reduced bleeding risk compared with rivaroxaban.
  • A phase 3 trial of abelacimab for stroke prevention is ongoing.

PHILADELPHIA — In a phase 2b trial, abelacimab, a novel factor XI inhibitor, drastically reduced bleeding compared with rivaroxaban in patients with atrial fibrillation requiring stroke prevention.

Results of the AZALEA-TIMI 71 trial, which, as Healio previously reported, was stopped early due to an “overwhelming reduction” in bleeding with abelacimab (Anthos Therapeutics), were presented at the American Heart Association Scientific Sessions. Abelacimab is not yet approved for commercial use in the United States.

‘The promise of factor XI inhibitors’

Christian T. Ruff

“We don’t want clots that are pathologic and lead to a stroke. But clotting can be good when we injure our blood vessels and we need to repair them,” Christian T. Ruff, MD, MPH, director of general cardiology at Brigham and Women’s Hospital in Boston, senior investigator for the TIMI Study Group and an associate professor of medicine at Harvard Medical School, told Healio. “Forming a clot in response to blood vessel injury is important. This is an important part of normal hemostasis. However, there’s an abnormal clotting pathway that leads to heart attacks and strokes. And they both converge in a central pathway. All four of the direct oral anticoagulants (DOACs) basically block factors in that central pathway. So, while DOACs prevent the bad clotting, they also cause bleeding; they interfere with the body’s ability to heal blood vessels in response to injury. And although DOACs are much safer than warfarin and other vitamin K antagonists, which we used for half a century with respect to serious bleeding, the rates of bleeding in general are still significant and lead to many patients not to take them. There is a lot of interest in factor XI because the role it plays in the body’s ability to clot is unique. Factor XI seems to only play a role when the body is pathologically forming the clots that cause strokes, but it doesn’t seem to play any significant role in the way the body forms clots in response to blood vessel injury. This is the promise of factor XI inhibitors.”

“There is a lot of interest in factor XI because where it sits in the body’s ability to clot is unique. It seems to only play a role when you are pathologically forming these clots that cause strokes, but it doesn’t seem to play any significant role in the way the body forms clots in response to blood vessel injury. It would be great if we could just figure out something to block that prevents the strokes but lets the body heal an injured blood vessel. That is the promise of factor XI inhibitors,” Ruff told Healio.

Reductions in bleeding

Ruff and colleagues randomly assigned 1,287 patients with AF at moderate to high risk for ischemic stroke to subcutaneous abelacimab 90 mg monthly, subcutaneous abelacimab 150 mg monthly or rivaroxaban (Xarelto, Janssen/Bayer) 20 mg daily (15 mg if creatinine clearance < 50 mL/min/1.73 m2).

At 3 months, abelacimab 90 mg reduced factor XI by 97% (interquartile range [IQR], 50-99) and abelacimab 150 mg reduced it by 99% (IQR, 98-99), Ruff said during a press conference.

Compared with rivaroxaban, both doses of abelacimab greatly reduced risk for the primary endpoint of major or clinically relevant nonmajor bleeding at approximately 2 years (HR for abelacimab 90 mg vs. rivaroxaban = 0.23; 95% CI, 0.13-0.42; P < .0001; HR for abelacimab 150 mg vs. rivaroxaban = 0.33; 95% CI, 0.19-0.55; P < .0001), he said during the press conference.

Both doses of abelacimab reduced risk for major bleeding alone as well as gastrointestinal bleeding compared with rivaroxaban, Ruff said.

“The most common type of bleeding that plagues the DOACs is gastrointestinal bleeding, particularly in the elderly. [Abelacimab 150 mg] reduced that by 93%. Abelacimab really almost eliminated gastrointestinal bleeding in this study,” Ruff told Healio. “With abelacimab, a monoclonal antibody and a very potent inhibitor of factor XI, the rates of bleeding are incredibly low. This study helps realize the promise of factor XI inhibition, and abelacimab further accounts for elderly populations, those with renal impairment and those on multiple treatments.”

There was no significant difference between the groups in stroke, but the trial was not powered for that outcome, Ruff told Healio.

“There were only 25 strokes across all three arms of this trial,” he said. “The rates were very low, about 1% to 1.5% per year, which is significantly lower than what we would see in patients not on anticoagulation where their rate would be approximately 7% per year. What would their rates of stroke be per year? Probably north of 7%. It shows that all patients from this trial, whether they were on rivaroxaban or abelacimab, were getting highly effective anticoagulation.”

The 150 mg dose of abelacimab will be tested in a large phase 3 pivotal trial of stroke prevention in patients with AF, Ruff told Healio. He said phase 3 trials are ongoing for abelacimab in patients with AF deemed ineligible for anticoagulation and in patients with cancer-associated venous thromboembolism.

“One of the important things we know is that bleeding drives decisions about anticoagulants,” Ruff told Healio. “We know with the DOACs, although they’re great drugs, but somewhere between 40% and 60% of patients aren’t prescribed them, don’t take them or are on an inappropriately low dose. These patients are undertreated and that leads to a lot of strokes which can be fatal or bring on neurologic disability. So we need a safer anticoagulant. This trial demonstrates that abelacimab may be a very attractive alternative for these patients.”