Reduced Bleeding With Abelacimab Could Transform Atrial Fibrillation Treatment

Christian Ruff, MD, MPH, cardiologist at Bergen Women's Hospital, Harvard Medical School and investigator at the TIMI Study Group, spoke with Pharmacy Times® about results from the AZALEA-TIMI 71trial (NCT04755283), the largest study of a factor 11 inhibitor against a direct-oral anticoagulant. According to the data, abelacimab (Anthos) resulted in clinically meaningful statistics for patients at high-risk of increased bleeding.

Pharmacy Times: Can you introduce yourself? What did/will you present at the American Heart Association (AHA) 2024 Scientific Sessions?

Christian Ruff: My name is Christian Ruff, and I'm a cardiologist at Bergen Women's Hospital at Harvard Medical School and investigator at the TIMI study group. And we'll be presenting a very important sub-study from the AZALEA-TIMI 71 trial, and we're going to be presenting data on the factor 11 inhibitor abelacimab versus rivaroxaban (Xarelto; Johnson & Johnson Health Care Systems Inc), a standard of care DAOC (direct oral anticoagulant), for stroke prevention and atrial fibrillation (AF). We're going to be focusing on a very high-risk group of patients, those patients who also acquire anti-platelet therapy for their atherosclerotic cardiovascular disease.

Anticoagulant attacking blood clot | Image Credit: © BURIN93 - stock.adobe.com

Pharmacy Times: Can you explain the relationship between AF and an increased risk of bleeding?

Ruff: We know that (AF) predominantly increases the risk of ischemic stroke. We know that increases that risk by 5-fold, and those strokes are the most likely to be fatal or lead to permanent neurologic disability. Now to reduce that stroke rate, we prescribe an anticoagulant or blood thinner, and that reduces that risk by about 70% or so. But the problem is that when you use traditional anticoagulants, you get a significant increase in bleeding. And so, it's not so much that the (AF) increases bleeding, but the treatment we give to it causes substantial bleeding each and every year. And it's important to remember this is a lifelong therapy for these patients, so that bleeding risk is elevated for a very long time.

Pharmacy Times: What were the most significant findings from the trial?

Ruff: We know in the overall trial, which we presented a year ago at the (AHA), that abelacimab, which is a very potent inhibitor of factor 11, the new target of anticoagulants, reduced the rate of bleeding compared to riboroxaban, which is the most common one of anticoagulants and DAOCs that we use throughout the world, by about 60 to 70% dramatic reductions in bleeding. And for this analysis, we look particularly at patients who not only needed to be on an anticoagulant therapy to fibrillation, but also needed to be on an anti-platelet therapy, say, for their coronary heart disease(CHD), they had a heart attack where they had stenting. And so, we're looking at those very high-risk patients, because we know when you use both those drugs together, their risk of bleeding increases by over 50%.

Pharmacy Times: According to the AZALEA-TIMI 71 trial results, abelacimab was superior to rivaroxaban in reducing bleeding events. Can you talk a bit about abelacimab and its mechanism of action? What advantages does this agent have over rivaroxaban?

Ruff: Anticoagulation is your body forms clots, and there's good clotting, and let's say you injure a blood vessel, or you get damaged you're you need to stop the bleeding. You don't want to bleed out, and so your body needs to form good clots to prevent bleeding, but the problem is, there's also bad clots. Those are the clots that lead to stroke and heart attack, and our traditional blood thinners, such as rivaroxaban and other DAOCs, they prevent both types of clotting. You don't get the bad clots, but you also can heal blood vessels. You get a lot of bleeding.

Abelacimab map targets just 1 factor in the blood clotting cascade. That's very important for the bad clotting causing a heart attack or stroke, but it doesn't seem necessary for forming the blood clots that allow injured blood vessels to heal. And so, when we presented the results from the AZALEA-TIMI 71 trial a year ago, we realized the promise of factor 11 inhibition with abelacimab, that we reduced bleeding by 60% to 70% and that's really just a ground-breaking result.

Now we were extending those results to say, “well, if we look at patients in the real world who are often not even prescribed a blood thinner, or who have very high rates of bleeding, it's not only those with (AF) who need to be on the blood thinner, but those who need to be on aspirin (Ecotrin; Prestige Consumer Healthcare, Inc.) or another antiplatelet therapy because they have coronary heart disease. And as I said, their rates of bleeding are 50% or more. And the results were really encouraging, and we saw those same 60% to 70% reductions in bleeding and on abelacimab; then, we didn't really see any step up in bleeding on the abelacimab arm, even when you added a drug such as aspirin, where in the rivaroxaban arm, those rates went up by 40% or more. So, this allows us to really treat patients at high-risk for bleeding, both abelacimab and their anti-platelet therapy, which they need for their heart disease or their peripheral arterial disease, and that's really an ability for us to treat really our most vulnerable patients, and those generally are patients who are at high-risk of stroke but also high-risk of bleeding.

Pharmacy Times: What are the next steps in research for abelacimab or similar anticoagulants?

Ruff: From the AZALEA trial, we're going to continue to look at these very high-risk patients, and we think there's a lot of important data for us to share. And I think the azalea study in general has really confirmed the promise of abelacimab, that this drug reduces bleeding to a level we've never seen with an anticoagulant for atrial fibrillation. And we're very excited to also be leading the phase 3 trial with abelacimab in the LILAC-TIMI 76 trial (NCT05712200), where we'll actually be establishing the efficacy of the drug in reducing stroke in the highest risk patients, those who can't even tolerate being on a traditional anticoagulant because they've been deemed ineligible, generally due to their high risk of bleeding, and that trial is ongoing.²

REFERENCES

1. Safety and tolerability of abelacimab (maa868) vs. rivaroxaban in patients with atrial fibrillation (azalea-timi 71). ClinicalTrials.gov Identifier: NCT04755283. Updated July 23, 2024. Accessed November 17, 2024. https://clinicaltrials.gov/study/NCT04755283

2. 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) (lilac-timi 76). ClinicalTrials.gov Identifier: NCT05712200. November 8, 2024. Accessed November 17, 2024. https://clinicaltrials.gov/study/NCT05712200?term=LILAC%20TIMI%2076&rank=1