Q&A: Dr Dan Bloomfield Elaborates on Novel Findings From AZALEA-TIMI 71 Trial, Future of FXI Inhibitor Abelacimab

The AZALE-TIMI 71 study was designed to investigate the efficacy of abelacimab, an investigational, fully human monoclonal antibody that closely binds with factor XI (FXI), versus rivaroxaban to reduce bleeding risks in patients with atrial fibrillation. This investigation carries important implications considering the great risks of bleeding that accompany combination therapies featuring anticoagulants and antiplatelets, explained Dan Bloomfield, MD, chief medical officer, Anthos.

At the American Heart Association (AHA) centennial event held in Chicago this past November, Bloomfield presented novel findings that demonstrated the great potential of abelacimab as an advantageous FXI inhibitor for patients needing concomitant antiplatelet therapy. Sitting down with The American Journal of Managed Care® (AJMC®), Bloomfield explored in-depth the nuances of this study, the promising future of abelacimab, notable challenges they encountered along the way, and more.

This transcript has been lightly edited.

Transcript

Monitoring heart activity in atrial fibrillation | image credit: sudok1 - stock.adobe.com

AJMC: Could you elaborate on the significance of FXI inhibition in reducing bleeding risk, especially in patients already on antiplatelet therapy?

Bloomfield: FXI inhibitors are a new generation of anticoagulants that prevent the risk of stroke or to treat thrombotic events. The challenge that this presentation addressed is that there are many patients with atrial fibrillation at risk for stroke who also need to take what are called antiplatelet agents. These are agents usually used if you have peripheral heart disease or coronary artery disease or if you've got a stem placed. The problem is adding anticoagulants to antiplatelet agents causes a lot more bleeding. And so, that's the challenge that people face, and very often they don't treat people with anticoagulants, and because they're afraid of bleeding because patients need an antiplatelet agent.

Our study was a study between rivaroxaban and abelacimab, the FXI inhibitor. And in patients who take rivaroxaban, if you look at those taking rivaroxaban with and without anti-pilot agents, the risk of bleeding goes significantly up if they're taking the combination. So, roughly 7% with rivaroxaban alone. When rivaroxaban is used on top of antiplatelet agents, it goes up to around 10%. That increase in bleeding is because the agents combined cause bleeding.

There was an overall 60% to 70% reduction in bleeding with rivaroxaban. That was one main finding for the overall study, and that same reduction in bleeding occurred whether you were on antiplatelet agents or not.

But I think the main finding is that if you're taking an antiplatelet agent, you can add abelacimab, and there's no difference in bleeding. So, the rate of bleeding was the same whether you're taking abelacimab alone or abelacimab plus antiplatelet agents. What that means is the concern about bleeding in patients taking antiplatelet is now ameliorated because you can safely give an FXI inhibitor and not have any additional bleeding. So, it solves the challenge that physicians face when they have to give an anticoagulation to somebody who needs antiplatelet agents. Now, with this agent, they can do so safely without increasing the risk of bleeding.

AJMC: What challenges did you encounter evaluating outcomes between abelacimab and rivaroxaban, and how were these addressed in trial?

Bloomfield: The study was designed to show a benefit in bleeding; it was not designed to show a benefit and stroke, and the study allowed people on rivaroxaban or on any anticoagulant to come in and then be randomized to abelacimab or the anticoagulant. And so, the study was designed to give us a really good randomized picture of the difference in bleeding in those 2 groups.

We didn't have any significant issues in any way trying to detect the role of bleeding. We have an independent events committee that evaluated the events. They were blinded to therapy. What's interesting, and not mentioned in this particular abstract, is we presented a study at the European Society of Cardiology in September, which showed that patients who were in the trial who had to undergo urgent surgery or procedures did fine, even though they were on abelacimab. Abelacimab is dosed monthly, and it resulted in 99% inhibition of FXI, so nearly completely knocking out FXI. And despite that, you could go through surgery, abdominal surgery, catheterizations, you know, stem placements, and yet there was no significant bleeding increase.

We have rivaroxaban to stop before surgeries. Because, you know, if you did surgery on top of rivaroxaban, you'd have a lot more bleeding. And so, essentially, we showed in this analysis that we had similar rates of bleeding to rivaroxaban, but people weren't taking rivaroxaban. So essentially, you're anticoagulated with abelacimab. You're not anticoagulated with rivaroxaban because you stop the drug, and yet the rate of bleeding is the same. So that's a really profound finding.

For a long-acting anticoagulant, you want to make sure that if something happens, you can manage it. And the fact you can go through surgeries further reinforces the knowledge that FXI inhibitors don't cause significant bleeding. The antiplatelet data is additional data supporting that.

So, the picture we're trying to create is a new class of anticoagulants where you can prevent thrombotic risk without having to suffer from the increased risk of bleeding. People call it the “holy grail” of anticoagulation: how can you prevent strokes but not cause bleeding? And that's what FXI inhibitors are now able to do. That's why it's so exciting.

AJMC: Do your findings suggest a potential shift toward using FXI inhibitors like abelacimab over traditional anticoagulants for patients on antiplatelet therapy?

Bloomfield: That’s a great question. So, ultimately, to answer that question, we have to have data on efficacy. This was a bleeding study, so we'd have to show first that we significantly reduced the risk of stroke in a way that's similar to what the rivaroxaban patients would get. We haven't got data from that study, so we're doing a study looking at abelacimab in patients who can't even take rivaroxaban. We have to prove that we can reduce the risk of stroke. Once we show that, or once our competitors show that, then you have established efficacy, then you have a class of drugs with much less bleeding than the existing agents, and so you'll be able to more safely use the anticoagulant in patients taking antiplatelet drugs.

But to answer your broader question, you have to first establish efficacy. We demonstrated a reduction in VT, or venous thromboembolism, after knee surgery by 80% with abelacimab compared with the standard of care. In that model that's venous clotting, we've established efficacy. We haven't done it yet for stroke or MI [myocardial infarction] or arterial clotting. That needs to be shown.

AJMC: Are there specific patient groups where abelacimab may offer clear benefits over rivaroxaban?

Bloomfield: There were no real differences in subgroups. The same people on or off antiplatelet agents got the same benefit in the reduction of bleeding compared with rivaroxaban. And that's true across multiple different subgroups, representing data on age, renal dysfunction. In the subgroups that we looked at, abelacimab seems to work equally as well. In the different subgroups, there hasn't been a subgroup that's identified where abelacimab is particularly better or worse. That speaks to the fact that it's going to be a very important drug and beneficial for all patients who take anticoagulants, just not a subgroup-type benefit.

Reference

Anthos Therapeutics Shares New Analysis from the Landmark AZALEA-TIMI 71 Study Demonstrating the Factor XI Inhibitor Abelacimab Substantially Reduced Bleeding in Patients on Antiplatelet Therapy Compared to Rivaroxaban. Anthos. Press Release. November 16, 2024. Accessed December 18, 2024. https://www.globenewswire.com/news-release/2024/11/16/2982367/0/en/Anthos-Therapeutics-Shares-New-Analysis-from-the-Landmark-AZALEA-TIMI-71-Study-Demonstrating-the-Factor-XI-Inhibitor-Abelacimab-Substantially-Reduced-Bleeding-in-Patients-on-Antipl.html