Abelacimab, a “Game Changer” for High-Risk Patients With AFib: Dr Ruff and Dr Bloomfield Elaborate on Latest Data From AZALEA-TIMI 71 Trial

Today, Anthos Therapeutics announced new data from the AZALEA-TIMI 71 study, which has been assessing the safety and efficacy of abelacimab, a factor XI (FXI) inhibitor, in comparison with rivaroxaban (Xarelto), a direct oral anticoagulant (DOAC), in patients with atrial fibrillation (AFib). To date, this study constitutes the longest investigation of a FXI inhibitor vs a DOAC and the current findings showcase the great promise of this novel medication.

Notably, patients with AFib who received abelacimab demonstrated major reductions in bleeding. Considering these results, Christian Ruff, MD, MPH, director, general cardiology, Brigham and Women’s Hospital and TIMI Study Group senior investigator, as well as Dan Bloomfield, MD, chief medical officer, Anthos Therapeutics, joined The American Journal of Managed Care^® (AJMC^®) to discuss the study’s design, implications, and future directions in more detail.

Bloomfield initially discussed the AZALEA-TIMI 71 trial at the American Heart Association (AHA) centennial event, held in Chicago, Illinois, from November 16-18, 2024. For more information on the trial, his previous interview with AJMC can be read here.

In part 1 of this interview, Ruff and Bloomfield focus on some of the key factors they believe contributed to the success of their research thus far, and what considerations were important for assessing the drug’s safety.

The latest data from the AZALEA-TIMI 71 trial has now been published in the New England Journal of Medicine.

This transcript has been lightly edited for clarity and length.

Transcript

The AZALEA-TIMI 71 study demonstrated a 62% reduction in major or clinically relevant non-major bleeding with abelacimab vs rivaroxaban. What key design elements or patient characteristics do you believe contributed to such compelling results?

Ruff: It's a great question. You know, in this trial we really enrolled a moderate- to high-risk patient population, but very representative of the garden variety, atrial fibrillation patients. Given this disease of aging, we know 1 in 3 people actually develop it in their lifetime, many of these patients are aged close to mid-70s, and they have a lot of comorbidities, including hypertension, heart failure, coronary disease. They may require being on an antiplatelet medication for their, say, atherosclerosis, that can also increase your risk of bleeding when you're on a blood thinner.

So, we know that patients’ atrial fibrillation, because they're older and have a lot of comorbidities, are, of course, at an increased risk of stroke, which is why they're prescribed an anticoagulant. But they're also have high risk of bleeding. We know that some of these patients, on a per year basis, can have bleeding rates that exceed 5%, get close to 10% per year in the high-risk bleeding patients, and so we know that's why 40% to 60% of patients in the community are either not prescribed the anticoagulant, don't take it, or are not on the correct dose. And it's because the rates of bleeding are, unfortunately, much higher than the rates of stroke once they're on an anticoagulant. So, we feel like these results are so compelling, because this remarkable reduction in bleeding that we saw with abelacimab really [happens] kind of across the board in the types of atrial fibrillation patients people are seeing in the community.

As the study has progressed, what considerations were necessary to manage patients’ comorbidities or potential medication interactions while evaluating abelacimab’s safety profile?

Bloomfield: So one of the nice things about abelacimab as a monoclonal antibody is it doesn't have drug interactions. It's not metabolized by the CYP enzymes. And so, in small molecules, where you have to adjust those sometimes because of interactions between drugs with antibodies, with abelacimab there is no interaction. So, there won't be any medications that will be used differently in the setting of abelacimab.

There is a big plus here—[that one was] kind of pharmacokinetic. The big plus is that one of the pharmacodynamic interactions that would have clinical significance would be the interaction between an anticoagulant and antiplatelet agent. And that's a very common challenge for physicians, because if patients need an antiplatelet agent, they don't want to add an anticoagulant, because of the risk of bleeding. Both would have a risk of bleeding, so the risk gets very high. In the case of FXI inhibitors, in abelacimab, you can add abelacimab to an antiplatelet agent, and there's no increase in bleeding. And we've shown that now at the abstract we presented at AHA; other companies have shown data that support the same thing. So, abelacimab I think is in a very good place with regard to patients with complex comorbidities and the need to take other drugs for other conditions.

With the study showing an 89% reduction in gastrointestinal bleeding, how do you see these findings impacting clinical approaches to/management of patients with AFib? Can you speak to other compelling long-term results and the additional avenues that need to be explored before abelacimab can be brought to market?

Ruff: Personally, that's actually one of the most compelling results from the AZALEA-TIMI 71 trial. When you look at important bleeding that happens to these patients, particularly bleeding that leads to hospitalization, two-thirds or three-quarters of those bleeds with an anticoagulant in the atrial fibrillation population are gastrointestinal [GI] bleeding. They are by far the most common. And what we know is that once someone has a gastrointestinal bleed, they stop their blood thinner, and we know as soon as they stop, they are back to that 5-fold increased risk of stroke. And many of them never go back on an anticoagulant, even when their bleeding subsides, because of the fear of another bleed. We know that that is the bleeding that plagues current treatment of atrial fibrillation.

What's important to note is that, 50 years ago, there was the warfarin and vitamin K antagonists, and we now are in the era of DOACs. And although DOACs decrease serious and life-threatening bleeding, particularly bleeding in the brain, compared to warfarin, when you look at GI bleeding, they're no better than warfarin. In fact, on average, the DOACs cause more GI bleeding than warfarin. So, the fact that abelacimab essentially eliminated gastrointestinal bleeding in the atrial fibrillation population, is incredibly exciting, because that's the bleeding we see the most. That's the bleeding that concerns their physicians and their health care providers as well as the patients.

This is really a game changer, because if you can essentially, virtually eliminate GI bleeding, that will lead to, I think, much more utilization of anticoagulation, particularly with abelacimab and FXI inhibitors. So, I think we were hoping to see reductions across the board, but the fact that gastrointestinal bleeding was vanishingly low with abelacimab, I think, is incredibly exciting.

Bloomfield: So just to go back to the GI bleeding, because the small molecules, the pills, are in the gut, you get more bleeding because they're affecting and anticoagulating in the gut, whereas abelacimab is systemic, so it never sees the gut. And so that's a real advantage for not having that increase in GI bleeding, which is the most common cause of bleeding that leads to transfusions and all the kinds of bleeding.

I think there's 2 things that are really remarkable that about the AZALEA study. One is that the reduction in bleeding is unprecedented. There's never been an improvement in anticoagulation with this magnitude of benefit in bleeding. In fact, even comparing warfarin to the DOACs, it's not clear how much difference there is bleeding. In some cases there's a little bit more. In some cases there's less. So here we have a 62% reduction in the composite of measuring of non-major bleeding, and a 91% reduction in GI bleeding. That's a really unheard of, unprecedented benefit. So that's the first thing I'd say. The second thing I'd say is, as you know, we presented an abstract at the ESC [European Society of Cardiology annual meeting] on patients who were undergoing invasive procedures and surgeries. And this is common, about one-third of the patients with AFib will go through surgeries over the course of a year or 2 years. And so, typically, with the DOAC, you stop the drug about w days or 4 days ahead of the surgery, because they don't want to have the anticoagulant on board during surgery because, as you can imagine, surgery or procedures are a bleeding risk. I mean, probably the biggest bleeding challenge is to open up someone's abdomen, and then bleeding is a real problem. So, you stop these DOACs, and often you stop the antiplatelet agents as well. What we saw was patients who are maximally inhibited with abelacimab, 90+ percent reduction in FXI activity, 99% in the high dose group, they were going through surgeries fully anticoagulated with FXI being inhibited. And yet, we saw very few bleeds. In fact, we saw a little less, or about the same number of bleeds as was observed in the rivaroxaban arm. And what does that mean? That mean rivaroxaban is stopped during surgery. So essentially, those patients are going through surgery without any anticoagulant. And so, we're showing similar rates of bleeding to patients not taking an anticoagulant or what would be a placebo. I think that's remarkable, and it takes away a lot of the complexity about stopping the drug before surgery.

When will it get restarted? What's the fear of some thrombotic episode happening after surgery because you don't have the anticoagulant on board? We solved that problem. So, I think that the message from that is it's remarkably that these people don't bleed, period. They don't have much bleeding at all post-surgery, despite the fact that the biggest stimulus to bleeding would be the surgery. And the second thing is that there's just this enormous reduction in bleeding overall, chronically, even, you know, around surgeries or just chronically. So that's the those are the big messages. What we don't know yet is the efficacy of any FXI inhibitor in the context of stroke, and those are the studies that are ongoing now.