Q&A: Failure of OCEANIC-AF trial may not dampen future of factor XI/XIa inhibitors
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Key takeaways:
- Factor XI/XIa inhibitors may be safer than direct oral anticoagulants, but the OCEANIC-AF trial calls their efficacy into question.
- The trial’s failure may have been due to dose and not a class effect.
Direct oral anticoagulants have become the standard of care for stroke prevention in patients with atrial fibrillation, among other indications, but factor XI/XIa inhibitors may have the potential to usurp them due to safety profiles.
However, on Nov. 19, Bayer announced that OCEANIC-AF, its phase 3 trial of the novel factor XIa inhibitor asundexian for prevention of stroke in patients with AF was stopped due to failure of efficacy compared with the direct oral anticoagulant (DOAC) apixaban (Eliquis, Bristol Myers Squibb/Pfizer).
The news came as a surprise, as phase 1 and 2 studies of factor XI and factor XIa inhibitors, including asundexian, milvexian (Bristol Myers Squibb/Janssen) and abelacimab (Anthos Therapeutics), had been successful.
Healio spoke to Jeffrey I. Weitz, MD, professor of medicine and biochemistry at McMaster University, Hamilton, Ontario, Canada, and an expert on anticoagulation, about how factor XI and factor XIa inhibitors work, how they differ from DOACs and each other, why the OCEANIC-AF trial failed and what the setback means for the entire drug class and the patient populations it could help.
Healio: What opportunities are there for factor XI/XIa inhibitors?
Weitz: The obvious opportunities are in stroke prevention in atrial fibrillation, stroke prevention in people with noncardioembolic stroke, prevention of recurrent ischemic events in people with acute coronary syndrome, treatment of cancer-associated venous thromboembolism and, if things look good, other opportunities as well.
Healio: How do these agents work differently from DOACs, and from each other?
Weitz: The current DOACs target either factor Xa or thrombin, which are enzymes [that] are downstream in the coagulation pathway. Because [of this], they are critical enzymes for the formation of bad clots, which occlude vessels and cause a heart attack or a stroke or a deep vein thrombosis/pulmonary embolism. But that pathway is also involved in good clot formation. These are the clots that seal holes in damaged blood vessels. By definition, these downstream inhibitors will not distinguish between thrombosis, which is bad clot formation, and hemostasis, which is good clot formation. In contrast, factor XI is essential for bad clot formation, but mostly dispensable for good clot formation. Therefore, factor XI inhibitors have the potential to be safer by preventing the thrombotic complications but not causing the bleeding complications.
We have different types of factor XI inhibitors. We have an antisense oligonucleotide (fesomersen, Ionis) that reduces the synthesis of factor XI and lowers factor XI levels, and the antibodies like abelacimab that bind to factor XI and paralyze it by preventing it from getting activated completely. And whether you knock down the levels or block its activation completely, the end result is that you don’t generate the active form, factor XIa, which would attenuate thrombosis and should be safe.
Then we have the small-molecule factor XIa inhibitors like milvexian and asundexian. What they do is once factor XIa is generated, then they have to race in and block its activity. It’s a little bit different in the mechanism by which they work.
In addition, the antibodies and the antisense oligonucleotides have to be given by subcutaneous injection — in the case of the antibodies, possibly intravenous injection — while the small molecules are given orally. The small molecules have to be given once or twice per day, and the antibodies and the antisense oligonucleotide probably once per month, possibly even longer.
Healio: Do subcutaneous formulations offer any advantages/disadvantages compared with oral formulations?
Weitz: The potential advantage of subcutaneous formulations is the duration of action. If you use them, it obviates the need for once- or twice-daily administration. We know from the DOACs that patients frequently forget to take a dose of their oral medications. It is estimated that with twice-daily medications, they might forget to take a dose as many as four times per week. That’s a problem. Adherence can be facilitated with subcutaneous administration once per month. The question is whether there is a disadvantage to that. One could be that the drug hanging around for a month could be a problem if there is a safety issue. Data so far from AZALEA-TIMI 71 show that with potent factor XI inhibition for almost 2 years with abelacimab, there was less bleeding than with rivaroxaban (Xarelto, Janssen/Bayer), one of the state-of-the-art DOACs of today. I think that is reassuring. Also, unlike the DOACs, which have to be stopped before every type of procedure, maybe we don’t have to stop factor XI inhibitors around the time of most procedures. The subcutaneous formulations may have advantages in terms of efficacy and adherence, as we can make sure patients will continue to take them the way they are supposed to.
Healio: Do monoclonal antibody agents offer any advantages/disadvantages compared with small molecule agents?
Weitz: The monoclonal antibodies can be given intravenously for an immediate effect or subcutaneously once per month for a longer effect with slower onset. The advantages of the extended duration of action means that if you are using it for prophylaxis, one dose provides 30 days of that, which you can’t do with an oral agent. Not all monoclonal antibodies against factor XI are created equal. Abelacimab is now in phase 3, but other antibodies such as osocimab (Bayer) inhibit the activated form of factor XI, and another (xisomab, Aronora) blocks factor XI activation by factor XIIa but not by thrombin. The big advantage of the monoclonal antibodies is the potential for rapid onset if you need that, and the extended duration, if it is safe, could give you better adherence. Antibodies like abelacimab could provide a more potent form of inhibition because they bind to the inactive form of factor XI and prevent it from getting activated. That creates the equivalent of factor XI deficiency, which is a more potent mechanism than waiting for the XIa, which propagates coagulation, to be activated, and then to catch it; it is always a race.
Healio: Why do you think the OCEANIC-AF trial failed?
Weitz: The most likely reason the trial failed is that the dose that was selected was too low. If we look at the OCEANIC program, the same dose of asundexian was being evaluated for recurrent stroke prevention, where it was being compared with placebo, on top of antiplatelet agents, and for stroke prevention in atrial fibrillation, where it was being compared with an active comparator, apixaban. There is very little precedent for the same drug concentration to be used for those two indications. Typically, when we are trying to prevent a clot in someone with stroke, we would go lower than we would when trying to prevent a clot in someone with atrial fibrillation, or at least think about a different dosing regimen. I think the dose to go against apixaban was too low.
To put it into context with milvexian, the dose of milvexian being trialed in the LIBREXIA-AF program is fourfold higher than the dose of asundexian that was used in the OCEANIC-AF program. The reason for that is the phase 2 knee replacement study with milvexian indicated that, if we think the two agents are equally potent, then a dose of 50 mg of milvexian was similar to enoxaparin for prevention of postoperative venous thromboembolism, whereas the dose selected for the LIBREXIA-AF program, 100 mg twice per day, was significantly superior to enoxaparin. And I think you need a dose that is more potent when you are going head-to-head with a potent anticoagulant like apixaban. I think it’s just a dosing problem.
Healio: Now that the news of OCEANIC-AF is out there, what are the implications for factor XI/XIa inhibitors going forward?
Weitz: The OCEANIC-AF data is all the more reason why we need to continue the current studies. We need to evaluate the factor XI hypothesis and see whether it’s true that factor XI inhibition can provide effective antithrombotic activity with reduced risk for bleeding. If we stop now, we’ll never know the answer to that. I think OCEANIC-AF reflects a problem with the dose, not a problem with the hypothesis. In support of that, to use an example related to abelacimab, we have the AZALEA TIMI-71 results. While it is a phase 2 study, it is a study where people with AF at moderate risk for stroke were treated with abelacimab, a potent factor XI inhibitor, for almost 2 years, and bled much less often compared with rivaroxaban, a DOAC. Abelacimab is also being compared with apixaban in the ASTER study in patients with cancer-associated venous thromboembolism, and there is no one at greater risk for recurrent thrombosis than patients with cancer. If abelacimab was failing in that setting, the data monitoring committee would have shut that study down by now. But they just recently had a look and gave a green light to keep going. I think if it can work in the setting of an already-established clot, then it has got to work for clot prevention.
The worst thing that could happen is that the OCEANIC-AF result leads to a halt in all factor XI studies. As I see it going forward, I don’t think that’s going to happen, and that’s a good thing. We need to continue these studies to drill down on the factor XI hypothesis.
Reference:
- OCEANIC-AF study stopped early due to lack of efficacy. https://www.bayer.com/media/en-us/oceanic-af-study-stopped-early-due-to-lack-of-efficacy. Published Nov. 19, 2023. Accessed Dec. 4, 2023.
For more information:
Jeffrey I. Weitz, MD, can be reached at weitzj@taari.ca.
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