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A novel class of antithrombotic medication, the factor XIa inhibitors, has had a rocky start but is powering through phase III trials, which are now underway. MedPage Today sat down to discuss the novel agents with Graeme Hankey, MBBS, MD, of the University of Western Australia School of Medicine & Pharmacology and Sir Charles Gairdner Hospital, both in Perth, Australia. He's also co-chair of the Secondary Stroke Prevention Executive Committee and the Program Executive Council for the Librexia trial program for one of the factor XIa agents, milvexian.

A transcript of the conversation follows:

Phend: This is Crystal Phend and I'm with Dr. Graeme Hankey, who is the Perron Institute chair of stroke research at The University of Western Australia in Perth. And we're here at the American Stroke Association's International Stroke Conference in Phoenix, talking about some developments in antithrombotic medicine. So one of the major developments in recent years for antithrombotic medication has been the development of the direct oral anticoagulants. And for the U.S. market, the first of those was approved, rivaroxaban [Xarelto], in 2011. Has there been a sense among clinicians that they need better tools now for prevention?

Hankey: Yes, I think there is. The direct oral anticoagulants have been a major advance for our ischemic stroke patients with atrial fibrillation to prevent a recurrent ischemic stroke without as much bleeding, particularly intracranial bleeding, as there was with warfarin. But there's still a risk of major bleeding with the direct oral anticoagulants that can be up to about 2% per year, which tends to put some patients off wanting to actually take the medication, or some doctors prescribing a lower dose of the direct oral anticoagulants. So we still have an unmet need to reduce ischemic stroke from inappropriate treatment or undertreatment in up to 25% of patients, and also safer therapy, less bleeding.

Phend: Interesting. So where do the new class that's being developed, the factor XIa inhibitors, come into this?

Hankey: Well, the factor XIa inhibitors are drugs that are in development that have the potential from basic science and epidemiological studies to prevent thrombosis but without disrupting hemostasis. So there's a suggestion they could be as effective as the direct oral anticoagulants for stroke prevention and atrial fibrillation and be safer.

Phend: That's interesting. So how did the discovery of this newer class develop? Has it been known all along that this is a step in the clotting pathway that we would want to target if we were able to find effective agents?

Hankey: Well, it started out from observations that individuals who were born without factor XI activity -- so-called congenital factor XI missing or deficiency -- those people tended to have lower rates of stroke and clots in the veins but not bleed and not have spontaneous bleeding, except for perhaps in the nasopharynx or urogenital tract, which are rich in fibrinolytic activity. So there's an observational evidence that congenital factor XI deficiency may have low thrombosis rates without too much bleeding. And then epidemiological studies in people with low factor XI levels have had lower rates of ischemic cardiovascular events and venous thromboembolism.

So there's been an epidemiological background to look into the basic science of why inhibiting a coagulation upstream in the coagulation pathway, the intrinsic factor pathway, might prevent thrombosis without compromising hemostasis in contrast to the current-used direct oral anticoagulants, which inhibit the thrombin, the merging of the final common pathway of both the extrinsic and intrinsic pathway, where factor Xa and thrombin are components of both pathways. So rather than inhibit the final common pathway of anticoagulation, could inhibiting an upstream factor in one pathway help to uncouple thrombosis and hemostasis?

Phend: So my understanding is that these are oral small molecule drugs. Is it a challenge to develop an oral agent like this?

Hankey: Well, it is a challenge. And to go back, there are several factor XI inhibitors. There are [antisense oligonucleotides] that reduced synthesis of factor XI in the liver, and there's monoclonal antibodies against factor XI, and both of them are parenteral forms that are administered subcutaneously with a long half-life. And so they're sort of injected once every month, the antibodies or the antisense oligonucleotides. But then there are the small molecules which are orally administered and have very short half-lives. They work within 2 to 4 hours and have a half-life of about 13 to 16 hours or so and are given once or twice daily orally. So there are some parentally administered factor XI inhibitors, and there are a couple of orally administered factor XI inhibitors that are available or being tested.

Phend: So let's talk a little bit about two of these factor XIa inhibitors that are now in phase III research. Can you talk a little bit about the development program for those?

Hankey: Yes, well, there are two small molecules that are orally administered that inhibit activated factor XI, that is asundexian and milvexian.

And asundexian has been studied in the PACIFIC program, the and the PACIFIC-Stroke study and the PACIFIC AMI study. And milvexian has been studied in the AXIOMATIC deep venous thrombosis study and the AXIOMATIC-Secondary Stroke Prevention [SSP] trial. So those five studies have all been phase II studies looking at the safety of the factor XIa inhibitors given orally in preventing thrombosis, or particularly in whether they've been causing any bleeding.

Phend: And so have those phase II trial programs suggested that there's a lot of promise for these agents?

Hankey: Yes, the phase II trials in stroke, for example, the PACIFIC-Stroke and the AXIOMATIC-SSP studies have both shown that the oral factor XIa inhibitors compared to placebo in patients with ischemic stroke did cause a small increase in bleeding, but it wasn't statistically significant. And there was a trend towards a reduction in symptomatic ischemic stroke. But these studies were not efficacy studies, they were safety studies. They were looking for a dose response and trying to find out the right dose to take forward into phase III.

Phend: So now we do have some phase III trials underway. What does the clinical trial program look like? Are we getting close to having some of the data?

Hankey: Well, I don't think we're close to having the data because the main aim of the phase III studies in ischemic stroke is to see whether patients with acute non-cardioembolic ischemic stroke with mild-to-moderate severity with a National Institute of Health Stroke Scale score of less than 7 or less than 15 in the different trials, randomized to the addition of an oral factor XIa inhibitor, asundexian or milvexian, to standard dual or single antiplatelet therapy compared to placebo. So the milvexian or asundexian XIa inhibitor is compared to placebo on top of standard antiplatelet and other best medical therapy. And the primary aim is to see whether they prevent ischemic stroke over the next 3 years. So they've really only kicked off last year. They're long-term follow-up studies to see not only is the safety from the phase II studies confirmed, but moreover whether there's a signal of efficacy and do they reduce recurrent ischemic stroke by about a fifth or so.

Phend: So that could take some time.

Hankey: Yes, because it's all very well to recruit the patients, but the power and meaning of the study comes from the outcome events that will accrue over the next 3 years. So we probably will not see any results until like 2026.

Phend: OK. So these drugs are also being studied outside of stroke for cardiovascular prevention indications. Can you talk a little bit about those indications and the trials that are being run?

Hankey: Yes. So of course, the factor XIa inhibitors may not only reduce atherothrombosis of the cerebral blood vessels, or the blood vessels to the brain, but also the coronary arteries, the blood vessels to the heart. So there's an ongoing trial of milvexian compared to placebo in patients with acute coronary syndrome. And there's also the prevention of blood clots in the left atrium in atrial appendage in patients with atrial fibrillation. So there's an ongoing trial of milvexian compared to standard care with the factor Xa inhibitor apixaban [Eliquis] in patients with atrial fibrillation. So that's got an active drug comparator of a direct oral anticoagulant for the atrial fibrillation study, whereas the acute coronary syndrome and the two stroke studies, the two ischemic stroke studies, have placebo as a comparator.

Phend: Interesting. So one of the trials not too long ago reported that it was not going to be continued due to lack of efficacy. Is there concern that might be an indicator of concern for the other trials that are going on or might it just be a specific patient population? Can you compare it to what we saw with some of the direct oral anticoagulant trials?

Hankey: I'm not in much of a position to answer that. I just understand from what's been published in the press that the trial comparing the factor XIa inhibitor asundexian with standard direct oral anticoagulant in patients with atrial fibrillation was stopped prematurely. I think several thousand patients had been randomized and had been followed up, but I understand that it was stopped because of futility. They didn't think that the outcome event rates were consistent with a significant reduction in ischemic events, or there was no difference in safety. I'm not privy to those results, so I can only speculate. But it was very disappointing for the whole program to have done so much work to get that trial going and for patients to consent and be committed to the trial and be followed up.

Phend: So there have been times where we'll ask, is this a class effect? Are these drugs very similar to each other within the class, or are they different? And is there a sense of that yet within the factor XIa inhibitors based on perhaps the phase II data?

Hankey: It's hard to know that. I know from the AXIOMATIC-Secondary Stroke Prevention trial that five doses or a 16-fold range of doses of milvexian was studied. So it was quite a comprehensive assessment of the safety of milvexian over a 16-fold range of doses. The PACIFIC-Stroke trial studied 10, 20, and 50 mg of asundexian when it was once daily. So I'm not sure whether the whole range of the asundexian doses have been studied and I guess that's a question of whether 50 mg is the maximal dose. But so it's hard to know if it was... if it's a class effect or a dose effect or a power, statistical power or other effect.

Phend: So one of the, so to speak, holy grails of this area of medicine is to uncouple the bleeding risk and the efficacy and prevention. Do you feel like we're getting closer to that as we develop new agents here?

Hankey: Yes, I think we are -- well at least in theory -- because thrombosis and hemostasis is sort of a bit like real estate. It's location, location, location. And thrombosis is an intravascular process, whereas hemostasis is an extravascular process. So thrombosis occurs inside blood vessels or inside heart chambers or veins. So for example, with an atherosclerotic plaque, if that ruptures ... blood inside the vessel gets exposed to subendothelial or small amounts of tissue factor under the plaque in the vessel wall. And that exposure of blood to tissue factor triggers activation of the extrinsic pathway or the tissue factor pathway that generates small quantities of thrombin.

Now for the thrombus to grow under those circumstances, it requires thrombin-mediated back-activation of factor XI in the intrinsic pathway to generate more thrombin and grow the clot. So inhibiting factor XI upstream here stops that thrombus growth or amplification of coagulation. Now, of course, exposure of blood to subendothelial collagen or polyphosphates, such as inorganic polyphosphates from activated platelets, they can activate the intrinsic pathway or the contact pathway and produce thrombin via factor XII and factor XI. And so that's another source of thrombosis, but that is also blocked by factor XI inhibitors. So factor XI is important for thrombosis whether by the extrinsic or tissue factor pathway or the intrinsic pathway. So inhibiting factor XI should stop intravascular thrombosis.

In contrast, hemostasis is an extravascular process. So when we cut ourselves and there's vascular injury, it breaches the adventitia surrounding the vessel wall and blood gets through the vessel wall and sees tissue factor outside the vessel wall and tissue factor is in abundance around blood vessels, particularly in the brain. And so once that blood sees all that tissue factor, it initiates the tissue factor or extrinsic pathway to produce explosive concentrations of thrombin and spark thrombosis to stop the bleeding.

And any thrombin-mediated back-activation of factor XI by the intrinsic pathway is almost redundant because there's already so much thrombosis from that extrinsic pathway because of all that tissue factor. So inhibiting factor XI here shouldn't really stop clotting due to bleeding, so hemostasis, whereas it should stop clotting in vessels due to atheroma. So that's the theory, and that's what we're testing out. That's the distinction between the Xa inhibitors and the direct thrombin inhibitors down the bottom of the final common pathway versus blocking just factor XI upstream in the intrinsic pathway.

Phend: That's very interesting. It sounds like we are getting closer to that holy grail in the antithrombotic medicine. So, well, thank you very much, Dr. Hankey, and I appreciate your time today.

Episode produced and hosted by Crystal Phend. Sound engineering by Greg Laub.

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