Factor XIa Inhibitor After MI, Stroke Encouraging in Early Phase 2 Studies

August 29, 2022

The factor XIa inhibitor asundexian, envisioned as a safer alternative to current oral anticoagulants, didn't cause excess bleeding when given with antiplatelets in a pair of large phase 2, dose-ranging trials in different secondary-prevention settings.

Asundexian displayed nuanced potential for prevention of recurrent ischemic events in a subset of patients with recent noncardioembolic stroke in one of the studies, PACIFIC-STROKE, with about 1800 patients.

Its use didn't up the risk of bleeding of any type, despite almost totally suppressing factor XIa at one of the tested dosages, even when given on top of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) for acute myocardial infarction (MI) in the 1600-patient PACIFIC-AMI trial.

In that study, those who took asundexian at the highest dosage of 50 mg daily showed a more than 90% drop from baseline in factor XIa activity after 4 weeks of treatment. They experienced no more bleeds than patients given placebo at that or lower tested dosages.

And their risk for ischemic events — cardiovascular (CV) death, MI, stroke, or stent-thrombosis — was reduced over a median follow-up of about 1 year, reported John H. Alexander, MD, MHS, Duke Clinical Research Institute, Durham, North Carolina, August 28 at the European Society of Cardiology (ESC) Congress 2022, held in Barcelona, Spain.

PACIFIC-AMI was published in Circulation, with lead author Sunil V. Rao, MD, also from Duke Clinical Research Institute, to coincide with Alexander's presentation.

Both phase 2 studies are, by definition, exploratory and vastly underpowered for clinical outcomes; they are useful mainly for guidance on whether a drug in development should be pursued further.

There seems to be consistent agreement that, given asundexian's performance in the phase 2 trials, along with its mass of preclinical data, the drug should advance to more statistically powerful, potentially more decisive phase 3 trials.

In PACIFIC-STROKE, also presented that morning at the ESC Congress, patients with recent acute noncardioembolic stroke given asundexian at any of several dosages, or placebo, showed no significant reduction in risk for the primary endpoint of ischemic stroke or covert brain infarction at 6 months.

The neutral finding apparently stemmed from the second endpoint component, silent strokes revealed on MRI, for which "there was absolutely no effect," said Ashkan Shoamanesh, MD, McMaster University, Hamilton, Ontario, Canada, during a press conference on the pair of phase 2 trials.

A PACIFIC-STROKE post hoc analysis showed a sharp dose-dependent decline in the exploratory endpoint of ischemic stroke or transient ischemic attack (TIA), Shoamanesh noted. It was "a significant 36% risk reduction with the 50 milligram dose" that appeared to favor the prespecified subgroup of patients with disease in large arteries, such as the aorta or carotids.

Indeed, patients with any degree of extracranial or intracranial atherosclerotic disease on vascular imaging showed "a robust 61% relative risk reduction" for the ischemic stroke/TIA outcome.

The upshot, Shoamanesh said, is that in patients with noncardioembolic stroke, "the addition of a factor XIa inhibitor on top of background antiplatelet treatment seems to be targeting those with atherosclerotic disease contributing to their stroke."

The "Working Hypothesis"

Asundexian's apparent benefit for ischemic events in PACIFIC-STROKE patients with large-artery atherosclerosis might be, at first glance, somewhat at odds with the neutral clinical outcome in PACIFIC-AMI. But the researchers attributed that to differences between the two patient cohorts, as well as to background therapies.

The addition of a factor XIa inhibitor to antiplatelets, Shoamanesh told theheart.org | Medscape Cardiology, might more effectively prevent ischemic events related to large-artery atherosclerosis than coronaries involved in an acute MI. Large-artery plaque rupture is more likely to cause clots that embolize, whereas ruptured coronary lesions are more likely to trigger occlusive plaque thrombosis. Also, factor XIa's mechanism of action is directed more at thrombosis progression and is less involved in hemostatic responses, he explained.

So, factor XIa inhibition might have more opportunity to prevent ischemic events related to large-artery disease than those stemming from coronary disease. At least, Shoamanesh said, that's "the current working hypothesis."

Clinical outcomes might have differed in PACIFIC-AMI also because "our background antiplatelet therapy and our procedural therapies were very different," Alexander told theheart.org | Medscape Cardiology. "In PACIFIC-AMI, almost everybody was stented prior to randomization, and everybody was on dual antiplatelet therapy. And that's different from acute stroke in practice, currently."

The two trials follow the previously reported phase 2 PACIFIC-AF study, in which asundexian, given as 20 mg or 50 mg per day, significantly cut the risk of major bleeding, compared with the twice-daily factor Xa inhibitor apixaban (Eliquis), in patients with AF. In that trial, asundexian supressed factor XIa activity about as thoroughly as it did in PACIFIC-AMI.

Advancing to Phase 3

On the day the two studies were presented, manufacturer Bayer said it is launching a phase 3 asundexian program that is expected to involve tens of thousands of patients, starting with trials called OCEANIC-AF and OCEANIC-STROKE.

Discussion after Alexander's PACIFIC-AMI presentation turned to potential lessons that might inform the upcoming phase 3 trials. For example, what did the phase 2 studies say about the best dosage to explore?

In PACIFIC-AMI, "there was no clear signal toward either efficacy or bleeding," observed Michelle L. O'Donoghue, MD, MPH, Brigham and Women's Hospital, Boston, the invited discussant, after the presentation.

"Therefore, one must largely rely on factor XIa assays to guide phase 3 dose selection. And their correlation with major adverse cardiac events and bleeding remains incompletely defined." However, O'Donoghue added, "it is encouraging that there was no clear bleeding signal."

Still, said Alexander, "of the doses we studied in PACIFIC-AMI, the 50 mg dose looks very attractive. It doesn't seem to cause bleeding, at least not in a modest-sized phase 2 trial. And it almost completely inhibits factor XI, so taking that forward would be interesting."

Also attractive, he offered, are prospects for the de-escalation of antiplatelet therapies that accompany factor XIa inhibitors. If the drugs are clinically effective, "it would certainly be interesting to know what happens if you back off on antiplatelet therapy. Do you do you lose efficacy or do you maintain efficacy and get rid of bleeding?"


As presented by Shoamanesh, PACIFIC-STROKE enrolled 1,809 patients who were within 48 hours from the symptoms of a non-cardioembolic stroke. They were randomly assigned to placebo or one of 3 daily oral doses of asundexian and followed for an average of about 10 months.

There were no significant differences in the primary endpoint, ischemic stroke or covert brain infarct at 6 months, across the 4 groups, and no trace of a variable response by dosage.

But the post-hoc exploratory endpoint of recurrent ischemic stroke or TIA was significantly reduced at about 10 months in the asundexian 50 mg group compared to the control group, with a hazard ratio (HR) of 0.64 (90% CI 0.41 - 0.98).

Primary Efficacy* and Post Hoc Exploratory Outcomes by Asundexian Dosage
Endpoints 10 mg/d (n = 455) 20 mg/d (n = 450) 50 mg/d (n = 447) Placebo (n = 456)
Ischemic stroke or covert brain infarction, %* 18.9 22.0 20.1 19.1
Recurrent ischemic stroke or TIA, % 7.7 6.2 5.4 8.3

As the formal discussant after the PACIFIC-STROKE presentation, Elaine M. Hylek, MD, MPH, Boston University School of Medicine, pointed to the "interesting, dramatic effect on TIA" by asundexian in the exploratory analysis.

Although TIA could be considered a "softer endpoint," she said, "I think the validity of TIA in a double-blind design, especially in a stroke trial where stroke neurologists are adjudicating these events, really increases the robust nature of this finding."

The study's "home run" was the ischemic stroke/TIA endpoint's "very clear dose response as you look from the 10 to the 20 to the 50 milligram dose of asundexian," Hylek said. "It's difficult to attribute that type of a finding to chance, bias, or confounding."

The rate of major or clinically relevant nonmajor bleeding ranged from 3.1% to 4.3% across the four dosage levels, and it was 2.4% for placebo, with no significant differences. The rate of any bleeding ranged from 8.3% to 10.8% across the asundexian groups and was nonsignificantly different, at 9.7%, for placebo, Shoamanesh reported.


This trial assigned 1600 patients with acute MI — about half-and-half ST-segment-elevation MI and non-ST-segment elevation MI, almost all of whom underwent PCI and received DAPT — to asundexian at one of the three dosage levels or placebo. They were followed a median of 368 days.

Their DAPT included, other than aspirin, ticagrelor in 53%, prasugrel in 27%, and clopidogrel in 20% of cases.

Factor XIa activity after 4 weeks, compared with baseline, had dropped by more than 70% in the 10 mg group, more than 80% in the 20 mg group, and by more than 90% in the 50 mg group, Alexander reported.

Safety, Efficacy, and Other Outcomes by Asundexian Dosage
Endpoint 10 mg/d 20 mg/d 50 mg/d Placebo
BARC type 2, 3, or 5 bleeding, %* 7.6 8.1 10.5 9.0
Any bleeding, % 17.7 18.9 20.4 21.3
CV death, MI, stroke, or stent thrombosis, %† 6.8 6.0 5.5 5.5
BARC: Bleeding Academic Research Consortium
*Prespecified safety outcome
†Prespecified efficacy outcome

"The phase 2 study is important, showing the apparent safety of asundexian in addition to DAPT in [acute coronary syndromes], although the lack of signal for reducing ischemic events is disappointing," notes an editorial accompanying the PACIFIC-AMI report in Circulation.

"However, the apparent safety yet the numerically fewer ischemic events seen with the 50 mg asundexian dose is encouraging and suggests the need to properly evaluate the potential ischemic benefit of this dose," states the editorial, with lead author Ying X. Gue, MBChB, PhD, and senior author Gregory Y.H. Lip, MD, both from the University of Liverpool, United Kingdom.

Bayer's upcoming OCEANIC-AF trial will pit asundexian directly against apixaban as the antithrombotic given to patients with AF, and will track stroke or systemic embolism as the primary endpoint, Bayer said. "The first patients are expected to be enrolled later this year."

The OCEANIC-STROKE trial will test asundexian against placebo in patients with recent noncardioembolic ischemic stroke or high-risk TIA. It's primary goal, the company said, will be "to show a lower risk for ischemic stroke in comparison to placebo, without a significant increase in bleeding risk."

PACIFIC-AMI and PACIFIC-STROKE were funded by Bayer AG. Alexander discloses receiving research grants from Artivion/CryoLife, Bayer, Bristol-Myers Squibb, CSL Behring, Ferring, Humacyte, and XaTek; and serving on an advisory board or consulting for AbbVie, Akros, Artivion/CryoLife, AtriCure, Bayer, Bristol-Myers Squibb, Ferring, GlaxoSmithKline, Janssen, Pfizer, Portola, and Quantum Genomics. Shoamanesh discloses receiving grants from Bayer and consulting, owning stock or equity interest in, or receiving royalties from Bayer. O'Donoghue has disclosed receiving consulting fees or honoraria from Amgen, Janssen Pharmaceuticals, and Novartis; receiving research grants from Amgen, AZ Medimmune, Intarcia, Janssen Pharmaceuticals, Merck, and Novartis; and serving on a data safety and monitoring board for AZ Medimmune. Hylek discloses receiving research funding from Anthos Therapeutics, Bristol-Myers Squibb, Janssen, Medtronic, and Pfizer; and receiving honoraria from Bayer, Boehringer Ingelheim, and Pfizer.

European Society of Cardiology (ESC) Congress 2022: Hot Line Session 5. Presented August 28, 2022.

Circulation. Published online August 27, 2022. Full Text, Editorial

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