Asundexian Phase 3 AF Study Halted for Lack of Efficacy

The phase 3 OCEANIC-AF trial of the investigational oral factor XI inhibitor asundexian (Bayer) has been stopped early due to inferior efficacy of the drug in comparison with apixaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF).

This decision is based on the recommendation of the study's independent data monitoring committee (IDMC) after ongoing surveillance showed that asundexian was inferior in efficacy to apixaban, Bayer announced.

The company says it will further analyze the data to understand the outcome and will publish them at a later date. Appropriate measures will be taken to close the OCEANIC-AF study. Patients will be contacted by their treating physicians/investigators to discuss next steps.

The co-chair of the OCEANIC-AF trial, Manesh Patel, MD, Duke Clinical Research Institute, Durham, North Carolina, commented to theheart.org | Medscape Cardiology: "At this stage, there is no explanation why asundexian did not have the desired effect on efficacy in terms of stroke prevention in patients with atrial fibrillation in OCEANIC-AF, and this will further be explored with additional analyses. Available safety data are consistent with previously reported safety profiles of asundexian. It is important to recognize that we were testing the agent against effective stroke prevention therapy."

Another phase 3 trial of asundexian in patients after an acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, OCEANIC STROKE, is continuing as planned. In that trial, asundexian is being compared to placebo on top of standard of care (antiplatelet therapy).

The IDMC recommended that OCEANIC STROKE continue as planned; thus, this study is not affected, Patel added.

"We conduct these studies to move medicine and our care forward, and when they are not successful, it is disappointing for our patients, our investigators, and our teams," Patel noted. "However, over the upcoming days and weeks we will continue to explore and learn from these results and share them they become fully available."

"Although the results from this analysis do not support the continuation of the OCEANIC-AF study, we will continue investigating asundexian in the OCEANIC-STROKE study and are currently re-evaluating other indications in patients in need of antithrombotic treatment," Christian Rommel, PhD, Global Head of Research and Development at Bayer, confirmed in the company press release.

Other evidence suggests benefit of anticoagulation therapy on top of standard of care in the population enrolled in the OCEANIC-STROKE study, which currently lacks adequate treatment options, the company says.

A third phase 3 trial, OCEANIC-AFINA, was planned in which asundexian was to be compared with placebo in AF patients at high risk for stroke or systemic embolism who were deemed ineligible for oral anticoagulant treatment because of bleeding concerns. This trial has not yet started recruiting patients; Bayer says it will now reevaluate the study design in light of the OCEANIC-AF decision.

Phase 2 studies have shown far less bleeding with factor XI inhibitors than with NOAC agents such as apixaban and rivaroxaban, and it was hoped that these agents would bring about safer anticoagulation.

The OCEANIC-AF study is one of the first major efficacy trials of a factor XI inhibitor. Other similar agents are being studied in phase 3 efficacy trials in AF patients, including abelacimab (Anthos), a monoclonal antibody given by subcutaneous injection once a month; and another small molecule, milvexian (BMS/Janssen).

The stopping of the OCEANIC-AF trial for lack of efficacy will be seen as a massive blow to the whole factor XI inhibitor field. These agents were being heralded as possible anticoagulation candidates without the high risk of bleeding risk associated with previous therapies.

John Alexander, MD, Duke University Medical Center, who is involved in clinical trials with asundexian including OCEANIC-AF, agreed this will have implications for the rest of the field.

"This certainly has implications for the development of factor XI inhibitors. We just don’t entirely know what these implications are as yet," he told theheart.org | Medscape Cardiology.

"It seems that asundexian at the dose of 50 mg daily doesn’t work as well as apixaban to prevent stroke in patients with AF. This could be that the dose is wrong, that the drug (asundexian) doesn’t work as well as apixaban for stroke prevention in AF, or that factor XI inhibitors don’t work for stroke prevention in AF. We still have more to learn," Alexander added.

Also commenting on this latest development for theheart.org | Medscape Cardiology, Christian Ruff, MD, Brigham and Women’s Hospital, Boston, who was lead investigator in recently reported phase 2 study of another factor XI inhibitor abelacimab, said the announcement was "certainly disappointing."

He noted that this demonstrates the importance of phase 3 trials in showing efficacy of novel therapies. "Other phase 3 trials will tell us whether the inferior efficacy is a class effect or not," he added.

Ruff pointed out that there were differences between the different factor XI inhibitors being studied that may be important.

"The antibody abelacimab prevents the formation of activated factor XI entirely, whereas small molecules such as asundexian and milvexian inhibit factor XI after it is already activated. There are also differences in the potency of factor XI inhibition across the agents and doses selected, which may be important clinically," he said.

Ruff pointed out that the 150-mg dose of abelacimab that was studied in the phase 2 AZALEA-TIMI 71 and the phase 3 LILAC-TIMI 76 AF trials "is highly potent, with around 99% inhibition of factor XI," and that it has also demonstrated efficacy in preventing venous thromboembolism (VTE) in phase 2 orthopedic surgery studies.

"Such efficacy in preventing VTE in the development of other classes of anticoagulants, such as the NOACs\DOACs, has translated to efficacy in stroke prevention in AF. Certainly, we will all be closely following the ongoing phase 3 trials," he added.

The LILAC-TIMI 76 trial is testing abelacimab against placebo in AF patients deemed unsuitable for currently available anticoagulation.

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Asundexian Phase 3 AF Study Halted for Lack of Efficacy

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