Breakthrough or Bust? The Future of Anti-Factor XI Anticoagulants

Anti-Factor XI Anticoagulants: Breakthrough or Bust?

Anti-factor XI anticoagulants are garnering significant attention in the cardiology and thrombosis prevention fields due to their potential to prevent ischemic events while minimizing bleeding risks. Despite promising preclinical studies and early-phase trials, their clinical effectiveness remains uncertain following disappointing results from key phase 3 trials, particularly the OCEANIC-AF trial. This raises the question: will these new anticoagulants revolutionize stroke prevention and venous thromboembolism (VT) management, or will they remain niche treatments?

At the 2025 European Days of the French Society of Cardiology in Paris, experts gathered to discuss the future potential of factor XI inhibitors. These drugs are being tested in various forms, including oral, subcutaneous, and intravenous, for conditions that carry a high thromboembolic risk. Early trials have suggested they could offer advantages in terms of safety and efficacy compared to existing anticoagulants, particularly in high-risk populations. However, the OCEANIC-AF trial's findings raise critical doubts about their real-world applicability.

The OCEANIC-AF Trial and Unexpected Results

The OCEANIC-AF trial, which aimed to assess the efficacy of asundexian (Bayer), an anti-factor XI peptide, in preventing stroke in atrial fibrillation (AF), ended in disappointment. The results were a significant setback for the development of this class of anticoagulants. Asundexian showed nearly four times the ischemic risk compared to apixaban, a widely used direct oral anticoagulant (DOAC). These unexpected findings, particularly the increased risk of stroke and embolic events despite fewer bleeding incidents, have made the future of anti-factor XI inhibitors uncertain.

Dr. Nicolas Meneveau, a cardiologist from the University Hospital Jean Minjoz in France, noted the surprising nature of these results, particularly considering the previous success of phase 2 trials. The trial’s failure was attributed to several factors, including possibly an insufficient dose of asundexian. Furthermore, Meneveau mentioned the challenges of preventing venous thrombosis after orthopedic surgery—another indication where anti-factor XI drugs have not yet demonstrated clear benefit.

Ongoing Trials and Hopes for Post-Stroke Prevention

While the OCEANIC-AF trial was a major blow, the OCEANIC-STROKE trial is ongoing, evaluating the effects of asundexian in preventing post-stroke thromboembolic events. This study may provide further clarity on whether anti-factor XI anticoagulants can indeed offer an alternative to existing therapies like DOACs. The trial has yet to present any red flags that would necessitate its termination, but questions about the effectiveness of these inhibitors in high-risk populations remain.

Potential Advantages and Areas of Use

One of the main selling points of anti-factor XI anticoagulants is their ability to prevent thrombosis without significantly increasing bleeding risks, a common concern with traditional anticoagulants. Research suggests that factor XI plays a pivotal role in thrombus formation, and inhibiting it could prevent thromboembolic events while leaving physiological hemostasis intact. This makes factor XI inhibitors particularly attractive for patients at high risk for thromboembolism, including those with end-stage renal disease, cancer, or mechanical heart valves.

Several promising drugs are currently in development, including FXI-ASO, an antisense RNA drug that demonstrated superior efficacy compared to enoxaparin in phase 2 trials for venous thrombosis prevention following knee replacement. Another drug, milvexian, is currently being evaluated for its potential to prevent ischemic events in patients with AF, stroke, or post-infarction. These therapies show promise, but ongoing phase 3 trials will be crucial in determining their long-term viability.

Shorter-Acting and Longer-Acting Inhibitors

Anti-factor XI inhibitors come in various formulations. Shorter-acting small peptide inhibitors, like asundexian, have been of particular interest due to their potential for oral administration. With a duration of action similar to DOACs (2-4 hours), these drugs could be taken once or twice daily. However, asundexian's once-daily dosing has been cited as a possible factor in its increased thrombotic risk, as the drug’s short half-life may not maintain sufficiently high anticoagulant levels throughout the day.

In contrast, milvexian, another anti-factor XI peptide, is dosed more frequently and has demonstrated higher factor XI inhibition rates. Phase 2 trials have shown promising results, particularly in preventing VT after knee replacement surgery. Nevertheless, these therapies have not yet been proven to prevent stroke recurrence, leaving clinicians cautious about their broader use.

Antibody-based inhibitors of factor XI, such as abelacimab, are also being investigated. These agents have a longer half-life (20-40 days) and are administered via a single monthly injection, making them more convenient for patients. Preliminary results suggest that abelacimab may be particularly effective at preventing VT after surgery and in patients with cancer. A phase 3 study (LILAC-TIMI) is currently evaluating its role in preventing ischemic risk in AF patients.

Conclusion

Anti-factor XI anticoagulants hold significant promise in treating thromboembolic diseases, but recent setbacks, including the failure of the OCEANIC-AF trial, have raised doubts about their widespread use. With several ongoing phase 3 trials, including studies of asundexian, milvexian, and abelacimab, the clinical community remains hopeful but cautious. Further data will be crucial to determining whether these agents can live up to their potential or remain limited to niche applications.