The FXI Gamble: To Bleed Less... Or To Protect Less?

By Sarah Farah, M.Sc., Celeste Callafe, M.Sc., and Kasia Koczula, Ph.D., Lifescience Dynamics

For over a decade, direct oral anticoagulants (DOACs) have set the standard in modern anticoagulation, but key challenges still remain. A new generation of FXI and FXIa inhibitors is stepping in with bold promises to reduce bleeding while preserving DOAC-like efficacy. Is this merely a modest refinement or the start of anticoagulation’s next era?

The DOAC Era: A Transformative But Incomplete Solution

When DOACs were introduced for a range of thromboembolic disorders, they rapidly displaced traditional vitamin K antagonists (VKAs), revolutionized anticoagulation practice, and generated billions of dollars in annual sales for a handful of dominant players. By offering more predictable pharmacokinetics, and an enhanced efficacy and safety profile compared with VKAs, DOACs enabled far more patients to access and persist with lifesaving anticoagulant therapy.

Yet important unmet needs remain. Clinicians still struggle with bleeding risk, complex polypharmacy, and treating the frail, those with renal dysfunction, and other high-risk groups. Despite the advances brought by DOACs, residual risks of stroke, systemic embolism, and clinically relevant bleeding continue to pose challenges. Beyond atrial fibrillation (AF), key populations, such as patients undergoing total knee arthroplasty, those with cancer, or those with recent coronary stent placement, often lack antithrombotic options that fully address their clinical realities.

The Rise Of FXI And FXIa Inhibitors

Recent mid- to late-stage FXIa inhibitor data from Bayer’s asundexian, milvexian from Bristol Myers Squibb and Johnson & Johnson, Regeneron’s paired FXI antibodies, and others have started to clarify whether this class can deliver on its promise; however, the results have been mixed.

Asundexian has delivered a clear Phase 3 win in the Bayer-funded OCEANIC-STROKE trial when added to antiplatelet therapy in patients with non-cardioembolic ischaemic stroke or high-risk transient ischemic stroke (IS). While awaiting full data, Bayer plans to engage regulators globally in preparation for marketing authorization filings.

Yet, despite the success, asundexian is a clear reminder that FXIa inhibition is far from a straightforward win. The early termination of the Phase 3 OCEANIC-AF trial after a surprisingly inferior efficacy versus apixaban has renewed concerns on efficacy trade-offs.

On a similar note, BMS and J&J have also recently discontinued the Phase 3 LIBREXIA-ACS trial of milvexian after it was deemed unlikely to meet its primary efficacy endpoint. While this is a clear setback for the program in acute coronary syndrome, there is limited read-across to the ongoing LIBREXIA-AF and LIBREXIA-STROKE trials, involving different patient populations, endpoints, and disease biology, with pivotal data expected in 2026.

On a more positive note, Regeneron’s dual-antibody factor XI program, REGN7508^Cat and REGN9933^A2, has gained momentum following their data presentation at AHA 2025, with the former showing encouraging Phase 2 data in total knee replacement (TKR). Two Phase 3 TKR prevention studies, ROXI-APEX (versus apixaban and enoxaparin) and ROXI-ASPEN (versus aspirin), are now underway, alongside a Phase 2 ROXI-ATLAS trial in atrial fibrillation. From 2026, further Phase 3 studies are planned in additional indications, positioning the FXI program for large, underpenetrated markets where bleeding risk continues to constrain DOAC use.

Parallel to Regeneron’s efforts, abelacimab, another long-acting FXI inhibitor now backed by Novartis following the Anthos acquisition, is steadily moving toward pivotal readouts. Phase 2 AZALEA-TIMI 71 delivered a positive bleeding-reduction signal but was not powered for ischemic efficacy, further sharpening focus on the ongoing Phase 3 program. Multiple AF and cancer-associated venous thromboembolism studies are slated to read out in mid-2026 that will help determine the asset’s true competitive profile in a crowded space.

The setbacks seen to date highlight the complexity of managing antithrombotic disorders rather than overturning FXI as a target, but they also raise the stakes: robust positive data from FXI/FXIa inhibitors now in development will be critical to fully validate the mechanism’s therapeutic potential and define its place in the future antithrombotic landscape.

Positioning FXI Inhibition: Promise, Pressure, And The Path Forward

Taken together, the mixed recent readouts spotlight both the excitement for FXI inhibition in anticoagulation and the growing scrutiny the class is facing. While bleeding reductions and selective efficacy signals in certain cardiovascular populations have kept momentum alive, the multiple setbacks have sharpened focus on what truly matters for their successful adoption and determining where they truly fit.

Beyond just efficacy, clinical and pharmacokinetic considerations will increasingly shape differentiation: unlike DOACs, which have established shorter half-lives and benefit from the availability of reversal agents and well-defined emergency pathways, FXI/FXIa inhibitors currently have no approved or pipeline antidotes, creating a practical adoption hurdle in high-emergency scenarios like trauma, urgent surgery, or major bleeding.

The next few years will determine whether FXI inhibition represents an incremental refinement or a true redefinition of anticoagulation. However, safety gains alone will not be enough. With registrational trials and regulatory submissions underway, it remains far from certain whether FXI/FXIa inhibitors can repeat the DOAC history and reset the standard of care once again. The bar is clear now: deliver meaningful bleeding reduction while delivering credible thrombotic protection, while also fitting seamlessly into real-world clinical workflows. This also calls for more rigorous head-to-head comparisons versus established DOACs to really trigger real prescribing changes.

If that balance can be achieved, FXI inhibitors may unlock new treatment opportunities, including populations long underserved by current therapy, representing true market expansion. Failure to meet this bar would risk relegating FXI inhibition to a niche population rather than expanding the boundaries of current anticoagulation.

About The Authors:

Sarah Farah, M.Sc., is a senior business analyst at Lifescience Dynamics with robust experience covering and leading CI projects spanning multiple therapeutic areas including cardiovascular medicine (with three+ years in atrial fibrillation), respiratory disorders, and infectious diseases. Her work spans end-to-end pipeline strategy, regulatory life cycle, and conference intelligence, helping clients shape evidence-based decisions for brand and portfolio planning.

Celeste Callafe, M.Sc., is a junior business analyst at Lifescience Dynamics. She has worked across a broad range of therapeutic areas, including oncology, rare diseases, cardiovascular diseases, and women’s health. Callafe specializes in competitive intelligence, market research, and market access, supporting clients in shaping effective commercialization and medical strategies.

Kasia Koczula, Ph.D., is an engagement manager at Lifescience Dynamics, bringing over eight years of consulting experience in the life sciences sector. She holds a Ph.D. in hematological oncology and has worked across a broad range of therapy areas, including oncology, cardiovascular diseases, and rare diseases. Koczula specializes in competitive intelligence, market research, and strategic advisory services, supporting clients with evidence-based insights to drive informed decision-making.