Translational Development of Oral FXIa Inhibitors: A Systematic Review of Molecular Design, Pharmacology, and Indication-Specific Clinical Evidence

Background/Objectives: Oral small-molecule inhibitors of activated factor XI (FXIa) are intended to attenuate thrombosis with less disruption of hemostasis than established anticoagulants, but clinical outcomes have not consistently paralleled pharmacodynamic target engagement. This systematic review integrated molecular design, preclinical pharmacology, human pharmacokinetics/pharmacodynamics (PK/PD), and clinical outcomes to identify where translation is maintained or lost. Methods: The review followed PRISMA 2020 and PRISMA-S and was registered in PROSPERO (CRD420261356169). PubMed/MEDLINE, Scopus, and Web of Science Core Collection were searched from inception through 30 March 2026 and rerun on 11 August 2026, with a final publication-eligibility cut-off of 30 June 2026. Owing to heterogeneity, evidence was synthesized narratively. Results: Sixty-eight eligible reports were included, comprising seven randomized parent outcome trials and nine reports with in vivo thrombosis or bleeding experiments. In the OCEANIC-STROKE trial, ischemic stroke occurred in 6.2% with asundexian versus 8.4% with placebo (HR 0.74, 95% CI 0.65–0.84), while major bleeding was 1.9% versus 1.7% (HR 1.10, 95% CI 0.85–1.44). In OCEANIC-AF, stroke or systemic embolism occurred in 1.3% with asundexian versus 0.4% with apixaban (HR 3.79, 95% CI 2.46–5.83), despite less major bleeding (0.2% vs. 0.7%; HR 0.32, 95% CI 0.18–0.55). Conclusions: Oral small-molecule FXIa inhibition is pharmacologically coherent, but clinical benefit is indication-, comparator-, and background-therapy-dependent. PD markers confirm target engagement but are not validated efficacy surrogates; hard clinical outcomes remain decisive.