asundexian (BAY 2433334) / Bayer - LARVOL DELTA

Factor XI inhibitors and atrial fibrillation: imminent breakthrough or false start? (PubMed, Eur Heart J Suppl) - "Molecules such as abelacimab, asundexian, and milvexian are under investigation for the prevention of thrombo-embolic events in patients with AF...The phase 2 AZALEA-TIMI 71 trial was prematurely terminated after demonstrating a clear reduction in the incidence of major bleeding with abelacimab compared to rivaroxaban, whereas the phase 3 OCEANIC-AF study on asundexian was stopped due to inferiority compared to apixaban. Ongoing trials, such as LILAC-TIMI 76 and LIBREXIA-AF, are crucial to confirm the efficacy and safety of this therapeutic class. While FXI inhibitors represent a potential breakthrough in the treatment of AF, further data are needed to determine their definitive role in clinical practice."

Journal • Atrial Fibrillation • Cardiovascular • Ischemic stroke

A Systematic Review of Factor XI/XIa Inhibitors Versus Direct Oral Anticoagulants in Patients with Atrial Fibrillation. (PubMed, Clin Appl Thromb Hemost) - "In AZALEA-TIMI 71, abelacimab reduced major or clinically relevant non-major bleeding by 62%-69% versus rivaroxaban...However, OCEANIC-AF showed asundexian was inferior in stroke prevention, with a 3.8-fold higher risk of stroke or systemic embolism compared to apixaban, leading to early trial termination. Abelacimab showed a trend toward higher ischemic stroke rates abelacimab (150 mg: 1.21 vs 0.59 events/100 person-years; and 90 mg: 1.24 vs 0.59 events/100 person-years), though not statistically significant.ConclusionFactor XI/XIa inhibitors significantly reduce bleeding risk in AF patients compared to DOACs, but their thrombotic efficacy remains uncertain. While promising, further research is needed to optimize their use."

Journal • Review • Atrial Fibrillation • Cardiovascular • Ischemic stroke

Hemorrhagic Infarction Does Not Worsen Functional Outcomes in Noncardioembolic Ischemic Stroke-Secondary Analysis From PACIFIC-STROKE. (PubMed, Stroke) - "This was a secondary analysis of the PACIFIC-STROKE trial (Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2433334 in Patients Following Acute Noncardioembolic Stroke), which enrolled patients with acute noncardioembolic ischemic stroke receiving either asundexian or placebo in addition to guideline-based antiplatelet therapy...Of note, the type of iron-sensitive sequences did not modify the results. The presence of HI did not lead to poor functional outcome on the modified Rankin Scale in patients with acute noncardioembolic ischemic stroke."

Journal • Cardiovascular • Hematological Disorders • Ischemic stroke

ORAL ANTICOAGULANTS IN ELDERLY PATIENTS WITH ATRIAL FIBRILLATION: A FREQUENTIST NETWORK META-ANALYSIS - Mrinal M. Krishna (ACC 2025) - "The risk of stroke/embolism was reduced with apixaban, rivaroxaban, and dabigatran compared with VKA. Asundexian increased the risk of stroke/embolism compared with all other drugs... In elderly patients with AF, apixaban had the highest likelihood of lower stroke/embolism, major bleeding, and ICH compared with other OACs."

Retrospective data • Atrial Fibrillation • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders

Factor XI inhibitors for the prevention and treatment of venous and arterial thromboembolism. (PubMed, Nat Rev Cardiol) - "Phase II trials in orthopaedic surgery showed dose-dependent reductions in venous thromboembolism without significantly increasing bleeding compared with enoxaparin. In the first phase III trial of a small-molecule inhibitor of activated factor XI in patients with atrial fibrillation, asundexian was associated with a reduction in bleeding but also a higher risk of stroke, compared with apixaban. Factor XI inhibitors appear safe and hold promise for secondary prevention in myocardial infarction and ischaemic stroke, with ongoing phase III trials assessing their broader efficacy and safety. This Review discusses the rationale, pharmacology, evidence and future directions of factor XI inhibitors across various clinical settings."

Journal • Review • Atrial Fibrillation • Cardiovascular • Ischemic stroke • Myocardial Infarction • Orthopedics • Venous Thromboembolism

Asundexian versus Apixaban in Patients with Atrial Fibrillation. (PubMed, N Engl J Med) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular

Asundexian versus Apixaban in Patients with Atrial Fibrillation. (PubMed, N Engl J Med) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular

Asundexian versus Apixaban in Patients with Atrial Fibrillation. Reply. (PubMed, N Engl J Med) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular

Asundexian or Apixaban in Patients With Atrial Fibrillation According to Prior Oral Anticoagulant Use: A Subgroup Analysis of the OCEANIC-AF Randomized Clinical Trial. (PubMed, JAMA Cardiol) - P3 | "The mechanism of these findings is unknown and deserves further research. ClinicalTrials.gov Identifier: NCT05643573."

Clinical • Journal • Atrial Fibrillation • Cardiovascular

OCEANIC-STROKE: A Study to Test Asundexian for Preventing a Stroke Caused by a Clot in Participants After an Acute Ischemic Stroke or After a High-risk Transient Ischemic Attack, a So-called Mini Stroke (clinicaltrials.gov) - P3 | N=12300 | Active, not recruiting | Sponsor: Bayer | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Ischemic stroke

Discovery of potent, highly selective, and orally bioavailable factor XIa inhibitors for anticoagulant therapy. (PubMed, Eur J Med Chem) - "Compound 43 significantly reduced thrombosis in both FeCl3-induced mouse and rabbit arterial thrombosis models, demonstrating superior efficacy compared to asundexian. Importantly, 43 did not increase bleeding risks and exhibited a favorable safety profile in mice, suggesting its potential as a promising FXIa inhibitor for the treatment of thrombosis."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

Dual versus single antiplatelet therapy in patients with non-cardioembolic acute ischemic stroke and baseline MRI. (PubMed, Eur Stroke J) - "Post hoc analysis of the Phase 2 PACIFIC-STROKE randomized clinical trial, which enrolled patients with non-cardioembolic stroke, all with baseline MRI and compared the Factor XIa inhibitor asundexian with placebo on a background of DAPT or SAPT...Stroke size did not modify the effect of DAPT on the safety endpoint. We found no evidence of major treatment effect heterogeneity with DAPT compared with SAPT in patients with and without LAA or by stroke size on MR-DWI."

Clinical • Journal • Atherosclerosis • Cardiovascular • Ischemic stroke

The emerging role of anticoagulants targeting factor XI in thromboembolism management. (PubMed, Expert Rev Respir Med) - No abstract available

Journal • Cardiovascular • Hematological Disorders • Oncology • Thrombosis

New Targets for Antithrombotic Medications: Seeking to Decouple Thrombosis from Hemostasis. (PubMed, J Thromb Haemost) - "Among the factor XI/XIa inhibitors of coagulation, a parenterally administered monoclonal antibody (abelacimab) and two orally administered small molecule inhibitors (asundexian, milvexian) are collectively being studied in patients with atrial fibrillation, cancer-associated venous thromboembolism, acute coronary syndrome, and ischemic stroke. One parenterally administered glycoprotein VI antiplatelet agent (glenzocimab) is currently being studied in patients with ischemic stroke. If shown to be efficacious and safe in ongoing phase 3 studies, both classes of emerging antithrombotic agents have the potential to greatly improve outcomes for patients with challenging thrombotic conditions."

Journal • Review • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Ischemic stroke • Nephrology • Oncology • Renal Disease • Thrombosis • Venous Thromboembolism

Discovery of potent and selective factor XIa inhibitors incorporating triazole-based benzoic acid as novel P2' fragments: Molecular dynamics simulations and anticoagulant activity. (PubMed, Eur J Med Chem) - "The representative compound (S)-10h (IC50 = 0.38 nM for FXIa) was approximately 3-fold more potent than asundexian for FXIa, along with up to 150-fold selectivity over PKa (13-fold for asundexian) and up to 100,000-fold selectivity over FXa and thrombin (5000-fold for asundexian)...Moreover, compound (S)-10h demonstrated potent in vitro anticoagulant activity with an EC1.5X value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound (S)-10h represents a promising lead for further optimization as a novel anticoagulant agent."

Journal

Asundexian: Primary completion of P3 OCEANIC-STROKE trial (NCT05686070) for prevention of 2⁰ stroke by end of 2025 (Bayer AG) - Q3 2024 Results

Trial primary completion date • Cardiovascular • Ischemic stroke

Effect of Age, Sex, Renal Impairment and Hepatic Impairment on the Safety, Pharmacokinetics and Pharmacodynamics of Asundexian. (PubMed, Clin Pharmacokinet) - "The effects of the investigated intrinsic factors on the exposure of asundexian were small and not considered clinically relevant. The impact of lower exposure in participants with ESKD requires further investigation. Pharmacodynamics were as expected."

Journal • PK/PD data • Cardiovascular • Chronic Kidney Disease • Hepatology • Nephrology • Renal Disease

Breaking boundaries: exploring recent advances in anticoagulation and thrombosis management: a comprehensive review. (PubMed, Ann Med Surg (Lond)) - "Asundexian, in the PACIFIC-AF trial, demonstrated a 34% reduction in bleeding events compared to Apixaban. In the RIVER trial, Rivaroxaban reduced significant bleeding events by 20% compared to warfarin in patients with bioprosthetic mitral valves. In the ENAVLE trial, Edoxaban achieved a 3.7% decrease in thromboembolic events compared to warfarin without increasing significant bleeding rates...Lastly, the ARCADIA trial highlighted that apixaban did not significantly reduce recurrent stroke risk compared to aspirin, with both treatments having an annualized stroke rate of 4.4%...While recent trials show promising data, ongoing patient-specific responses and monitoring challenges require further research. Continuous innovation and investigation are essential to refine anticoagulation practices and tailor treatments."

Journal • Review • Cardiovascular • Hematological Disorders • Myocardial Infarction • Pulmonary Embolism • Respiratory Diseases • Thrombosis

The impact of OCEANIC-AF and the future of factor XIa inhibitors. (PubMed, Med) - "The OCEANIC-AF trial was terminated early due to inferiority of asundexian compared with apixaban for the prevention of stroke and systemic embolism in patients with atrial fibrillation.1 However, the promisingly low bleeding rates support continued exploration of factor XIa inhibitors. Future efforts should focus on achieving greater factor XIa inhibition and identifying patient populations that may benefit most from these therapies."

Journal • Atrial Fibrillation • Cardiovascular

Structure-based design and synthesis of novel FXIa inhibitors targeting the S2' subsite for enhanced antithrombotic efficacy. (PubMed, Mol Divers) - "In this study, we designed and synthesized a series of novel FXIa inhibitors based on the structure of Asundexian, with a particular focus on optimizing the P2' region to enhance binding to the S2' subsite of FXIa...Further studies demonstrated that F47 exhibits dose-dependent antithrombotic efficacy in a rat FeCl3-induced thrombosis model. Ongoing research aims to further elucidate the potential of compound F47 as a promising lead in antithrombotic therapy."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

Weekly Journal Scan: the rise and OCEANIC fall of asundexian in atrial fibrillation. (PubMed, Eur Heart J) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular

OCEANIC-AF and the inferior efficacy of asundexian compared to apixaban in patients at high risk with atrial fibrillation: Have we come to the end of the road for factor XIa inhibitors? (PubMed, Am Heart J Plus) - No abstract available

Journal • Atrial Fibrillation • Cardiovascular

Laboratory Evaluation of Interferences Associated with Factor XIa Inhibitors Asundexian and Milvexian in Routine Coagulation Assays. (PubMed, Diagnostics (Basel)) - "Asundexian and milvexian induce concentration-dependent prolongations in APTT-based assays with curvilinear regressions, which may be suitable for the measurement of pharmacodynamic effects at peak levels ex vivo. We also report differential sensitivities of APTT-based assays-particularly at higher FXIa inhibitor concentrations-highlighting the clinical need for an extensive evaluation of interferences associated with FXIa inhibitors in coagulation assays."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

A pharmacokinetic and pharmacodynamic evaluation of asundexian: a novel factor XIa inhibitor for stroke prevention. (PubMed, Expert Opin Drug Metab Toxicol) - "Despite asundexian being inferior to apixaban for cardioembolic ischemic stroke, it could be useful in patients with non-cardioembolic ischemic stroke. However, clinical trials on asundexian confirmed its safety for bleeding, even when used with antiplatelets. A phase 3 trial is currently investigating the efficacy of asundexian in preventing non-cardioembolic ischemic stroke."

Journal • PK/PD data • Review • Cardiovascular • Hematological Disorders • Ischemic stroke

OCEANIC-AF: Asundexian vs. Apixaban in Patients With AFib (American College of Cardiology) - P3 | N=14,830 | OCEANIC-AF (NCT05643573) | Sponsor: Bayer | "Asundexian was associated with a higher incidence of stroke or systemic embolism, but less major bleeding, compared with apixaban among patients with atrial fibrillation (AFib) who were at high risk for stroke, based on findings from the OCEANIC-AF trial presented at ESC Congress 2024 in London and simultaneously published in The New England Journal of Medicine. However, researchers noted that the trial was stopped prematurely and more research is necessary....OCEANIC-AF researchers randomized 14,810 patients to receive either 50 mg once daily of asundexian, an activated XI (Xia) inhibitor, or a standard dose of apixaban. Of the participants, 35.2% were women, 18.6% had chronic kidney disease, 18.2% had a previous stroke or transient ischemic attack, 16.8% had received oral anticoagulants for no more than six weeks, and the mean CHA2DS2-VASc score was 4.3±1.3."

P3 data • Atrial Fibrillation