asundexian (BAY 2433334) / Bayer - LARVOL DELTA

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

Asundexian versus Apixaban in Patients with Atrial Fibrillation. (PubMed, N Engl J Med) - P3 | "Among patients with atrial fibrillation at risk for stroke, treatment with asundexian at a dose of 50 mg once daily was associated with a higher incidence of stroke or systemic embolism than treatment with apixaban in the period before the trial was stopped prematurely. There were fewer major bleeding events with asundexian than with apixaban during this time. (Funded by Bayer; OCEANIC-AF ClinicalTrials.gov number, NCT05643573; EudraCT number, 2022-000758-28.)."

Journal • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Nephrology • Renal Disease

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

Journal • Atrial Fibrillation • Cardiovascular

OCEANIC-AF - Asundexian versus apixaban in patients with atrial fibrillation (ESC 2024) - No abstract available

Clinical • Atrial Fibrillation • Cardiovascular

Factor XI inhibitors - Rising stars in anti-thrombotic therapy? (PubMed, J Neurol Sci) - "One large phase 3 study is testing the mAbs Abelacimab in patients with atrial fibrillation. The synthetic, small molecules Asundexian and Milvexian are tested in several phase 3 trials, mainly in patients with non-cardioembolic ischemic stroke. Results can be expected in the coming years. Clinical testing of ASOs to inhibit factor XI are still in their infancies."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Ischemic stroke • Musculoskeletal Diseases • Orthopedics

Therapeutic Potential of FXI Inhibitors: Hype or Hope? (PubMed, Drugs) - "A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs."

Journal • Review • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Ischemic stroke • Myocardial Infarction • Nephrology • Orthopedics • Pain • Renal Disease • Thrombosis

Pharmacokinetics, pharmacodynamics, and safety of asundexian in healthy Chinese and Japanese volunteers, and comparison with Caucasian data. (PubMed, Clin Transl Sci) - "Asundexian induced dose-dependent prolongation of activated partial thromboplastin time and inhibition of FXIa activity, with no effects on prothrombin time or FXI concentration in Japanese participants. There were no clinically relevant interethnic differences in PK profile across the Japanese, Chinese, and Caucasian (data from the previous phase I study) participants and no clinically relevant difference in PD response between Japanese and Caucasian participants."

Clinical • Journal • PK/PD data • Cardiovascular

What is the Future Position of Factor XIa Inhibitors for Patients with Atrial Fibrillation? (PubMed, Eur Cardiol) - "However, the OCEANIC-AF study was recently halted due to the inferior efficacy of asundexian versus the apixaban control arm. The present report describes up-to-date evidence of FXIa inhibitors and discusses the future position of FXIa inhibitors for patients with AF."

Journal • Review • Atrial Fibrillation • Cardiovascular • Thrombosis

Factor XI inhibition in patients with acute coronary syndrome. (PubMed, Eur Heart J Suppl) - "In this study, the primary endpoint-represented by the Bleeding Academic Research Consortium (BARC) composite of Type 2, 3, or 5 bleeding-showed no significant differences between the various doses of asundexian tested (10, 20, and 50 mg quoque die), and between these and placebo (asundexian all doses vs. placebo: hazard ratio, 0.98; 90% confidence interval, 0.71-1.35). The data on efficacy, however, showed neutral results, but it should be noted that the study did not have the adequate statistical power to evaluate this outcome. Valuable information could, therefore, derive in the future from the ongoing Phase 3 trial with milvexian, LIBREXIA-ACS (A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome) and from any future studies that could be started by testing different molecules."

Journal • Acute Coronary Syndrome • Cardiovascular • Hematological Disorders • Myocardial Infarction • Thrombosis

Exploring the therapeutic utility of the factor XIa inhibitor asundexian. (PubMed, Am J Health Syst Pharm) - "Phase 3 trials have recently been launched; however, the OCEANIC-AF trial was prematurely discontinued due to inefficacy of asundexian vs apixaban for stroke prevention in atrial fibrillation. Another phase 3 trial, OCEANIC-AFINA, is planned to compare asundexian to placebo in patients with atrial fibrillation at high risk for stroke who are deemed ineligible for anticoagulation."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Ischemic stroke • Myocardial Infarction • Thrombosis

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 | Recruiting | Sponsor: Bayer | N=9300 ➔ 12300

Enrollment change • Cardiovascular • Ischemic stroke

Asundexian in atrial fibrillation: A predictable failure based on pharmacodynamic data (ISTH 2024) - P3 | "The concentrations needed to halve the peak and the mVRI in PPP reagent low were above 1500 ng/mL for asundexian and around 400 ng/mL for milvexian. Pharmacokinetic investigations showed that the maximum concentration (Cmax) of asundexian (oral doses from 25 to 100 mg once daily) and milvexian (100 mg once daily) were 358 to 1230 ng/mL and 350 to 1000 ng/mL, respectively. Inhibition with apixaban was more potent in all conditions."

PK/PD data • Atrial Fibrillation • Cardiovascular

Asundexian in atrial fibrillation: A predictable failure based on pharmacodynamic data (ISLH 2024) - P3 | "We aimed to investigate the thrombin generation assay profiles of asundexian, milvexian and apixaban to detect possible differences that could explain the results of the OCEANIC-AF trial. Pharmacokinetic investigations showed that the maximum concentration (Cmax) of asundexian (oral doses from 25 to 100 mg once daily) and milvexian (100 mg once daily) were 358 to 1230 ng/mL and 350 to 1000 ng/mL in plasma, respectively. Conclusion These results confirm that asundexian 50 mg daily is unable to prevent thromboembolism in patients with AF while milvexian 100 mg twice daily (LIBREXIA-AF, NCT05757869) may be more adequate in this setting."

PK/PD data • Atrial Fibrillation • Cardiovascular

DUAL VERSUS SINGLE ANTIPLATELET THERAPY IN PATIENTS WITH ACUTE ISCHEMIC NON-CARDIOEMBOLIC STROKE AND AVAILABLE MRI - PLACEHOLDER (ESOC 2024) - "Participants were prescribed DAPT or SAPT at the discretion of the treating physician and were randomized to placebo or asundexian, a factor XIa inhibitor... Pending: PLACEHOLDER ABSTRACT."

Clinical • Cardiovascular • Ischemic stroke