milvexian (BMS-986177) / BMS, J&J - LARVOL DELTA

Targeting factor XI as a compromise between thrombosis and bleeding. (PubMed, Cardiol J) - "They include: a) orally administered small molecule inhibitors such as milvexian and asundexian; b) monoclonal antibodies such as abelacimab, osocimab, and xisomab, which specifically bind and inactivate FXI; c) FXI-antisense oligonucleotide (FXI-ASO), which downregulate FXI synthesis at the mRNA level and reduce plasma FXI concentrations. Their development is an important step in the history of anticoagulant therapy, striving to find a balance between preventing thromboembolism and reducing bleeding risk, ultimately improving patient outcomes. In this context, a discussion on the characteristics of FXI inhibitors, a summary on data regarding the efficacy and safety of FXI inhibitors based on preclinical and clinical studies, and an outline of future perspectives regarding therapeutic strategies of FXI inhibition in venous thrombosis are presented in this study."

Journal • Cardiovascular • Hematological Disorders • Osteoporosis • Rheumatology • Thrombocytopenia • Thrombosis

Factor XI and Atrial Fibrillation: A Mismatched Pairing? (PubMed, Eur Cardiol) - "The failure of the Phase III OCEANIC-AF trial comparing the FXI inhibitor asundexian to the FXa inhibitor apixaban in AF obliged the scientific community to reconsider the bleeding-free hypothesis and the pathophysiology of FXI. Here, the molecular, disease-related and pharmacological features of FXI were analysed to provide possible explanation(s) and hypotheses for this (temporary) failure of FXI targeting. Specifically, the authors describe the peculiar features of the molecule in the coagulation cascade, the possible mechanisms for the bypassing of FXI activity, the clinical evidence related to FXI congenital deficiency, levels measured in pro-thrombotic settings, the pathophysiology of different thromboembolic disorders and the pharmacodynamics of FXI blockade in Phase I and II studies."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Orthopedics • Thrombosis

LIBREXIA-AF: A Study of Milvexian Versus Apixaban in Participants With Atrial Fibrillation (clinicaltrials.gov) - P3 | N=20296 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Atrial Fibrillation • Cardiovascular

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

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Milvexian in Healthy Chinese Adults. (PubMed, Drug Des Devel Ther) - "No new safety signals were identified. The pharmacokinetic, pharmacodynamic, and safety profiles of milvexian demonstrate suitability for further clinical development in Chinese participants."

Clinical • Journal • PK/PD data

Oral Factor XIa Inhibitor Milvexian After a Recent Acute Coronary Syndrome: Rationale and Design of the Phase 3 (Librexia ACS). (PubMed, Am Heart J) - P3 | "The Librexia-ACS trial will determine the efficacy and safety of milvexian after ACS and will be the first trial to test whether factor XIa inhibition in addition to standard-of-care antiplatelet therapy reduces major adverse cardiovascular events without an increased risk of significant bleeding."

Clinical • Journal • P3 data • Acute Coronary Syndrome • Cardiovascular • Ischemic stroke • Myocardial Infarction • Venous Thromboembolism

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

Randomized Trial of Milvexian versus Placebo in Acute Ischemic Stroke and Transient Ischemic Attack: Rationale and Methods for the LIBREXIA-Stroke Trial (ISC 2025) - P3 | "The LIBREXIA-Stroke trial will assess the efficacy and safety of milvexian. This new anticoagulant may have a favorable risk-benefit profile in a large international population of patients presenting acutely with ischemic stroke or high-risk TIA."

Clinical • Cardiovascular • Cerebral Hemorrhage • Hematological Disorders • Ischemic stroke • Thrombosis

Factor XIa Inhibitor Reversal in Intracranial Hemorrhage: A Case Report. (PubMed, Neurohospitalist) - "Reversal of FXIa inhibitors is challenging but may best be achieved using a combination of rFVIIa and TXA. Clinicians should consider administration of low dose recombinant activated factor VII (rFVIIa) in conjunction with an anti-fibrinolytic inhibitor such as tranexamic acid (TXA) for reversal of life-threatening hemorrhage in bleeding patients with exposure to novel factor XIa inhibitors that are currently in clinical trials."

Journal • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Mood Disorders

Milvexian: Data readout from P3 LIBREXIA-STROKE trial (NCT05702034) for secondary stroke prevention in 2026 (43rd Annual J.P. Morgan Healthcare Conference, Bristol-Myers Squibb) - Data readout from P3 LIBREXIA-ACS trial (NCT05754957) for acute coronary syndrome in 2026

P3 data • Acute Coronary Syndrome • Cardiovascular • Ischemic stroke

Milvexian: Data readout from P3 LIBREXIA-STROKE trial (NCT05702034) for secondary stroke prevention in 2026 (43rd Annual J.P. Morgan Healthcare Conference, Bristol-Myers Squibb) - Data readout from P3 LIBREXIA-ACS trial (NCT05754957) for acute coronary syndrome in 2026

P3 data • Acute Coronary Syndrome • Cardiovascular • Ischemic stroke

Milvexian: Data readout from P3 LIBREXIA-AF trial (NCT05757869) for atrial fibrillation in 2027 (Bristol-Myers Squibb, 43rd Annual J.P. Morgan Healthcare Conference)

P3 data • Atrial Fibrillation • Cardiovascular

Milvexian: Data readout from P3 LIBREXIA-AF trial (NCT05757869) for atrial fibrillation in 2027 (Bristol-Myers Squibb, 43rd Annual J.P. Morgan Healthcare Conference)

P3 data • Atrial Fibrillation • Cardiovascular

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

The anticoagulant effects of milvexian, a novel small molecule factor XIa inhibitor, are neutralized by activated prothrombin complex concentrates and recombinant factor VIIa in human plasma and whole blood in vitro. (PubMed, Res Pract Thromb Haemost) - "Although direct oral anticoagulants (DOACs) have a reduced incidence of major bleeding compared with warfarin, they still carry a bleeding risk, resulting in a suboptimal therapeutic index. This study demonstrated that currently available activated PCCs and rFVIIa normalize the anticoagulation induced by milvexian in vitro. The clinical utility of these agents remains to be established."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Musculoskeletal Diseases • Orthopedics • Pain • Thrombosis

Effect of Factor XIa Inhibition by Milvexian on Coagulation Biomarkers in Patients With Acute IS or TIA in the AXIOMATIC-SSP Trial (CVCT USA 2024) - No abstract available

Biomarker • Clinical

Reversal of the Anticoagulant Effect of Milvexian By 4-Factor PCC and rFVIIa in Healthy Participants (ASH 2024) - "Discussion/Conclusion : Anticoagulant effect of milvexian was successfully reversed by two commonly available, non-specific reversal agents - 4F-PCC and a low dose of rFVIIa. This may provide clinicians with additional data to assess treatment options in cases of active bleeding or the need for urgent surgical interventions in patients treated with milvexian."

Clinical • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Ischemic stroke • Thrombosis

Characterization of the Pharmacokinetic and Pharmacodynamic Relationship of Milvexian in Total Knee Replacement Patients (CVCT USA 2024) - No abstract available

Clinical • PK/PD data • Musculoskeletal Diseases • Orthopedics • Pain

A Study to Assess the Safety and Tolerability of Milvexian in Pediatric Participants at Risk of Thromboembolic Events (clinicaltrialsregister.eu) - P1 | N=48 | Sponsor: Janssen Research & Development, LLC

New P1 trial • Cardiovascular • Pediatrics • Thrombosis

From the INVICTUS Trial to Current Considerations: It's Not Time to Retire Vitamin K Inhibitors Yet! (PubMed, Pharmaceuticals (Basel)) - "In this study, rivaroxaban failed to prove superiority over VKA in preventing the composite primary efficacy endpoints of stroke, systemic embolism, myocardial infarction, and death...Close to the heels of the dismal results of INVICTUS, an apixaban trial in prosthetic heart valves, PROACT-Xa, was also prematurely terminated due to futility...Multiple agents (monoclonal antibodies-e.g., osocimab, anti-sense oligonucleotides-e.g., fesomersen, and small molecule inhibitors-e.g., milvexian) have garnered positive data from phase II studies, and many have entered the phase III studies in AF/Venous thromboembolism. Future studies on conventional DOAC and new-generation DOAC will shed further light on whether DOAC can dethrone VKA in valvular heart disease."

Journal • Review • Atrial Fibrillation • Cardiovascular • Cerebral Hemorrhage • Heart Failure • Hematological Disorders • Myocardial Infarction • Venous Thromboembolism

Absolute oral bioavailability of milvexian spray-dried dispersion formulation under fasted and fed conditions in healthy adult participants: An intravenous microtracer approach. (PubMed, Clin Transl Sci) - "The milvexian SDD formulation at 25 mg and 200 mg resulted in similar F in a fasted state; under fed conditions, milvexian F decreased at 25 mg and increased at 200 mg. These findings clarify pharmacokinetic-related gaps observed in previous studies."

Clinical • Journal • Cardiovascular

DETERMINANTS OF 90-DAY COGNITIVE PERFORMANCE AFTER ACUTE ISCHEMIC STROKE: A SECONDARY ANALYSIS OF THE AXIOMATIC-SSP TRIAL (WSC 2024) - "Methods AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial of Factor XIa inhibitor, milvexian...Only older age and recurrent ischemic stroke were associated with impaired recovery between baseline and 90 days. Conclusions Recurrent ischemic stroke is an important potentially modifiable determinant in preventing post-stroke cognitive impairment."

Alzheimer's Disease • Cardiovascular • Cognitive Disorders • Diabetes • Ischemic stroke • Metabolic Disorders

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

Milvexian a novel factor XIa inhibitor for stroke prevention: pharmacokinetic and pharmacodynamic evaluation. (PubMed, Expert Opin Drug Metab Toxicol) - "In patients affected by acute non-cardioembolic ischemic stroke or high-risk transient ischemic stroke, milvexian, in addition to dual antiplatelet therapy, seems to have a positive efficacy profile without any safety concerns, especially in terms of intracranial hemorrhage. Two phase 3 trials are ongoing to investigate the efficacy and safety of milvexian for preventing cardioembolic and non-cardioembolic ischemic stroke."

Journal • PK/PD data • Review • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Ischemic stroke • Renal Disease • Vascular Neurology

Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design. (PubMed, Am Heart J) - P3 | "The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter."

Clinical • Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Thrombosis