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

Coagulation factor XI and coronary artery disease: is there room for factor XI inhibitors? (PubMed, Pol Arch Intern Med) - "Among FXI inhibitors, asundexian was evaluated in patients following acute MI in a phase 2 randomized PACIFIC AMI trial, without clear benefits from this intervention, while the phase 3 LIBREXIA ACS study aimed to assess milvexian on top of dual antiplatelet therapy in the prevention of secondary ischemic events in high-risk MI survivors was discontinued after interim analysis on basis of futility. The current review summarizes the latest preclinical and clinical studies on the role of FXI in atherogenesis and its thromboembolic manifestations. Moreover, it discusses potential therapeutic options offered by FXI inhibitors."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Ischemic stroke • Myocardial Infarction • Thrombosis

Bristol Myers Squibb…announced it would discontinue its Phase 3 Librexia ACS trial for milvexian in acute coronary syndrome patients. (Investing.com) - "The decision follows a scheduled interim analysis by the Independent Data Monitoring Committee, which determined the trial was unlikely to meet its primary efficacy endpoint...The company’s two other Phase 3 trials in the Librexia program will continue as planned. These include Librexia AF for atrial fibrillation patients and Librexia STROKE for secondary stroke prevention, with topline data expected in 2026."

P3 data: top line • Trial termination • Acute Coronary Syndrome • Atrial Fibrillation • Ischemic stroke

Discovery and preclinical characterization of SB-01, a novel allosteric inhibitor of human factor XIa (ASH 2025) - "This approach is supported by strong clinical and geneticevidence: individuals with congenital FXI deficiency exhibit reduced thrombosis risk without spontaneousbleeding, while elevated FXI levels are associated with a dose-dependent increase in thrombosis.Although recent drug development has focused on small-molecule orthosteric inhibitors of FXIa, such asasundexian and milvexian, an alternative strategy of allosterically disrupting the catalytic triad offers apotentially superior mechanism...Crucially, SB-01 showed a clean safety profile with nosignificant effects on body weight, bleeding time, human ether-à-go-go-related gene (hERG) activity, orCYP450 inhibition.In conclusion, this study introduces SB-01 as a highly promising, structurally unique, and potent allostericinhibitor of hFXIa. Its high selectivity and proven efficacy in multiple preclinical thrombosis models,coupled with an excellent safety profile, position it as a strong candidate for pre-IND studies..."

Preclinical • Lung Cancer • Solid Tumor • Venous Thromboembolism

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

RANDOMIZED TRIAL OF MILVEXIAN VERSUS PLACEBO IN ACUTE ISCHEMIC STROKE AND TRANSIENT ISCHEMIC ATTACK: RATIONALE AND METHODS FOR THE LIBREXIA-STROKE TRIAL (WSC 2025) - P3 | "The LIBREXIA-Stroke trial will assess the efficacy and safety of milvexian (25 mg BID) in a large international population of patients presenting acutely with IS or high-risk TIA."

Clinical • Cardiovascular • Hematological Disorders • Ischemic stroke • 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 | Trial completion date: May 2027 ➔ Oct 2026 | Trial primary completion date: Mar 2027 ➔ Oct 2026

Trial completion date • Trial primary completion date • Atrial Fibrillation • Cardiovascular

Milvexian: Data readout from P3 LIBREXIA-AF trial (NCT05757869) for non-valvular atrial fibrillation in 2027 (Bristol-Myers Squibb) - Q2 2025 Results

P3 data • Atrial Fibrillation • Cardiovascular

Milvexian: Data readout from P3 LIBREXIA-STROKE trial (NCT05702034) for secondary stroke prevention in 2026 (Bristol-Myers Squibb) - Q2 2025 Results: Data readout from P3 LIBREXIA-ACS trial (NCT05754957) for acute coronary syndrome in 2026

P3 data • Acute Coronary Syndrome • Cardiovascular

Quantitative Model-Informed Dose Selection for a Milvexian Phase III Study in Patients With Atrial Fibrillation. (PubMed, Clin Pharmacol Ther) - "At this regimen, the simulated median venous thromboembolism rate was 9.4% (lower than enoxaparin at ~21%). Simulations using the model-based meta-analysis estimated that milvexian 100 mg twice-daily would lead to a systemic embolism odds ratio of 0.84 (95% CI: 0.65, 1.12) compared with apixaban 5 mg twice-daily for patients with atrial fibrillation. This integrated model-informed dose-selection approach supported 100 mg twice-daily as a regimen of milvexian to be evaluated in the phase III milvexian LIBREXIA AF study."

Journal • P3 data • Atrial Fibrillation • Cardiovascular • Musculoskeletal Diseases • Orthopedics • Venous Thromboembolism

EFFECTS OF MILVEXIAN ALONE OR WITH HEPARIN ON CATHETER-INDUCED CLOTTING AND THROMBIN GENERATION. (PubMed, J Thromb Haemost) - "Catheters promote FXI autoactivation, bypassing FXII and highlighting the critical role of FXI. The limited capacity of milvexian supports the need for adjunctive heparin in patients treated with milvexian undergoing PCI."

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

DOAC-Stop reverses the anticoagulant effect of asundexian and milvexian (ISTH 2025) - "Dabigatran was a positive control, and abelacimab and heparin were negative controls. DS reversed the aPTT prolongation induced by milvexian but not by heparin. Table or Figure Upload"

Comparison of the effects of abelacimab asundexian and milvexian on catheter-induced clotting (ISTH 2025) - "Abelacimab and milvexian prolonged the catheter-induced clot time by fourfold, with IC50 values of 0.04 µM and 1.12 µM, respectively, whereas asundexian had less effect. Similarly, abelacimab and milvexian attenuated catheter-induced peak thrombin with IC50 values of 13.2 nM and 112.8 nM, whereas it was 6 µM for asundexian."

Acute Coronary Syndrome • Oncology • Pulmonary Embolism • Respiratory Diseases

Effect of factor XIIa or XIa inhibitors on catheter-initiated thrombin generation: an in vitro study (ISTH 2025) - "Aims We investigated the effect of garadacimab, abelacimab, asundexian, milvexian, apixaban, dabigatran, fondaparinux and enoxaparin, compared to UFH, using a previously validated in vitro model of catheter-initiated thrombin generation (TG) in platelet-rich plasma (PRP). Adding garadacimab and abelacimab directly to collection tubes, rather than to PRP, resulted in greater efficacy, with LT increasing by 89% and 32%, respectively; in this setting, the IC50 were 25 µg/mL and 12.5 µg/mL, respectively. Table or Figure Upload"

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

An in vitro comparison of therapeutic FXIa inhibitors (ISTH 2025) - "Aims To compare the effects of milvexian, asundexian, and abelacimab on a standard activated partial thromboplastin time (aPTT) assay. Abelacimab prolonged the aPTT to 75 seconds at a concentration matching that of FXI in plasma (30nM), with no additional prolongation at higher concentrations. This value represents inhibition of 98.5% of FXI activity in normal plasma."

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Effect of heparins, DOACs, and FXII/FXI inhibitors on catheter-initiated thrombin generation in PRP: an in vitro study. (PubMed, J Thromb Haemost) - "Heparins were by far the most effective anticoagulants in our in vitro model. Factor XIIa and XI(a) inhibitors did not adequately prevent coagulation on the studied artificial surface. DOACs and fondaparinux showed limited efficacy, aligning with clinical observations."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Comparison of inhibitory effects between FXIa inhibitors and DOACs in thrombin generation assay (ISTH 2025) - "Aims This study evaluated the thrombin inhibitory effects of the FXIa inhibitors asundexian and milvexian using an intrinsic pathway thrombin generation assay (TGA) and compared these effects with those of direct oral anticoagulants (DOACs). For apixaban, the peak values at concentrations of 100–5000 ng/mL were 647.5, 570.4, 530.2, 537.4, 495.8, 403.7, and 102.8 nM, respectively; for milvexian, 497.5, 466.1, 370.8, 269.6, 169.8, 48.5 and 11.3 nM. The ranges of peak values for dabigatran, rivaroxaban, apixaban, and edoxaban at 100–1000 ng/mL were 148.1–10.0, 425.3–11.5, 547.2–156.4, and 425.4–42.5 nM, respectively."

Direct comparison of inhibitory effects by one-stage assay in factor XIa inhibitors (ISTH 2025) - "In the dilution assay, FXI activities were recovered in a dilution ratio-dependent manner for both drugs. At 5000 ng/mL, FXI activities at dilution ratios of 4, 16, and 32 were 25%, 60%, and 93% for asundexian, and 12%, 46%, and 93% for milvexian, respectively."

Reagent variability of APTT prolongation in factor XIa inhibitors of asundexian and milvexian (ISTH 2025) - "For asundexian, the ratios ranged from 1.0 to 2.5, and for milvexian, from 1.0 to 3.8, with ratios increasing proportionally with concentration. At 1000 ng/mL, APTT ranged from 3.1 to 4.1 for dabigatran, 2.0 to 2.9 for rivaroxaban, 1.3 to 1.5 for apixaban, and 1.7 to 2.2 for edoxaban."

DOAC-Stop™ reverses the anticoagulant effect of asundexian and milvexian. (PubMed, J Thromb Haemost) - "DS reverses the effect of asundexian and milvexian on the APTT and distinguishes between the APTT effects of milvexian and heparin."

Journal

Interferences Associated with the Factor XIa Inhibitors Asundexian and Milvexian in Routine and Specialised Coagulation Assays and their Removal by Activated Charcoal-Based Adsorbents. (PubMed, J Thromb Haemost) - "Emerging FXIa inhibitors interfere significantly with FXIa-dependent coagulation assays, potentially leading to misinterpretation of haemostatic function. However, charcoal-based adsorbents efficiently remove these interferences and enable routine and specialised coagulation testing in the presence of asundexian and milvexian."

Journal

RANDOMISED TRIAL OF MILVEXIAN VERSUS PLACEBO IN ACUTE ISCHAEMIC STROKE AND TRANSIENT ISCHAEMIC ATTACK: RATIONALE AND METHODS FOR THE LIBREXIA-STROKE TRIAL (ESOC 2025) - P3 | "For this outcome event-driven trial, it was estimated that ~15,000 subjects will be randomized in 47 countries (Figure 2) and followed until 909 primary efficacy outcome events occur to achieve 90% power to detect a 20% hazard reduction with milvexian. Figure 1. Trial Overview Figure 2."

Clinical • Late-breaking abstract • Cardiovascular • Ischemic stroke • Thrombosis

Anticoagulation in Atrial Fibrillation: Is a Paradigm Shift From Xa to XIa Inhibitors on the Horizon? (PubMed, Cardiol Rev) - "The effective management of atrial fibrillation, particularly regarding the prevention of ischemic stroke and systemic embolism, has progressed with the introduction of direct oral anticoagulants, which have shown a reduction in bleeding risks when compared to warfarin. The oral factor Xa inhibitors, such as apixaban and rivaroxaban, are considered the first line for anticoagulation in cases of atrial fibrillation. Several factor XI inhibitors, including abelacimab, asundexian, osocimab, gruticibart, milvexian, and fesomersen, are currently undergoing clinical trials for similar therapeutic purposes...This review article aims to emphasize the recent trials evaluating these factor XI inhibitors with a special focus on abelacimab. Abelacimab may signify a promising advancement in anticoagulation therapy, providing potential advantages such as reduced gastrointestinal bleeding risks and the convenience of monthly dosing."

Journal • Atrial Fibrillation • Cardiovascular • Gastroenterology • Ischemic stroke

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