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

LIBREXIA-AF: A Study of Milvexian Versus Apixaban in Participants With Atrial Fibrillation (clinicaltrials.gov) - P3 | N=20284 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | N=8505 ➔ 20284

Enrollment change • Atrial Fibrillation • Cardiovascular

Rationale for the Milvexian Dosing in the Phase 3 LIBREXIA Program. (PubMed, J Thromb Haemost) - P3 | "The milvexian dose regimen selected for the LIBREXIA AF trial is 100 mg twice daily, and for the LIBREXIA ACS and Stroke trials is 25 mg twice daily. The Phase 3 LIBREXIA program will determine whether these dose regimens afford safe and effective anticoagulation in approximately 50,000 patients with AF, ACS, or prior stroke."

Journal • P3 data • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Ischemic stroke

Direct Oral Anti-Xa Anticoagulants and the Future of Factor XI/FXIa Inhibition: A New Paradigm in Thrombosis Prevention. (PubMed, Pharmacy (Basel)) - "This biological paradigm has catalyzed the development of novel FXI/FXIa inhibitors, including small-molecule agents (asundexian, milvexian) and biological therapies (abelacimab). Clinical trials such as AXIOMATIC-TKR, PACIFIC-AF, and OCEANIC-AF, and ongoing programmes including ASTER and MAGNOLIA suggest that FXI inhibition may preserve antithrombotic efficacy while substantially reducing bleeding risk. This review summarizes the current landscape of oral FXa inhibitors, outlines the biological rationale for FXI/FXIa inhibition, and discusses the evolving clinical evidence supporting what may represent the next major advance in anticoagulant therapy."

Journal • Review • Cardiovascular • Gastroenterology • Genito-urinary Cancer • Geriatric Disorders • Hematological Disorders • Nephrology • Oncology • Renal Disease • Thrombosis • Venous Thromboembolism

Milvexian: Data readout from P3 LIBREXIA-STROKE trial (NCT05702034) for secondary stroke prevention in 2026 (Bristol-Myers Squibb) - Q4 2025 Results: Data readout from P3 LIBREXIA-AF trial (NCT05757869) for non-valvular atrial fibrillation in 2026

P3 data • Cardiovascular • Ischemic stroke

Simplifying the next-generation of anticoagulants: Elexians - Why a unified nomenclature for FXI/Xia inhibitors is needed. (PubMed, Thromb Res) - No abstract available

Journal

A Thorough QT Study to Assess the Effects of Milvexian on Cardiac Repolarization in Healthy Participants. (PubMed, Clin Pharmacol Drug Dev) - "Milvexian regimens were safe and well tolerated. These data indicate that milvexian does not prolong the QTc interval at clinically relevant concentrations."

Clinical • Journal • Cardiovascular

Individualized antithrombotic therapy in acute coronary syndrome: The role of thrombin pathway inhibition and aspirin. (PubMed, Kardiol Pol) - "In this scenario, potential oral agents include FXa (rivaroxaban, apixaban, edoxaban), FXIa (asundexian and milvexian) and FXIIa inhibitors. Understanding the relative contributions of platelet and coagulation pathways to clot formation in an individual patient is likely critical to achieve a balance between anti-ischemic effects and bleeding risk. In this line, we discuss the importance of objectively measuring thrombogenicity and its potential role in personalizing DPI strategies in patients with ACS."

Journal • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular

LIBREXIA-ACS: A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome (clinicaltrials.gov) - P3 | N=14194 | Active, not recruiting | Sponsor: Janssen Research & Development, LLC | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Coronary Syndrome • Cardiovascular

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

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

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."