A small-molecule factor XIa inhibitor produces antithrombotic efficacy with minimal bleeding time prolongation in rabbits

SummaryThe antithrombotic efficacy of AT-1459, a novel, direct thrombin inhibitor (Ki = 4.9 nM) was evaluated in rat models of venous thrombosis combined with a bleeding time test and arterial thrombosis.After drugs were given by i. v. bolus injection plus a continuous infusion, the ID50 (a dose that exhibits 50% inhibition of thrombus formation over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.04 mg/kg plus 0.04 mg/kg/h, 0.1 mg/kg plus 0.4 mg/ kg/h, and 13.0 IU/kg plus 26.0 IU/kg/h, respectively, in the venous thrombosis study. The BT2 (a dose that causes 2-fold prolongation of bleeding time over each vehicle group) values of AT-1459, argatroban, and dalteparin were 0.9 mg/kg plus 0.9 mg/kg/h, 1.0 mg/kg plus 0.6 mg/kg/h, and 345.5 IU/kg plus 691.0 IU/kg/h in the rat tail transection model. The ratios of BT2/ID50 of AT-1459, argatroban, and dalteparin were 22.5, 10.0, and 26.6, respectively.In a rat model of arterial thrombosis induced by topical FeCl2 application, intravenous administration of AT-1459, argatroban, and dalteparin improved the vessel patency significantly (P <0.01) at 0.6 mg/kg plus 0.6 mg/kg/h, 0.6 mg/kg plus 2.4 mg/kg/h, and 300 IU/kg plus 600 IU/kg/h, respectively.The oral antithrombotic effect of AT-1459 lasted for 6 after administering 30 mg/kg and improved the vessel patency significantly 1 h after administering the same dose in venous and arterial thrombosis models, respectively, with a rapid onset of action. Warfarin also inhibited thrombus weight and improved the vessel patency significantly after oral administration of 0.3 mg/kg for three consecutive days in the same study. The antithrombotic and hemorrhagic effects of all drugs studied were correlated with plasma concentration or clotting times.These results suggest that AT-1459 may be clinically useful as an orally available antithrombotic agent for the prevention of venous and arterial thrombosis.

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The Antiaggregating and Antithrombotic Activity of Ticlopidine Is Potentiated by Aspirin in the Rat

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650529 ◽

1996 ◽

Vol 76 (01) ◽

pp. 094-098 ◽

Cited By ~ 35

Author(s):

J M Herbert ◽

A Bernat ◽

M Samama ◽

J P Maffrand

Keyword(s):

Platelet Aggregation ◽

Carotid Artery ◽

Bleeding Time ◽

Ex Vivo ◽

Experimental Models ◽

Silk Thread ◽

Antithrombotic Activity ◽

Additive Type ◽

Wire Coil ◽

Antithrombotic Efficacy

SummarySince ticlopidine specifically inhibits ADP-induced platelet aggregation without affecting prostaglandin metabolism, it seemed interesting to evaluate the effect of aspirin with regard to the antithrombotic efficacy of ticlopidine. Ticlopidine was administered orally to rats alone or in combination with aspirin and the efficacy of the association was determined in several experimental models. A synergistic effect of the ticlopidine/aspirin association was demonstrated with regard to ADP- and collagen-induced platelet aggregation measured ex vivo but also in several experimental thrombosis models including silk thread-induced thrombosis in an arteriovenous shunt, wire coil-induced thrombosis and 111In-labelled platelet deposition on the subendothelium following air drying injury of the rat carotid artery. Similar results were obtained with regard to myointimal proliferation following air-induced injury of the rat carotid artery which occurred as a consequence of vascular injury. The ticlopidine/aspirin combination showed only additive-type effects on bleeding time prolongation induced by tail transection in the rat.

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First-in-human study to assess the safety, pharmacokinetics and pharmacodynamics of BMS-986177/JNJ-70033093, a direct, reversible, small molecule Factor XIa inhibitor in healthy volunteers

European Heart Journal ◽

10.1093/ehjci/ehaa946.3362 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Perera ◽

Z Wang ◽

J Luettgen ◽

J Wang ◽

D Li ◽

...

Keyword(s):

Plasma Concentration ◽

Healthy Volunteers ◽

Small Molecule ◽

Healthy Subjects ◽

Funding Source ◽

Private Company ◽

Factor Xia ◽

Clinically Significant ◽

Oral Doses ◽

The Impact

Abstract Background Inhibition of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation without increasing the risk of clinically significant bleeding in many conditions predisposing to a high risk of thrombotic or bleeding events. BMS-986177/JNJ-70033093 (BMS-177/JNJ-3093) is a small molecule that inhibits FXIa with high affinity and selectivity. Depending on the indication, BMS-177/JNJ-3093 may provide benefit to patients as add-on therapy to current standard of care (SOC) antithrombotic agents or potentially as a replacement for current SOC. Purpose To assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of BMS-177/JNJ-3093 in healthy subjects. Methods This was a 2-part, randomized, double-blind, placebo-controlled, sequential single- (Part A) and multiple- (Part B) ascending dose study to assess the safety, tolerability, PK, and PD of BMS-177/JNJ-3093 in healthy subjects. In Part A (SAD) of the study, 48 subjects were treated in 6 panels (8 subjects per panel). The 200 mg and 500 mg dose panels investigated the impact of a high fat diet on PK. In Part B (MAD), 56 subjects were treated in 7 panels (8 subjects per panel) on a once daily (QD) or twice daily (BID) regimen for a 14-day period. Within each panel in Parts A and B, subjects were randomized to receive either BMS-177/JNJ-3093 or matched placebo (3:1). Results Administration of single ascending doses of BMS-177/JNJ-3093 up to 500 mg and multiple ascending doses of BMS-177/JNJ-3093 up to 200 mg BID or 500 mg QD for 14 days were safe and well tolerated. No subjects had a clinically significant bleeding event. All treatment-emergent adverse events were mild in severity. After single doses of BMS-177/JNJ-3093 ranging from 4 to 500 mg in fasted status, BMS-177/JNJ-3093 plasma concentration reached Cmax at 3 h postdose in all panels, indicating a similar rate of absorption. The terminal half-life ranged from 8.26 to 13.8 h across SAD panels. Over 20 to 200 mg, a dose proportional increase was observed; however, saturable absorption was seen at higher doses of 300 and 500 mg. Food also increased the bioavailability of BMS-177/JNJ-3093. In the MAD portion of the study, based on visual inspection of trough plasma concentration profiles, BMS-177/JNJ-3093 plasma concentration steady state was reached between 1–3 dosing days (ie, Days 2–4) for the QD panels and 6 dosing days (ie, Day 7) for the 200 mg BID panel. Renal excretion was relatively low, ranging from 8–20%. After single oral dose or multiple oral doses, there is a clear trend that aPTT was prolonged and the magnitude of change was related to drug exposure. Conclusion BMS-177/JNJ-3093 was safe and well tolerated in healthy volunteers. The PK and PD profile demonstrates suitable dosing properties for further clinical studies. Currently, two Phase II studies are ongoing. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): This work was sponsored by Bristol-Myers Squibb and Janssen Research & Development, LLC

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Abstract TMP117: Preclinical and Early Clinical Characterization of a Parenterally Administered Direct Factor XIa Inhibitor

Stroke ◽

10.1161/str.48.suppl_1.tmp117 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Joseph M Luettgen ◽

Pancras C Wong ◽

Vidya Perera ◽

Zhaoqing Wang ◽

Cesare Russo ◽

...

Keyword(s):

Healthy Subjects ◽

Bleeding Time ◽

Ex Vivo ◽

Thrombin Time ◽

Antithrombotic Agent ◽

Serious Adverse Events ◽

Risk Of Bleeding ◽

Oral Agents ◽

Increased Risk ◽

Antithrombotic Efficacy

Introduction: Acute stroke intervention with antithrombotic agents is limited due to an increased risk of bleeding and a frequent inability to swallow existing oral agents. Preclinical and early clinical data with an antisense oligonucleotide suggest inhibition of Factor XI (FXI) as a means to achieve antithrombotic efficacy with a reduced risk of bleeding. Here we report a preclinical characterization and results from first-in-human studies of BMS-962212, a first in class, direct, reversible, and highly selective IV small molecule inhibitor of FXIa (FXIa K i = 0.7 nM). Methods: BMS-962212 at 0.001+0.0063 to 0.46+3.1 mg/kg+mg/kg/h or its vehicle were administered IV in anesthetized rabbit models of electrically-induced carotid artery thrombosis and cuticle bleeding time. To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-962212 in humans, 6 healthy subjects per dose panel received BMS-962212 at 1.5, 4, 10, and 25 mg/h as 2 hour IV infusions and, respectively, 1, 3, 9, and 20 mg/h as 5 day IV infusions, randomized with placebo. Additionally, 12 healthy subjects received BMS-962212 at 15 mg/h co-administered with 325 mg ASA for 5 days. Results: In rabbits, BMS-962212 reduced thrombus weight with an EC 50 of 80 nM. At a dose that produced 80% antithrombotic efficacy, BMS-962212 did not increase bleeding time. BMS-962212 increased ex vivo activated partial thromboplastin time (aPTT) dose-dependently without changing prothrombin time and thrombin time. In humans, IV administration of BMS-962212 was well tolerated with no serious adverse events observed. Within 30 minutes of BMS-962212 administration, >90% of the mean maximal aPTT within each dose group was achieved. Following completion of the infusion, BMS-962212 demonstrated rapid drug elimination with a direct relationship observed with aPTT decreasing by more than 50% within 4 hours. Template bleeding times were not increased by BMS-962212 alone or when co-administered with ASA. Conclusion: BMS-962212 exhibits properties suited for investigational use as an acute care antithrombotic agent including robust antithrombotic activity with a low potential to increase bleeding risk in preclinical models, and a rapid onset and offset of aPTT activity in humans.

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Subcutaneous Dosing of CRA-027483, a Small Molecule FVIIa Inhibitor, Prevents Arterial Thrombosis in a Baboon Model.

Blood ◽

10.1182/blood.v106.11.1867.1867 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1867-1867

Author(s):

Ulla M. Marzec ◽

Juthamas Sukbuntherng ◽

Stacie A. Dalrymple ◽

Wendy B. Young ◽

Dange Vijaykumar ◽

...

Keyword(s):

Tissue Factor ◽

Small Molecule ◽

Bleeding Time ◽

Thrombus Formation ◽

Reversible Inhibitor ◽

Thrombosis Model ◽

Shunt Thrombosis ◽

Venous Shunt ◽

Fixed Concentration ◽

Indium 111

Abstract Vessel injury may expose tissue factor leading to the activation of FVII, initiation of coagulation, and thrombosis. A small reversible inhibitor of FVIIa (CRA-027483), dosed by subcutaneous (SC) injection, was investigated in an arterio-venous shunt thrombosis model in non-anticoagulated awake baboons. Drug pharmacokinetics (PK) and pharmacodynamics (PD) were studied in non-shunted baboons; PK and PD results were closely correlated with ~ 100% bioavailability following SC drug administration. Thrombosis was initiated by interposing within the shunt a segment of porous expanded (poly)tetrafluoroethylene vascular graft (ePTFE, 4mm ID), filled with relipidated tissue factor. Upon initiation of blood flow at 100mL/min (wall shear rate =256/sec) thrombus growth was monitored by gamma camera imaging of autologous Indium-111 labeled platelets for 1 hour. Fibrin accumulation was quantified using trace amounts of homologous fibrinogen labeled with I-125. Both bleeding time and prothrombin time (PT), the PD marker, were monitored throughout. Animals were dosed SC 90min prior to the initiation of thrombus formation, a regimen that was predicted from PK/PD to result in a fixed concentration of CRA-027483 during the thrombosis phase. Dosing of baboons with CRA 027483 at 1mg/kg, 2mg/kg and 4mg/kg SC (4–5 animals in each study group) inhibited total platelet deposition on the tissue factor surface by 13±4%, 43±30% and 67±26% respectively, vs. control results. Fibrin accumulation was reduced by 22±9%, 50±34%, and 76±19% respectively for these doses. PT values remained stable throughout the thrombosis phase and increased 1.3-, 1.6- and 2.1-fold over baseline with the escalating doses. Bleeding time measurements were slightly prolonged at the higher doses (7.3±1.6min and 7.1±2.5min for the 2mg/kg and 4mg/kg doses, respectively) as compared to the pre-drug measurement of 3.8±0.7min. We conclude that SC administration of CRA-027483, a reversible small molecule inhibitor of FVIIa, effectively reduces tissue factor-initiated thrombus formation in baboons with minimal hemostatic impairment.

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Reduction of thrombus size in murine models of thrombosis following administration of recombinant α1-proteinase inhibitor mutant proteins

Thrombosis and Haemostasis ◽

10.1160/th11-09-0604 ◽

2012 ◽

Vol 107 (05) ◽

pp. 972-984 ◽

Cited By ~ 15

Author(s):

Louise J. Eltringham-Smith ◽

Varsha Bhakta ◽

Sharon Gataiance ◽

William P. Sheffield

Keyword(s):

Recombinant Proteins ◽

Ferric Chloride ◽

Activated Protein C ◽

Vena Cava ◽

Thrombin Inhibitors ◽

Dependent Manner ◽

Mutant Proteins ◽

Nickel Chelate ◽

Factor Xia ◽

Antithrombotic Efficacy

SummaryThe variant serpin α1-PI M358R inhibits thrombin and other proteases such as activated protein C (APC) and factor XIa. We previously described recombinant proteins HAPI M358R (α1-PI M358R containing an N-terminal extension corresponding to residues 1–75 of heparin cofactor II) and HAPI RCL5 (HAPI M358R with F352-I356 and I360 substituted for the corresponding residues of antithrombin), with enhanced selectivity for thrombin over APC inhibition. We tested the hypotheses that these recombinant proteins would limit thrombosis in three mouse models, and that the HAPI chimeric proteins would be more effective than α1-PI M358R. Recombinant serpins were purified from Escherichia coli by nickel chelate and ion exchange affinity chromatography, and administered to mice intravenously. HAPI RCL5 reduced incorporation of radiolabelled fibrin(ogen) into thrombi in the ferric chloride-injured vena cava in a dose-dependent manner; HAPI M358R was less effective and α1-PI M358R was without effect. In a model of murine endotoxaemia, HAPI RCL5 was more effective than α1-PI M358R in reducing radiolabelled fibrin(ogen) deposition in heart and kidneys; immunohis-tochemistry of tissue sections showed lesser staining with anti-fibrin(ogen) antibodies with both treatments. In the ferric chloride-injured murine carotid artery, administration of both recombinant serpins was equally effective in lengthening the vessel’s time to occlusion. Our results show that the antithrombotic efficacy of the recombinant serpins correlates with their potency as thrombin inhibitors, since HAPI RCL5 inhibits thrombin, but not factors Xa, XIa, XIIa, or neutrophil elastase, more rapidly than α1-PI M358R.

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Inhibition of the von Willebrand (VWF)–collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons

Blood ◽

10.1182/blood.v99.10.3623 ◽

2002 ◽

Vol 99 (10) ◽

pp. 3623-3628 ◽

Cited By ~ 79

Author(s):

Dongmei Wu ◽

Karen Vanhoorelbeke ◽

Nancy Cauwenberghs ◽

Muriel Meiring ◽

Hilde Depraetere ◽

...

Keyword(s):

Monoclonal Antibody ◽

Arterial Thrombosis ◽

Bleeding Time ◽

Ex Vivo ◽

Thrombus Formation ◽

High Shear ◽

Pharmacologic Effect ◽

Antithrombotic Efficacy ◽

Von Willebrand

The interaction between collagen, von Willebrand factor (VWF), and glycoprotein Ib is the first step in hemostasis and thrombosis especially under high shear conditions. We studied the inhibition of the VWF-collagen interaction by using an antihuman VWF monoclonal antibody 82D6A3 to prevent arterial thrombosis in baboons to develop a new kind of antithrombotic strategy and determine for the first time experimental in vivo data concerning the importance of the collagen-VWF interaction. We used a modified Folts model to study the antithrombotic efficacy of 82D6A3, where cyclic flow reductions (CFRs) were measured in the femoral artery. Administering a dose of 100, 300, and 600 μg/kg resulted in a 58.3%, 100%, and 100% reduction in the CFRs, respectively. When 100 μg/kg 82D6A3 was infused into the baboons, 80% of VWF-A3 domain was occupied, corresponding to 30% to 36% ex vivo inhibition of VWF binding to collagen, with no prolongation of the bleeding time. The bleeding time was also not significantly prolonged when the CFRs were abolished at doses of 300 μg/kg and 600 μg/kg. At these doses 100% of VWF was occupied by the antibody and 100% ex vivo inhibition of the VWF-collagen binding was observed. 82D6A3 has a high affinity for VWF; after 48 hours still 68% VWF (300μg/kg) was occupied with a pharmacologic effect up to 5 hours after administration (80%-100% occupancy). In conclusion, these results clearly indicate that the VWF-collagen interaction is important in vivo in thrombosis under high shear conditions and thus might be a new target for preventing arterial thrombosis.

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