Factor IXa as a Target for Pharmacologic Inhibition in Acute Coronary Syndrome

Roser-Jones, Christopher; Chan, Mark Y.; Howard, Emily L.; Becker, Kristian C.; Rusconi, Christopher P.; Becker, Richard C.

doi:10.1111/j.1755-5922.2010.00134.x

Cited by 6 publications

(7 citation statements)

References 90 publications

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“…2010; Roser‐Jones et al. 2011). A second finding stemmed from the fact that antithrombotic activity was almost paralleled by CBT prolongation upon inhibition of fX and fXa.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, there were no major differences between siRNA and pharmacological modalities applied to fIXa as both could mimic the human hemophilia B observations (Sramek et al 2003;Darby et al 2007). Thus, differences existed in EO levels that may reflect the key amplification role of fIXa in the coagulation cascade (Eikelboom et al 2010;Roser-Jones et al 2011). A second finding stemmed from the fact that antithrombotic activity was almost paralleled by CBT prolongation upon inhibition of fX and fXa.…”

Section: Discussionmentioning

confidence: 99%

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Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Ankrom

Wood

et al. 2016

Pharmacology Res & Perspec

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The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An I max and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA‐mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.

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“…2010; Roser‐Jones et al. 2011). A second finding stemmed from the fact that antithrombotic activity was almost paralleled by CBT prolongation upon inhibition of fX and fXa.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Ankrom

Wood

et al. 2016

Pharmacology Res & Perspec

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“…Aptamers are small oligonucleotides with high affinity that are used as active drugs. Partial inhibition using TTP889 was not an effective strategy for VTE prophylaxis and TTP889 is currently being investigated for advanced heart failure to determine the potential benefit of attenuated thrombin generation ( Roser-Jones et al ., 2011 ). Natural factor IX binding proteins and factor IXai are under pre-clinical trials.…”

Section: Anticoagulants Under Developmentmentioning

confidence: 99%

New Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

Kim

Lim

Gwak

2017

Biomolecules & Therapeutics

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Anticoagulant drugs, like vitamin K antagonists and heparin, have been the mainstay for the treatment and prevention of venous thromboembolic disease for many years. Although effective if appropriately used, traditional anticoagulants have several limitations such as unpredictable pharmacologic and pharmacokinetic responses and various adverse effects including serious bleeding complications. New oral anticoagulants have recently emerged as an alternative because of their rapid onset/offset of action, predictable linear dose-response relationships and fewer drug interactions. However, they are still associated with problems such as bleeding, lack of reversal agents and standard laboratory monitoring. In an attempt to overcome these drawbacks, key steps of the hemostatic pathway are investigated as targets for anticoagulation. Here we reviewed the traditional and new anticoagulants with respect to their targets in the coagulation cascade, along with their therapeutic advantages and disadvantages. In addition, investigational anticoagulant drugs currently in the development stages were introduced.

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“…Such levels of thrombin directly promote fibrin formation and also prime the propagation phase of coagulation that involves fV and fVIII, and later on fXIa. In this interlinked model, fIXa plays a critical role as it can get activated by activated fXI, the TF/fVII activated complex and thrombin itself, thus, acting as a gate-keeper of the amplification process (42,43). fIX(a) plays a key role in both coagulation and thrombosis.…”

Section: Clinical Perspectivementioning

confidence: 99%

Titrating haemophilia B phenotypes using siRNA strategy: evidence that antithrombotic activity is separated from bleeding liability

Metzger¹,

Tadin‐Strapps

Thankappan³

et al. 2015

Thromb Haemost

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Haemophilia A and B are characterised by a life-long bleeding predisposition, and several lines of evidence suggest that risks of atherothrombotic events may also be reduced. Establishing a direct correlation between coagulation factor levels, thrombotic risks and bleeding propensity has long been hampered by an inability to selectively and specifically inhibit coagulation factor levels. Here, the exquisite selectivity of gene silencing combined with a gene knockout (KO) approach was used to define the relative contribution of factor IX (fIX) to thrombosis and primary haemostasis in the rat. Using a lipid nanoparticle (LNP) formulation, we successfully delivered fIX siRNAs to the liver by intravenous administration. The knockdown (KD) of target gene mRNA was achieved rapidly (within 24 hour post-siRNA dosing), sustained (maintained for at least 7 days post dosing) and not associated with changes in mRNA expression levels of other coagulation factors. We found that intermediate levels of liver fIX mRNA silencing (60-95 %) translating into a 50-99 % reduction of plasma fIX activity provided protection from thrombosis without prolonging the cuticle bleeding time. Over 99 % inhibition of fIX activity was required to observe increase in bleeding, a phenotype confirmed in fIX KO rats. These data provide substantial evidence of a participation of fIX in the mechanisms regulating thrombosis prior to those regulating primary haemostasis, therefore highlighting the potential of fIX as a therapeutic target. In addition, hepatic mRNA silencing using LNP-encapsulated siRNAs may represent a promising novel approach for the chronic treatment and prevention of coagulation-dependent thrombotic disorders in humans.

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Factor IXa as a Target for Pharmacologic Inhibition in Acute Coronary Syndrome

Cited by 6 publications

References 90 publications

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target

New Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

Titrating haemophilia B phenotypes using siRNA strategy: evidence that antithrombotic activity is separated from bleeding liability

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