Study Design of the Phase 3 Sparsentan Versus Irbesartan (DUPLEX) Study in Patients With Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), a histologic lesion in the kidney caused by varied pathophysiological processes, leads to end-stage kidney disease in a large proportion of patients. Sparsentan is a first-in-class orally active compound combining endothelin type A (ET) receptor blockade with angiotensin II type 1 (AT) receptor antagonism in a single molecule. A Randomized, Multicenter, Double-Blind, Parallel, Active-Control Study of the Effects of Sparsentan, a Dual Endothelin Receptor and Angiotensin Receptor Blocker, on Renal Outcomes in Patients With Primary FSGS (DUPLEX) study evaluates the long-term antiproteinuric efficacy, nephroprotective potential, and safety profile of sparsentan compared with an AT receptor blocker alone in patients with FSGS.

Endotoxaemia induces resistance to activated protein C in healthy humans.

Systemic inflammation activates the tissue factor/factor VIIa complex (TF/FVIIa), leading to a procoagulant state, which may be enhanced by impairment of physiological anticoagulant pathways, such as the protein C system. Besides impaired protein C activation, resistance to activated protein C (APC) may occur. We studied the effect of endotoxemia on APC resistance, analysed its determinants and evaluated the effect of TF/FVIIa inhibition on endotoxin-induced APC resistance.

Local activation of the tissue factor-factor VIIa pathway in patients with pneumonia and the effect of inhibition of this pathway in murine pneumococcal pneumonia.

Objective: The tissue factor (TF)-factor VIIa (FVIIa) complex not only is essential for activation of blood coagulation but also affect the inflammatory response during sepsis. The objective of this study was to determine the role of TF-FVIIa in pneumonia caused by Streptococcus pneumoniae, the most important causative organism in community-acquired pneumonia and a major cause of sepsis.

Design: A controlled, in vivo laboratory study.

Inhibition of the tissue factor/factor VIIa pathway does not influence the inflammatory or antibacterial response to abdominal sepsis induced by Escherichia coli in mice.

Background: Anticoagulants have gained increasing attention for the treatment of sepsis. Inhibition of the tissue factor (TF)/factor (F) VIIa pathway has been shown to attenuate the activation of coagulation and to prevent death in a primate model of sepsis caused by gram-negative bacteria.

Methods: To determine the role of the TF/FVIIa complex in the host response to peritonitis, mice received an intraperitoneal injection of live Escherichia coli with or without concurrent treatment with recombinant nematode anticoagulant protein c2 (rNAPc2), a selective inhibitor of the TF/FVIIa pathway.

Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys.

Background: Infection with the Ebola virus induces overexpression of the procoagulant tissue factor in primate monocytes and macrophages, suggesting that inhibition of the tissue-factor pathway could ameliorate the effects of Ebola haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue factor is beneficial after infection with Ebola virus.

Methods: We used a rhesus macaque model of Ebola haemorrhagic fever, which produces near 100% mortality.

Pharmacokinetics and anticoagulant properties of the factor VIIa-tissue factor inhibitor recombinant Nematode Anticoagulant Protein c2 following subcutaneous administration in man. Dependence on the stoichiometric binding to circulating factor X.

Recombinant Nematode Anticoagulant Protein c2 (rNAPc2) is a potent (K(i) =10 pM), inhibitor of the factor VIIa/tissue factor (fVIIa/TF) complex that requires the prerequisite binding to zymogen or activated factor X (fX). In two double blind, place-bo-controlled, sequential dose-escalation phase I studies, rNAPc2 was found to be safe and well tolerated following single and repeat subcutaneous administrations in healthy human male volunteers at doses ranging from 0.3 to 5 micro g/kg.

Recombinant nematode anticoagulant protein c2, an inhibitor of the tissue factor/factor VIIa complex, in patients undergoing elective coronary angioplasty.

Objectives: We investigated the safety and pharmacodynamics of escalating doses of recombinant nematode anticoagulant protein c2 (rNAPc2) in patients undergoing elective coronary angioplasty.

Background: Recombinant NAPc2 is a potent inhibitor of the tissue factor/factor VIIa complex, which has the potential to reduce the risk of thrombotic complications in coronary artery disease.

Methods: In a randomized, double-blinded, dose-escalation, multicenter trial, 154 patients received placebo or rNAPc2 at doses of 3.

Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.

An association between cancer and thrombosis has been recognized for more than a century. However, the manner by which tumor growth is regulated by coagulation in vivo remains unclear. To assess the role of coagulation on tumor growth, in vivo, we tested coagulation inhibitors specific for either tissue factor (TF)/factor VIIa (fVIIa) complexes or factor Xa (fXa) for antitumor activity.

Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects.

The activation of coagulation has been shown to contribute to proinflammatory responses in animal and in vitro experiments. Here we report that the activation of coagulation in healthy human subjects by the administration of recombinant factor VIIa also elicits a small but significant increase in the concentrations of interleukin 6 (IL-6) and IL-8 in plasma. This increase was absent when the subjects were pretreated with recombinant nematode anticoagulant protein c2, the inhibitor of tissue factor-factor VIIa.

Inhibition of factor VIIa/tissue factor with nematode anticoagulant protein c2: from unique mechanism to a promising new clinical anticoagulant.

Recombinant nematode anticoagulant protein c2 (rNAPc2) is a potent (K(i) = 10 pM) inhibitor of the factor VIIa/tissue factor complex (fVIIa/TF) that involves the pre-requisite binding to either zymogen or activated factor X (fX) prior to the formation of the final quaternary complex with fVIIa/TF. The formation of the binary complex with circulating fX governs the pharmacokinetic profile of rNAPc2 in humans, resulting in a prolonged elimination half-life of >50 h. The clinical antithrombotic potential of rNAPc2 has been evaluated in a phase-II trial in which the incidence of deep-vein thrombosis was reduced over 50% compared to historic controls with low-molecular-weight heparin in patients undergoing knee replacement surgery.