Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A

Prasad, Srinivasa R.; Lillicrap, David; Labelle, Andrea; Knappe, Sabine; Keller, Tracy; Burnett, Erin; Powell, Sandra; Johnson, Kirk W.

doi:10.1182/blood-2007-07-098913

Cited by 93 publications

(79 citation statements)

References 35 publications

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“…Additional studies of human plasma clotting assays initiated with dilute TF demonstrated that anti-TFPI antibodies shorten the clotting time of hemophilia plasma more than normal plasma, suggesting that pharmacological inhibitors of TFPI may represent a novel treatment for hemophilia (5,6). Consistent with these in vitro studies, in vivo studies performed in FVIII-deficient rabbits (18), dogs (19), and monkeys (20) have demonstrated that inhibition of TFPI activity reduces injuryinduced blood loss in animal models of hemophilia.…”

supporting

confidence: 61%

“…Thus, a 50% reduction in TFPI activity is not sufficient to alter hemophilia bleeding in this mouse model. However, treatment of F8 −/− mice with an anti-TFPI polyclonal antibody to reduce TFPI activity resulted in decreased blood loss in tail bleeding assays, demonstrating that generalized intravascular inhibition of TFPI activity limits bleeding in this murine model of hemophilia, as has previously been demonstrated in rabbit (18), canine (19), and monkey (20) models of hemophilia A. Interestingly, the lowest concentration of antibody used in these studies, 2.5 mg/kg, which corresponds to about 7.5-fold more antibody than TFPI in mouse plasma on a molar basis, essentially totally blocked plasma TFPI activity and also presumably other forms of intravascular TFPI accessible to antibody binding, such as that expressed on the endothelium surface, yet tail bleeding Fig. 2.…”

Section: Discussionmentioning

confidence: 86%

“…The selective production of TFPIα by platelets, compared with the production of TFPIβ by other mouse tissues, suggests that platelet TFPI may have a unique function in the regulation of hemostasis and/or thrombosis. Pharmaceutical agents for treatment of hemophilia that inhibit TFPI are in development (19,20). The data presented here suggest that development of pharmaceutical agents that specifically target platelet TFPI, but not endothelial TFPI, may allow hemostasis at the site of vascular injury in patients with hemophilia while minimizing the potential risk for thrombosis that could result from total intravascular inhibition of TFPI activity.…”

Section: Discussionmentioning

confidence: 99%

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Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Maroney

Cooley

Ferrel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tissue factor pathway inhibitor (TFPI) blocks thrombin generation via the extrinsic blood coagulation pathway. Because the severe bleeding in patients with hemophilia occurs from deficiency of intrinsic blood coagulation pathway factor VIII or IX, pharmacological agents that inactivate TFPI and, therefore, restore thrombin generation via the extrinsic pathway, are being developed for treatment of hemophilia. Murine models of combined TFPI and factor VIII deficiency were used to examine the impact of TFPI deficiency on bleeding and clotting in hemophilia. In breeding studies, Factor VIII null (F8 −/− ) did not rescue the embryonic death of TFPI null (Tfpi −/− ) mice. Tfpi +/− did not alter the bleeding phenotype of F8 −/− mice. However, total inhibition of intravascular TFPI through injection of anti-TFPI antibody mitigated tail vein bleeding. Interestingly, tail blood loss progressively decreased at doses greater than needed to totally inhibit plasma TFPI, suggesting that inhibition of a sequestered pool of TFPI released at the injury site mitigates bleeding. Because TFPI is sequestered within platelets and released following their activation, the function of platelet TFPI was examined in F8 −/− mice lacking hematopoietic cell TFPI that was generated by fetal liver transplantation. Blood loss after tail transection significantly decreased in Tfpi +/− ;F8 −/− mice with hematopoietic Tfpi −/− cells compared with Tfpi +/− ;F8 −/− mice with Tfpi +/+ hematopoietic cells. Additionally, following femoral vein injury, Tfpi +/− ;F8 −/− mice with Tfpi −/− hematopoietic cells had increased fibrin deposition compared with identical-genotype mice with Tfpi +/+ hematopoietic cells. These findings implicate platelet TFPI as a primary physiological regulator of bleeding in hemophilia.hemostasis | Kunitz | coagulopathy

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supporting

confidence: 61%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Maroney

Cooley

Ferrel

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…NASP can accelerate the clotting times of plasma from hemophilia patients, and improve hemostasis when administered subcutaneously to hemophilic mice 49 and dogs. 50 Most notably, NASP improved hemostasis when administered orally to severe hemophilia A dogs. 50 Aptamers are single-stranded nucleic acids that can directly inhibit function by folding into a specific three-dimensional structure with a high affinity for the target.…”

Section: Alternative Hemostatic Agentsmentioning

confidence: 99%

“…50 Most notably, NASP improved hemostasis when administered orally to severe hemophilia A dogs. 50 Aptamers are single-stranded nucleic acids that can directly inhibit function by folding into a specific three-dimensional structure with a high affinity for the target. They can theoretically be generated to bind to any protein of interest.…”

Section: Alternative Hemostatic Agentsmentioning

confidence: 99%

Hemophilia: New Protein Therapeutics

Pipe

2010

Hematology

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Therapeutic advances for patients with hemophilia have resulted in reduced mortality, improved joint outcomes, safety from blood-transmitted pathogens, improved quality of life, and a normalized life span in the developed world. The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. However, this has come at significant cost, and barriers remain to broad application of prophylaxis. Recombinant DNA technology remains a promising platform to develop novel hemophilia therapeutics with improved functional properties to try to overcome some of these remaining barriers. Bioengineering strategies have produced novel therapeutics with increased production efficiency, increased potency and resistance to inactivation, prolonged plasma half-lives, and reduced immunogenicity. Alternative nonbiologic therapies may lead to new treatment paradigms. The current pipeline of new technologies and products is promising and growing with several agents already advancing from preclinical to clinical trials.

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New Drugs in the Pipeline: From Concept to Clinic

Valentino

2014

Textbook of Hemophilia

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Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A

Cited by 93 publications

References 35 publications

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

Hemophilia: New Protein Therapeutics

New Drugs in the Pipeline: From Concept to Clinic

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