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Vascular Injury Expert Working Group 19 July NCSS Report

Vascular Injury Expert Working Group 19 July NCSS Report. Committee Members David Essayan-CBER Don Robertson-Pfizer Fred Miller-NIEHS Kerry Blanchard-Boehringer-Ingleheim Les Schwartz-GlaxoSmithKline-CoChair Paul Snyder-Purdue Prakash Nagarkatti-Virginia Commonwealth Univ.

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Vascular Injury Expert Working Group 19 July NCSS Report

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  1. Vascular InjuryExpert Working Group19 July NCSS Report Committee Members • David Essayan-CBER • Don Robertson-Pfizer • Fred Miller-NIEHS • Kerry Blanchard-Boehringer-Ingleheim • Les Schwartz-GlaxoSmithKline-CoChair • Paul Snyder-Purdue • Prakash Nagarkatti-Virginia Commonwealth Univ. • Robert Johnson-Schering-Plough • Scott Burchiel-University of New Mexico • Bill Kerns-Pharma Consulting-CoChair

  2. Vascular InjuryExpert Working Group19 July NCSS Report Committee Charge • establish common understanding of problem • confirm issue criticality and validity • develop initial list of potential biomarkers • define potential IP issues and resolve • define funding mechanisms • develop validation strategy • resolve issues of confidentiality

  3. Vascular InjuryExpert Working Group19 July NCSS Report Establish Understanding of Problem • drug-induced vasculitis vs vascular injury? • clinical vs preclinical impressions • 7 major categories of vasculitis in humans • none (rarely) observed in toxicity testing • vasculitis, to indicate small molecule induced vascular injury in animals, is potentially misleading to clinicians

  4. Rat Mesentery DA 1 Agonist

  5. Rat Mesentery DA 1 Agonist

  6. Rat Mesentery DA 1 Agonist

  7. Rat Mesentery DA 1 Agonist

  8. Vascular InjuryExpert Working Group19 July NCSS Report Confirm Criticality and Validity of Problem • new drugs that cause vascular injury do not fit the mechanistic concepts developed in the 1980/90s for vasoactive drugs that cause hypotension, reflex tachycardia and subsequently myocardial and vascular injury • new drugs, including non-cardiovascular drugs, cause vascular injury without affecting systemic BP or HR

  9. Vascular InjuryExpert Working Group19 July NCSS Report Confirm Criticality and Validity of Problem • drug-induced microscopic polyangitis in humans is not, or rarely, observed in toxicology studies • common drug-induced vascular lesions in animals are “not known” to occur in humans and have unknown relevance • there are, however, no methods for detecting drug-induced vascular injury in animals or humans

  10. Vascular InjuryExpert Working Group19 July NCSS Report Confirm Criticality and Validity of Problem • drug-induced vascular injury warrants investment of resources to define early and predictive biomarkers of injury and possibly mechanism • EWG recommends proceeding to organize the funds necessary to develop and validate specific and sensitive biomarkers

  11. Vascular InjuryExpert Working Group19 July NCSS Report Develop Initial List Potential Biomarkers • pathogenesis of vascular injury in animals is not clear • evidence to date suggests that injury is a consequence of altered function and not a direct toxic effect • endothelial compromise appears as an early event in preclinical species

  12. Vascular InjuryExpert Working Group19 July NCSS Report Develop Initial List Potential Biomarkers • develop non-invasive methods to monitor endothelial and vascular smooth muscle injury and loss of vascular integrity in dog, rat, monkey • develop ex-vivo assays to monitor PMN, platelet, endothelial activation • validate assays and transfer to Phase I/II clinical studies

  13. Vascular InjuryExpert Working Group19 July NCSS Report Develop Initial List Potential Biomarkers • VEGF and sF1t-1 • vWF, thrombomodulin, CD62E, • Circulating endothelial cells • VCAM-1 • sß thromboglobulin, CD62P • Endothelin • PECAM, ICAM-1 • sFAS Ligand

  14. Vascular InjuryExpert Working Group19 July NCSS Report Develop Initial List Potential Biomarkers • metabonomics • proteomics • genomics • other omics

  15. Vascular InjuryExpert Working Group19 July NCSS Report Define RFP-like Funding Mechanisms • NIEHS, NTP, NIH • NCTR/FDA • Pharma Industry • ILSI/HESI

  16. Vascular InjuryExpert Working Group19 July NCSS Report RFP Process • FDA (other agencies-NIEHS) need to promote RFP mechanism • EWG could participate in proposal review • EWG needs to enlist support of Pharma, ILSI and others to promote research in this area • RFP--animal model development • RFP--novel and specific markers of endothelial and vascular injury • RFP--biomarker validation

  17. Vascular InjuryExpert Working Group19 July NCSS Report Immediate Path Forward • meet by conference call on 31 July • ILSI application • workshop in association with ACT/SOT to discuss issues with broader contribution • define potential IP issues and resolve • refine funding mechanisms • develop validation strategy • resolve issues of confidentiality

  18. Vascular InjuryExpert Working Group19 July NCSS Report EWG Recommendation • drug-induced vascular injury warrants investment of resources to define early and predictive biomarkers of injury and possibly mechanism • develop non-invasive methods to monitor vascular injury • validate methods– reduce to practice in Phase I/II

  19. Heart Minoxidil A1/A2 agonists Hydralazine PDE III Arteries Minoxidil A1/A2 agonists Hydralazine PDE III PDE IV DA1 agonists ET-1 antagonists Others as discussed at the meeting Vascular InjuryExpert Working GroupMay 3-4 Minutes New Drugs

  20. Vascular InjuryExpert Working GroupMay 3-4 Minutes Summary • arterial lesions are associated with sustained changes in hemodynanics in selected arterial beds independent of MAP and HR • endothelial compromise appears to be the earliest morphological event in lesion induction • shear stress, hoop stress and/or other mechanical factors may be important in pathogenesis

  21. Vascular InjuryExpert Working GroupMay 3-4 Minutes Summary • pathogenesis of vascular injury in animals is not clear • evidence to date suggests that injury is a consequence of altered function and not a direct toxic effect • endothelial compromise appears as an early event in preclinical species • predictive biomarkers of toxicity have not been developed

  22. Vascular InjuryExpert Working GroupMay 3-4 Minutes Pathogenesis Model decrease in local resistance increase in flow? increase in shear and/or tension endothelial compromise medial necrosis inflammation

  23. Information SlideArterial Lesions by Drug Class • Vasodilators - L, M sized arteries • DA1 agonist • Endothelial Receptor Antagonists • Adenosine Agonists • PDEIII • PDEIV • PDEV

  24. Information SlideArterial Lesions by Drug Class • Vasopressors – small arteries/arterioles • Neopinephrine • Epinephrine • Methoxamine • Vasopressin • Dopamine

  25. Information SlideArterial Lesions by Drug Class • Unknown vascular pharmacology • 5HTZ - aorta • Mitomycin analog - sm vessels • RTI’s arteriole • Cpd X - veins • Cpd Y - L, M, S arteries • Biologics - Arterioles? • Most cytokines - IL-2 (postcap venules) • etc

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