1 vascular injury expert working group 19 july ncss report committee members david essayan-cber don...
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Vascular InjuryExpert Working Group
19 July NCSS ReportCommittee 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Rat MesenteryDA 1 Agonist
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Rat MesenteryDA 1 Agonist
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Rat MesenteryDA 1 Agonist
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Rat MesenteryDA 1 Agonist
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 July NCSS Report
Develop Initial List Potential Biomarkers• metabonomics• proteomics• genomics• other omics
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Vascular InjuryExpert Working Group
19 July NCSS Report
Define RFP-like Funding Mechanisms• NIEHS, NTP, NIH• NCTR/FDA• Pharma Industry• ILSI/HESI
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
19 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
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Vascular InjuryExpert Working Group
May 3-4 Minutes
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
New Drugs
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Vascular InjuryExpert Working Group
May 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
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Vascular InjuryExpert Working Group
May 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
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Vascular InjuryExpert Working Group
May 3-4 Minutes
Pathogenesis Model
decrease in local resistanceincrease in flow?increase in shear and/or tensionendothelial compromisemedial necrosisinflammation
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Information SlideArterial Lesions by Drug Class
• Vasodilators - L, M sized arteries
– DA1 agonist– Endothelial Receptor Antagonists– Adenosine Agonists– PDEIII
– PDEIV
– PDEV
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Information SlideArterial Lesions by Drug Class
• Vasopressors – small arteries/arterioles– Neopinephrine– Epinephrine– Methoxamine– Vasopressin– Dopamine
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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