Vascular Injury Expert Working Group 19 July NCSS Report

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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

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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

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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

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Rat Mesentery DA 1 Agonist
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Rat Mesentery DA 1 Agonist
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Rat Mesentery DA 1 Agonist
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Rat Mesentery DA 1 Agonist
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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

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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
  

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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

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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

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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

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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

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Vascular InjuryExpert Working Group19 July
NCSS Report

• Develop Initial List Potential Biomarkers
• metabonomics
• proteomics
• genomics
• other omics

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Vascular InjuryExpert Working Group19 July
NCSS Report

• Define RFP-like Funding Mechanisms
• NIEHS, NTP, NIH
• NCTR/FDA
• Pharma Industry
• ILSI/HESI

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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

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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

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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

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Vascular InjuryExpert Working GroupMay 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 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

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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

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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

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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
• RTIs arteriole
• Cpd X - veins
• Cpd Y - L, M, S arteries
• Biologics - Arterioles?
• Most cytokines - IL-2 (postcap venules)
• etc