Transcript Vascular Injury Expert Working Group Biomarkers of Drug-Induced Vascular Injury

Vascular Injury Expert
Working Group
Biomarkers of Drug-Induced
Vascular Injury
NCSS 10 September 02 Report
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Vascular Injury
Expert Working Group
Committee Members
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Bill Kerns, Pharma Consulting-CoChair
Les Schwartz, GlaxoSmithKline-CoChair
David Essayan, CBER
Don Robertson, Pfizer
Fred Miller, NIEHS
Kerry Blanchard, Boehringer-Ingleheim
Jim MacGregor, NCTR
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Vascular Injury
Expert Working Group
Committee Members
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Frank Sistare, CDER
Paul Snyder, Purdue
Prakash Nagarkatti, Virginia Common. Univ.
Robert Johnson, Schering-Plough
Scott Burchiel, University of New Mexico
Tom Papoian, CDER
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Vascular Injury
Expert Working Group
Active Contributors
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Eric Fung-Ciphergen
Mike Lawton-Pfizer
Calvert Louden-AstraZeneca
Heath Thomas-GlaxoSmithKline
Anthony Ward-BD Biosciences
Jun Zhang-CDER
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Vascular Injury
Expert Working Group
• Meetings
– 31 July 01 conference call
– 9 October 01 conference call
– 7 November 01 meeting at ACT
– 13 November 01 NCSS report
– 25 February 02 conference call
– 12 March 02 conference call
– 20 March 02 meeting at SOT
– 10 June 02 NCSS report
– 27 June 02 conference call
– 22/23 July 02 meeting at FDA
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Vascular Injury
Expert Working Group
• Meetings
– 8 August NCTR
– 9/10 Sept NCSS
– Sept Conference Call
– Nov-ACT Meeting
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Vascular Injury
Expert Working Group
Today’s Objectives
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Review EWG Mandate
Why is vascular injury in animals an issue?
Review EWG progress to date
Review discussion points and get feedback
from NCSS on next steps
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EWG Mandate
• Evaluate and develop a current
understanding of vascular injury in
animals and humans
• Identify opportunities for biomarkers
based on probable mechanisms
• Develop validation plans
• Transition new markers from animals to
Phase 1
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Issue
• drug-induced microscopic polyangitis
(hypersensitivity angitis) and leukocytoclastic
angitis of humans is not, or rarely, observed
in toxicology studies
• current animal models are poor predictors of
drug-induced angitis in humans
• common drug-induced vascular lesions in
animals are “not known” to occur in humans
and have unknown relevance
• lesions in animals occur in areas that are
prone to spontaneous vascular disease
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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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2 yr old rat
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Canine
Idiopathic Polyarteritis
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Human-Hypersensitivity
Angitis
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Normal Physiology
endothelium
IEL
SMC
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Normal Physiology
Shear Stress (t=F/A)
(t=32μQ/πD3)
blood flow
endothelium
endothelium
IEL
SMC
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Normal Physiology
Hoop Stress (σ=PR/h)
endothelium
endothelium
IEL
SMC
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Acute Drug-Induced
Vascular Injury
Selectins
ICAM-1
VCAM-1
PECAM
edema
IEL
SMC
MCP-1, RANTES, IL-1, IL-8. TNFa, CD62P, INFg, LPS, ...
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Acute Drug-Induced
Vascular Injury
Selectins
ICAM-1
VCAM-1
PECAM
endothelium
edema
IEL
SMC
IL-1, IL-8. TNFa, ECF...
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Potential Mechanisms
• Biomechanical injury following changes
in shear or tension
• Direct pharmacological or chemical
perturbation
• Immune-mediated
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Summary
• regardless of mechanism, endothelial
compromise appears as an early event
in rats and dogs
• drug-induced lesions in the rat and dog
appear in sites of spontaneous disease,
further complicating interpretation of
toxicology studies
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Summary
• common drug-induced vascular injury of
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 validated methods for
detecting drug-induced vascular injury in
animals or humans
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Q&A
Is the problem clear?
The EWG confirms that this is an
issue that requires resolution.
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Progress to Date
• thoroughly educated group on the issue
• agreed standard rat protocol
– need more discussion on data management,
protocol review, centralized analyses
• agreed standard compounds for inducing
vascular injury (fenoldopam, PDE IV,
dopamine)
• crafted a list of potential biomarkers
• sE selectin proposal for review
• new research data from contributing
companies is emerging monthly
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Potential Biomarker Targets
• Injury Phase
– Apoptosis markers (sCD44, sFASL)
– Circulating endothelial cells (CD31 or Annexin)
• Inflammatory Phase
– Acute Phase Proteins (α2, haptoglobin, fibrinogen,
CRP)
– HA, eSelectin, thrombomodulin, vWF, ET-1, TNF,
IL-6, IL-1beta, tryptase, MPO
• Genomics/Proteomics/Metabonomics
– Gene expression mapping. Endothelial cells and
vascular smooth muscle cells
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– Urinary or plasma NMR spectra
Biomarkers: Early Leads
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Urinary NMR (Pfizer)
Circulating endothelial cells (GSK)
Acute phase proteins (FDA, BI)
sE-selectin (CD62E)
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Discussion Points
Draft White Paper
• Plan to polish and submit for publication
– Stimulate interest
– Let public know what FDA and industry are doing
– What is formal process for NCSS to ratify our final
draft
• Comments on content/organisation
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Discussion Points
NCSS/NCTR
• develop collaborations between FDA/industry
and NCTR to support genomics, proteomics
and metabonomics with tissues from
standard studies done by collaborators
• comments
• what is process?
• CRADA
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Discussion Points
• Letter to Abbot and Pfizer for drug supplies
– Approval process?
– How do we manage drug distrbution?
• Organise Oct 2003 symposium
– Comments
– Process
• Biomarkers identified to date
– Comments
• Develop reagents, broad data sets, and high potential
targets for further validation
– Comments
– Process ($$)
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Timeline-13 Nov 01
• February 2002
– Agree on study protocols and endpoints
– Agree on model compounds
– Agree on collaborative responsibilities
• March 2002
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Finalize a terminology position/document
Define budget for sourcing study compounds
Review any new data from committee
Finalize plans for NCTR and Pharma support and
any other support
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Timeline-13 Nov 01
• April 2002-March 2003
– Initiate standard protocol studies
– Acquire model compounds
– Organize data centrally
• March 2003
– Review first data sets from multiple standardized
experiments
– Develop plans and timeline for guidance
recommendations
• October 2003
– symposium
• November 2003
– Target date for initial biomarker (s)
recommendation for validation
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