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Vascular Injury Expert Working Group

Biomarkers of Drug-Induced Vascular Injury

NCSS 10 September 02 Report

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Vascular InjuryExpert Working Group

Committee Members• 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 InjuryExpert Working Group

Committee Members• 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 InjuryExpert Working Group

Active Contributors• Eric Fung-Ciphergen• Mike Lawton-Pfizer• Calvert Louden-AstraZeneca• Heath Thomas-GlaxoSmithKline• Anthony Ward-BD Biosciences• Jun Zhang-CDER

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Vascular InjuryExpert 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 InjuryExpert Working Group

• Meetings– 8 August NCTR– 9/10 Sept NCSS– Sept Conference Call– Nov-ACT Meeting

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Vascular InjuryExpert Working Group

Today’s Objectives• 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 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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2 yr old rat

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CanineIdiopathic Polyarteritis

16Human-HypersensitivityAngitis

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Normal Physiology

endothelium

IEL

SMC

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Normal Physiology

Shear Stress (t=F/A)

(t=32μQ/πD3)

endothelium

IEL

SMC

blood flow

endothelium

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Normal Physiology

Hoop Stress (σ=PR/h)

endothelium

IEL

SMC

endothelium

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Acute Drug-Induced Vascular Injury

Selectins ICAM-1VCAM-1 PECAM

IEL

SMC

MCP-1, RANTES, IL-1, IL-8. TNFa, CD62P, INFg, LPS, ...

edema

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Acute Drug-Induced Vascular Injury

Selectins ICAM-1VCAM-1 PECAM

endothelium

IEL

SMC

IL-1, IL-8. TNFa, ECF...

edema

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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– Urinary or plasma NMR spectra

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Biomarkers: Early Leads

• Urinary NMR (Pfizer)

• Circulating endothelial cells (GSK)

• Acute phase proteins (FDA, BI)

• sE-selectin (CD62E)

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Discussion PointsDraft 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 PointsNCSS/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– 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