Cardiotox Expert Working Group

1
Cardiotox Expert Working Group

• Report to the NCSS
• September 9 10, 2002

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NCSS Cardiotoxicity Expert Working Group

• Kendall B. Wallace (University of Minnesota)
  -Chair
• Gene Herman (CDER, FDA)
• Gordon Holt (Oxford GlycoSciences)
• Alan L. Metz (Pfizer)
• Elizabeth Murphy (NIEHS)
• I.Y. Rosenblum (Schering-Plough)
• Malcolm J. York (Glaxo SmithKline)
• James T. MacGregor (NCTR, FDA)
• Elizabeth Hausner (CDER, FDA)
• David M. Essayan (CBER, FDA)

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Order of Business

• Review document outline - Serum troponins as
  biomarkers of drug-induced cardiac toxicity
• Approach to filling data gaps in troponin
  document
• Implementation of the next generation of cardiac
  biomarkers

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Serum Troponins as Biomarkers of Drug-induced
Cardiac Toxicity- Document Outline -

• Statement of purpose
• Define the current status of scientific evidence
  regarding the utility of serum troponins I and T
  as biomarkers of drug-induced cardiac injury in
  nonclinical and clinical drug evaluation studies.
  Identify scenarios in which this biomarker could
  be of benefit to nonclinical studies and identify
  barriers and knowledge gaps that limit such usage.

5
Justification of Need

• Incidence of adverse cardiac events with
  pharmaceuticals
• Attrition during clinical trials
• Revoking of registrations
• Limitations of current biomarkers
• Specificity
• Sensitivity
• Interspecies differences

6
Introduction to biomarkers

• Categories
• Structure
• Contractile function
• Rhythm
• Homeostasis
• Characteristics
• Specific
• Sensitive
• Favorable kinetics
• Robust detection assay
• Bridge non-clinical and clinical scenarios

7
Background to the troponins

• Biology
• Component of the thin myofilaments
• Participation in the contractile process
• Multiple isoforms
• Differential expression and turnover

8
Characterization of the troponins as biomarkers
of drug-induced myocardial injury

• Specificity
• Sensitivity
• Kinetic
• Assay
• Bridge nonclinical/clinical
• Limitations
• Data gaps

9
Specificity

• Serum cTnI and cTnT are the most highly specific
  of the currently employed biomarkers of
  drug-induced myocardial injury.
• The appearance of cTnI or cTnT in serum signifies
  a generalized disruption of the limiting cell
  membrane or the disruption of the myofilaments
  and leakage from the cell.
• Cardiac injury that does not result in altered
  cardiac cell membrane permeability may not be
  associated with increases in serum troponins.

10
Sensitivity

• Serum cTnI and cTnT, when measured in the
  critical diagnostic window of time, are highly
  sensitive indicators of myocardial injury
• The serum troponins are detected as early, if not
  earlier, in the course of pathogenesis as are
  other biomarkers of myocardial injury

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Kinetics

• The troponins are released from cardiac tissue
  during the active phase of cell lysis and return
  to baseline following termination of active
  pathogenesis. In situations of progressive cell
  injury, there is a propagation of cell injury as
  reflected by a long-sustained increase in serum
  troponins.
• The increases in serum cTnI and cTnT are
  proportionate to the extent of myocardial injury.
  

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Robustness of the assay

• The commercially available assays for cTnI and
  cTnT are simple, accurate, reproducible, and
  inexpensive.

13
Bridge nonclinical and clinical

• The troponins are highly conserved across species
  and are thus excellent candidates for biomarkers
  that bridge between nonclinical and clinical
  studies.

14
Limitations

• Critical diagnostic window
• cTnT assay is available from only a single vendor
• Baseline values and quantitative changes in serum
  troponin may be altered by disease
• Validation of assays

15
Plans to fill data gaps

• Gather more nonclinical data
• cTnI versus cTnT
• Kinetic characteristics of serum Tn
• Correlate with the degree of cardiac
  histopathology
• Discriminate type of cardiac toxicity
• EWG to discuss experimental design(s)
• Research avenues of sponsorship and implementation

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Plans to fill data gaps

• Evaluate examples of nonclinical-to-clinical
  correlations
• EWG to investigate feasibility of
• Data mining within FDA and PhRMA
• Develop partnership(s) through ILSI, Soc Tox
  Path, etc. to devise an agreement amongst
  stakeholders for data sharing and evaluation

17
Plans to fill data gaps

• Peer reviewed publication of final troponin
  document.

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Approaching the next generation of cardiac
biomarkers

• Biomarkers of types of drug-induced cardiac
  toxicity that are not marked by the troponins
• Consider emerging technologies
• EWG to plan a meeting amongst stakeholders to
  identify and evaluate the most promising
  candidates

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Action items for the NCSS

• Approve draft of troponin document
• Approve plans to address the data gaps regarding
  the troponins.
• Approve plans to address additional biomarkers of
  drug-induced cardiac toxicity.