1. Cardiotox Expert Working Group Report to the NCSS September 9 & 10, 2002

2. 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)

3. 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

4. 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

11. 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.

12. 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

16. 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.

18. 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

19. Action items for the NCSS 1.Approve draft of troponin document 2.Approve plans to address the data gaps regarding the troponins. 3.Approve plans to address additional biomarkers of drug-induced cardiac toxicity.