Critical Path Initiative and Lab-Based Bio-Research (Small Molecules) Jerry M. Collins, Ph.D.

1. Critical Path Initiative and Lab-Based Bio-Research (Small Molecules) Jerry M. Collins, Ph.D. Laboratory of Clinical Pharmacology Division of Applied Pharmacology Research ACPS October 19, 2004

2. Translational Research Critical Path Initiative March 2004: www.fda.gov/oc/initiatives/criticalpath/whitepaper.pdf

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4. Office of Testing and Research, OTR Ajaz Hussain, Acting Director Division of Applied Pharmacology Research, DAPR J.Collins, Act.Dir. Division of Product Quality, DPQR M. Khan, Director Division of Pharmaceutical Analysis, DPA L. Buhse, Director Laboratory of Clinical Pharmacology, LCP J.Collins, Director

5. Laboratory of Clinical PharmacologyPrograms Goals Outcomes---------------------- ---------------- ------------------------Metabolism/ interpret Guidance x2 Interactions data predict/manageHepatotoxicity develop explain toxicity models predict/managePET Imaging early consulting reviewsfor Efficacy therapy PK-PD extensions assessment

6. Reducing Adverse Drug Interactions • In vitro human liver studies identified drug interactions • Guidance developed greatly decreased potential for adverse effects • Markedly improved the efficiency and design of human clinical trials • Drug withdrawals from the market

7. Inter-Agency Studies: FDA-NCI * Memorandum of Understanding for Drug Metabolism Investigations • NCI Employee Working in FDA Lab * FDA Lab Analyzing Drug Metabolites in NCI Phase 1 Trial.

8. Office of Testing & Research Laboratory of Clinical Pharmacology Metabolism/Drug-Drug Interaction Studies in OTR Lab Input from Review Experiences Collaborative Clinical Studies of Metabolism-Based Drug-Drug Interactions

9. HEPATOTOXICITYRegulatory SignificanceA leading source of serious adverse drug reactions.Recent examples producing liver failure or death include: felbamate, troglitazone, and trovafloxacin. Scientific SignificanceReactive metabolites linked to many adverse events. Human liver tissue can help identify reactive metabolites. Enzyme pathways can be modulated.Links to FDA: John Strong on Steering Committee for FDA’s Hepatotoxicity Initiative

11. PET Imaging for Efficacy Early Detection of Drug Action Encouraging Innovation!

12. PET Probes as Biomarkers for Efficacy Regulatory Significance: An emerging technology that is increasingly being applied to drug development. FDA/CDER’s long-standing interest in use of PK-PD principles for regulatory decision-making.Scientific Significance: Unique opportunity to examine PK-PD directly at level of drug target, rather than indirectly via plasma concentrations and/or downstream effectindicators. Can determine drug distribution in body, or drug impact directly at receptors, enzymes, transporters, etc.

13. Frank & Hargreaves (2003)

14. DAPR Molecular Toxicology Research • MICROARRAY STANDARDS & QUALITY METRICS • Rat Mixed Tissue RNA Standard - Design & Testing • Collaborators: Affymetrix, Agilent, GE, Amgen, Abbott, NIEHS, NCTR, Rosetta/Merck, Iconix • Gene Correlates of Sample Quality • CDER Statisticians, Affymetrix, GeneLogic • GENE MARKERS OF TOXICITY • Cardiotoxicity - Cross-Platform & Cross-Site • Affymetrix, Agilent, GE, Rosetta/Merck • Renal Toxicity (Current) • CDRH Animal Model of Subclinical Injury • Hepatotoxicity (Proposed, with LCP, NCI) • Mechanism of Anti-Cancer Drug Toxicity • Genomic Analysis for Hepatotox & Pediatric Tox

15. Incorporating Pharmacogenomic Technologies into Drug Development Lab Staff Connected to: SSC Interest Group: N.Alderson Inter-Center Working Group: L. Lesko FDA-PhRMA Workshops #1, #2, #3

16. DAPR Preclinical Biomarkers Group • Identification of blood biomarkers of Phosphodiesterase Inhibitor-induced vascular injury • Evaluation of cardiac Troponin-T as a preclinical marker for cardiac injury • Evaluation of flow cytometric endpoints for prediction of drug hypersensitivity using the Lymph Node Proliferation Assay • Development of preclinical model system for assessment of differential pediatric toxicity • Identification of novel blood biomarkers for liver toxicity

17. Emphasis on Clinical Toxicities That Are Difficult to Monitor Bio-Markers Bridging “One-at-a-Time” with Arrays of Indicators via Genomics/Proteomics

19. Effect of Doxorubicin (DOX) on Serum Cardiac Troponin T (cTnT) in SH Rats Serum Cardiac TnT ( ng/ml ) Cumulative Dose DOX ( mg/kg )

21. Genes (by category) significantly changed by DOX at 3 weeks and modulation of changes by cardioprotectant DOX/DZR DOX DZR Cardiac muscle function & structure Fatty acid metabolism Glucose metabolism Immune response Stress induced Color Scale (Log 2)

22. PDEi-Induced VascularInjury • Unusual vascular injury caused by PDE-III, -IV, -V inhibitors, and some other vasoactive drugs. • Characterized by small bleeds into vessel wall in anatomically restricted areas. • Observed in rats, dogs, primates, and rarely mice. • Goal of research is to identify biomarkers in blood associated with vascular injury.

23. PDEi-Induced Vascular InjuryAssociation between proposed biomarkers and vascular injury IL-8 TIMP-1 C-Reactive Protein a1-Acid Glycoprotein Vascular Injury Histopathology Score

24. Summary of PDEi Blood Biomarkers • Significant increases seen in at least 6 different proteins in serum following treatment with either of two unrelated PDE IV inhibitors. • Changes are generally proportional to severity of pathological lesions. • Changes are highly correlated between the two PDE IV inhibitors. • These biomarkers represent a possible new tool for evaluating preclinical safety.