1. Peter K.S. Siegl, Ph.D. Siegl Pharma Consulting LLC peter.siegl@comcast.net SAFETY PHARMACOLOGY: Opportunities and Expectations 8 th Annual Safety Pharmacology Society Meeting Madison, Wisconsin September 24, 2008

2. Siegl Pharma Consulting LLC Safety Pharmacology 1979 “The adverse drug reactions which the standard toxicological test procedures do not aspire to recognize include most of the functional side-effects. Clinical experience indicates, however, that these are much more frequent than the toxic reactions due to morphological and biochemical lesions…” Gerhard Zbinden, 1979 Pharmacol Methods in Toxicology Opportunities/Expectations Nonclinical studies to identify pharmacological activities of drug candidate that increase risk of adverse drug reactions in patients. Complement toxicology studies. Improve clinical safety and reduce attrition of drug candidates. 2

3. Siegl Pharma Consulting LLC ICH Guideline M3, 1997 “ Safety pharmacology includes the assessment of effects on vital functions, such as cardiovascular, central nervous system and respiratory systems, and these should be evaluated prior to human exposure.” ICH M3: Nonclinical safety studies for the conduct of human clinical trials for pharmaceuticals. (July 1997) Opportunities/Expectations Value of safety pharmacology acknowledged by regulators and sponsors. 3

4. Siegl Pharma Consulting LLC ICH Guideline S6, 1997 “[Safety pharmacology studies].. investigate the potential for undesirable pharmacological activity in appropriate animal models and, where necessary, to incorporate particular monitoring for these activities in the toxicity studies and/or clinical studies.” “.. these studies may allow for a mechanistically-based explanation of specific organ toxicities, which should be considered carefully with respect to human use and indication(s).” ICH S6 “Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals” (July 1997) Opportunities/Expectations Pharmacological activity in animals should be considered in toxicology and clinical studies. Mechanism-based understanding of toxicities (or pharmacological activities) should be carefully considered in the risk assessment. 4

5. Siegl Pharma Consulting LLC ICH Guideline S7A, 2001 “ This guidance was developed to help protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals, while avoiding unnecessary use of animals and other resources.” ICH S7A “Safety Pharmacology Studies for Human Pharmaceuticals” (July 2001) Opportunity/Expectation Safety pharmacology studies have the potential to reduce use of animals and other resources. 5

6. Siegl Pharma Consulting LLC ICH Guideline S7B, 2005 “ The study results can be used to elucidate the mechanism of action and, when considered with other information, estimate risk for delayed ventricular repolarization and QT interval prolongation in humans.” ICH S7B: Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals (October 2005) Opportunities/Expectations Mechanism of action can be a goal of studies. Use data with other data to estimate risk for QT prolongation in humans. 6

7. Siegl Pharma Consulting LLC Safety Pharmacology: Roadmap from ICH Guidelines Improve clinical safety and reduce attrition of drug candidates Identify pharmacological activities of drug candidates that could increase risk of adverse drug reactions in patients. Characterize safety pharmacological activity Relative potency Mechanism of action Compare to reference drugs with clinical experience. Include all data (safety pharmacology, toxicology, metabolism and clinical) in risk assessment. Estimate risk for AE in humans. 7

8. Siegl Pharma Consulting LLC Scientific approach encouraged in guidelines Animal safety studies and human clinical trials should be planned and designed to represent an approach that is scientifically and ethically appropriate for the pharmaceutical under development. (M3 ) It is important to adopt a rational approach when selecting and conducting safety pharmacology studies. The specific studies that should be conducted and their design will vary based on the individual properties and intended uses of the pharmaceuticals. (S7A) The investigational approach and evidence of risk should be individualized for the test substance, depending on its pharmacodynamic, pharmacokinetic, and safety profiles. (S7B) 8

9. Siegl Pharma Consulting LLC Lessons from ICH S7B and Assessing Risk for QT Interval Prolongation. 9

10. Siegl Pharma Consulting LLC Opportunity: Risk factor = molecular mechanism Long QT syndromes (1) Two components of cardiac delayed rectifier K+ current (2) Genetic linkage analysis and long QT syndrome (3) Drug-induced prolongation of the QT interval (4) 1. Schwartz et al. Am Heart J 1975;89:378-390 2. Sanguinetti & Jurkiewicz, 1990;J. Gen. Physiol. 96:195 -215. 3. Keating M. Circulation 1992; 85:1973-1986. 4. Roden D, NEJM 2004; 350: 1013-1022. 10 Continuous ECG tracing

11. Siegl Pharma Consulting LLC Drugs Removed From Market Prenylamine (Anti-anginal) 1989 (UK) Terodiline (Urinary incontinence) 1991 (UK, US) Sparfloxacin (Antibiotic) 1996 (US) Sertindole (Antipsychotic) 1998 (UK) Terfenadine (Antihistamine) 1998 (US) Astemizole (Antihistamine) 1999 (US) Grepafloxacin (Antibiotic) 1999 (UK, US) Cisapride (Gastro-esophageal reflux) 2000 (UK, US) Droperidol (Schizophrenia) 2001 (UK, US) Levacetylmethadol (Opiate addiction) 2003 (UK) 11 Associated with Cardiac Arrhythmia: Torsade de Pointes Turner JR and Durham TA, Integrated Cardiac Safety: Assessment methodologies for noncardiac drugs in discovery, development, and postmarketing surveillance. Copyright © 2009 by John Wiley & Sons, Inc., All Rights Reserved

12. 12 DRUGS WITH RISK FOR WITH TORSADE DE POINTES QT/QTc Prolongation I Kr Inhibition Delayed Ventricular Repolarization Arrhythmia ADDITIONAL RISK FACTORS

13. Siegl Pharma Consulting LLC QT is unique 13 QT is first case where we have: A molecular mechanism for a pharmacologically- mediated risk factor. Positive and negative reference drugs with clinical outcomes. A regulatory-guided clinical assay (ICH E14) to validate nonclinical risk assessment (for QT/QTc interval prolongation).

14. Siegl Pharma Consulting LLC Evolution of QT/ TdP Testing Eliminate risk of Torsade de Pointes (TdP) by screening for compounds that inhibit I Kr (hERG). Many compounds interact with hERG protein – margins and importance of PK/PD relationships Improved methodology for data capture and analysis QT interval is imperfect index of ventricular repolarization HR correction can be source of error Autonomic nervous system influences Multi-channel activity E14 TQT assay – false positives Not all QT prolonging drugs have the same risk for TdP TRIaD (Hondeghen) Instability (Vos, Fossa) 14

15. 15 DRUGS WITH RISK FOR WITH TORSADE DE POINTES QT/QTc Prolongation I Kr Inhibition Delayed Ventricular Repolarization Arrhythmia ADDITIONAL RISK FACTORS Do all I Kr blockers have equal risk for arrhythmia? Does QT Interval prolongation always reflect delayed repolarization? Does QT Interval prolongation always have similar proarrhythmic risk?

16. 16 DRUGS WITH RISK FOR WITH TORSADE DE POINTES QT/QTc Prolongation I Kr Inhibition Delayed Ventricular Repolarization Arrhythmia ADDITIONAL RISK FACTORS I Kr inhibitory potency: can help predict risk of QT/QTc prolongation. is not a biomarker for Torsade de Pointes.

17. What Does the Future Look Like?

18. Siegl Pharma Consulting LLC 18 Characterizing potent toxicity of drug candidate is usually straight forward. The real challenge is to determine and document if a drug candidate with potentially adverse activity is safe in broad patient populations. Often Safety Pharmacology findings by themselves do not represent a risk but may be clinically important in a small subset of patients when combined with multiple additional risk factors. Safety Pharmacology

19. ILLUMINATE Data, redrawn from Figure 1, N Eng J Med 356:1304 – 16, 2007 (Credit: John Szumiloski)

20. Siegl Pharma Consulting LLC 20 Summary of Nonclinical Studies Increase in blood pressure is observed in nonclinical and clinical assays. Mechanism: The blood pressure effect is not due to primary mechanism of action (CETP inhibition). Adrenalectomy in animals prevents the blood pressure response. Competitor drug candidates without blood pressure effects. Case study: Torcetrapib blood pressure effects Forrest et al., British J Pharmacol. 2008

21. Siegl Pharma Consulting LLC Risk or No Risk? FDA updates boxed warning for GlaxoSmithKline's Avandia (November 14, 2007) “A meta-analysis of 42 clinical studies … showed Avandia to be associated with an increased risk of myocardial ischemic events such as angina or myocardial infarction." The updated labeling also indicates that other studies of the product have "not confirmed or excluded this risk" and "in their entirety, the available data on the risk of myocardial ischemia are inconclusive." The FDA stated it has concluded that there is not enough evidence to "indicate that the risks of heart attacks or death are different between Avandia and some other oral type 2 diabetes treatments." The regulatory agency has requested that GlaxoSmithKline conduct a new long-term study in an effort to evaluate the potential cardiovascular risk of Avandia compared with an active control agent. Results expected in 2014. 21

22. Siegl Pharma Consulting LLC Opportunity? US panel recommends cardiovascular studies for diabetes drugs An FDA advisory panel voted 14-2 in favor of recommending that drugmakers be required to conduct long-term studies examining the cardiovascular risks for all new diabetes drugs. “The FDA already has to decide whether the safety database of a drug in the approval application is sufficient to rule out harm. But the committee is now recommending we should have more data to do this and an unacceptably high risk needs to be ruled out before approval. This approach could also well be applied to drugs in other classes such as the NSAIDs.” FDA official Dr. John Jenkins Reference: Heartwire (http://www.theheart.org/article/879839.do)http://www.theheart.org/article/879839.do 22 July 02, 2008

23. Siegl Pharma Consulting LLC FDA Critical Path = Opportunity “The first Critical Path paper, published in March 2004, was intended as a wake-up call to all stakeholders: that without significant investment in development science, our ability to evaluate and predict product performance would continue to be quite limited, and the path to market and beyond, fraught with problems” “The public and private sectors have made massive investments in basic biomedical research over the past three decades. At the same time, investment in development science, or what we call “regulatory science,” needed to predict and evaluate product performance, has lagged significantly.” Janet Woodcock Aug 17, 2007. 23

24. Siegl Pharma Consulting LLC Opportunities for Safety Pharmacology Public Watch Dogs: Flushing out potential safety issues with new and marketed drugs. Critical Path:Advancing “development science”. FDA (and public):Asking for more information in safety data base before approvals. Guidelines:Encouraging scientific approach. 24

25. Siegl Pharma Consulting LLC Leverage Science with Technology “Unfortunately, much of current drug invention is driven by an obsession with technology such that techniques have taken the place of looking for drug ideas rather than the reverse.” Sir James Black, Safety Pharmacology Society: 7th Annual Meeting 19 – 20 September 2007, Edinburgh, UK Ref: Icilio Cavero, Expert Opin. Drug Saf. (2008) 7(1):91-100 25

26. Siegl Pharma Consulting LLC Safety Pharmacology: Roadmap from ICH Guidelines Improve clinical safety and reduce attrition of drug candidates Identify pharmacological activities of drug candidates that could increase risk of adverse drug reactions in patients. Characterize safety pharmacological activity Relative potency Mechanism of action Compare to reference drugs with clinical experience. Include all data in risk assessment (safety pharmacology, toxicology, metabolism and clinical). Estimate risk for AE in humans. 26

27. Siegl Pharma Consulting LLC Parting Editorial Comments Most commonly asked questions: How can we move more drug candidates through development faster and use fewer resources? What do we have to do to get into man? Will these results be good enough to satisfy the FDA? 27

28. Siegl Pharma Consulting LLC Parting Editorial Comments Most commonly asked questions: How can we move more drug candidates through development faster and use fewer resources? What do we have to do to get into man? Will these results be good enough to satisfy the FDA? Drug development should not be an obstacle course of hurtles set by regulatory expectations. 28

29. Siegl Pharma Consulting LLC Parting Editorial Comments Most commonly asked questions: How can we move more drug candidates through development faster and use fewer resources? What do we have to do to get into man? Will these results be good enough to satisfy the FDA? Drug development should not be an obstacle course of hurtles set by regulatory expectations. When approached as a rational-based endeavor supported by sound scientific principles, drug development will have the greatest probability of providing maximum benefit to patients. 29

30. Siegl Pharma Consulting LLC THANK YOU FOR YOUR KIND ATTENTION, VALUDED FELLOWSHIP AND MANY COLLABORATIONS! Safety Pharmacology Society ROCKS! 30

31. Peter K.S. Siegl, Ph.D. Siegl Pharma Consulting LLC peter.siegl@comcast.net SAFETY PHARMACOLOGY: Opportunities and Expectations 8 th Annual Safety Pharmacology Society Meeting Madison, Wisconsin September 24, 2008