Adverse Preclinical Events: Now What?

1. Adverse Preclinical Events: Now What? • tive (eHI) Cynthia J. Davenport, Ph.D. President www.tigertox.com PreClinical Discussion Group- San Diego, CA USA 26 July 2011

2. Adverse Preclinical Events: Now what? • Drug development = complex process • Prediction of drug toxicity in humans is major challenge • Toxicology studies designed to produce toxicity. • Absence of toxicity may mean incorrect dose selection and/or use of invalid nonclinical model. • Can’t erase an adverse event • Optimized preclinical dose selection is essential! • Rare adverse events difficult to predict preclinically, and generally require post-market surveillance

3. Agenda Outline process for dealing with APEs to: • Optimize chances of successful drug development or • Create a scientific basis for early termination of development

4. No Single Answer for all Problems Adverse Preclinical Events: Now What?

5. What are Adverse Preclinical Events? • Genetic Toxicity (e.g., aneuploidy, mutagenicity, chromosomal rearrangements) • Clinical signs (e.g., ataxia, morbidity, seizures) • Safety Pharmacology Disturbances (e.g., QT prolongation, respiratory distress, GI transit irregularities, seizures) • Clinical Pathology/Hematology Changes (e.g., leukopenia, anemia, enzymatic changes [ALT, AST, etc.]) • Immunological Toxicity (immuno-stimulation/-suppression) • Morphological Toxicity (e.g., gross and histological pathology, reproductive toxicity, developmental toxicity) • Other APEs can belong to >1 category

6. Process: How to Proceed? • Assemble internal/external team of “experts” • Increased focus by Regulators on safety-related issues. Trending from passive to active surveillance (discovery, preclinical through post-marketing) Safety Signal Identification: • Compare structure/adverse events (nonclinical and clinical) of compounds with similar MOA and/or structure (published literature, data bases, FOI, scientific community) • Primary: patents, conference papers, case reports, journal articles, correspondence, and theses • Secondary: bibliographies, reviews, indexing and abstracting services • Tertiary: reference sourcebooks, textbooks

7. Process: How to Proceed? Clinical/Epidemiological/Pharamcovigilance data • Clinical trial database (ClinicalTrials.gov) • Pharmacovigilance: FDA Sentinel system, the Observational Medical Outcomes Partnership (OMOP), and the eHealth Initiative (eHI) • Epidemiologic data: information on disease and disease population • Text mining/analytics of social media channels and call center notes

8. Process: How to Proceed? Determine available options: • Terminate development (e.g., unfavorable risk:benefit ratio, budget, available backup[s], competition/time to market) • Outlicense(different indication, assume higher risks) • Therapeutic indication • More serious disease = higher risk tolerance • Different therapeutic indication may require lower dose

9. Process: How to Proceed? • Issue resolution plan: objectives, time frame, budget, potential exit points, responsibilities, bulk availability/timing, etc. • Availability of backup: start to develop (?); continue to work on lead drug candidate (?) • If class effect, screen backup(s) • Contact Authorities if IND present and/or drug in clinical trials (see guidelines) • Agreement with Authorities to continue/terminate development. • Option to publish results in peer-reviewed journals • Risk evaluation/risk management may allow clinical development to proceed until further risk evaluation possible based on quality human data.

10. Adverse Preclinical Events: What do I do now? Imperatives: • Identification and characterization of APE • Risk evaluation and management

11. Application of Imperatives Imperatives: Identification and characterization of APE • Identification:Recognition/assessment of suspected APE • Increased risk of thyroid follicular tumors in 2-year carcinogenicity study (mice) • Characterization:Target Organ(s), Dose (exposure)/response, severity, reversibility, ADME • No genotoxicity, so tumors likely epigenetic (hormonal). • 4-week study: T(4)UDP-GT (T4 uridine 5'-diphosphoglucoronosyl transferase activity) • 13-week study: T4, TSH,  liver & thyroid weights.

12. Application of Imperatives Imperatives Hazard identification and characterization Risk evaluation and risk management • Risk Evaluation: MOA, relevance of finding for man, and safety ratios • Drug induces UDP-GT glucuronidation of T4 T4 excretion T4 serum levels  TSH thyroid follicular cells  thyroid follicular tumors. • Humans less susceptible to hormonal imbalance. •  TSH (e.g., Hashimoto goiter) benign thyroid hyperplasia or thyroid adenoma. • Safety ratio: at what multiple of the clinical dose does APE occur? • Risk Management: implement precautions for use of drug in man • Limit initial starting dose • Monitor thyroid hormones and TSH in clinical studies to ensure changes don't occur in man at therapeutic doses.

13. Risk Evaluation: qualitative and quantitative • Qualitative: determination of MoA necessary to assess relevance to man • Quantitative: calculation of safety ratio • Exposure at NO(A)EL of most sensitive and relevant preclinical species guides clinical starting dose • Safety ratios especially important when APE not species-specific or when MOA is not entirely clear

14. Quantitative Risk Evaluation • Weight of evidence (WoE): analyses of multiple parameters (e.g., therapeutic dose/safety margin, medical need, market alternatives, severity and reversibility of toxicity, therapeutic indication, dose/response, ADME/metabolites, early biomarkers, age of target population, intended duration of use, ethnicity, etc.) • WoE evolves throughout product lifecycle. • Safety ratio + WoE necessary to assess risk:benefit • Greater benefit justifies higher risk (severe disease, no/few therapeutic alternatives)

15. Risk Evaluation Using Weight of Evidence (WoE) Analysis Does MOA of drug candidate lead to observed APE? No or partially Is MOA potentially relevant for man? Continue development Sufficient safety factor? Yes Continue development with risk management Development depends upon further WoE analyses No MOA = mechanism of action; APE = adverse preclinical event Ettlin et al. J. Toxicol. Pathol. 2010; 23:189-211.

16. Risk Management: precautions to minimize risk (1) • Carefully monitor patients at increased risk • Concurrent medications/drug interactions/comparator studies • Consider reproductive/developmental risk to WoCBP 1 • Careful selection of first dose/dose-escalation scheme in humans • Biomarker monitoring (e.g., serum chemistry, hematology, urinary, EKG) 1 WoCBP = women of child-bearing potential

17. Risk Management: precautions to minimize risk (2) • Alerting health professionals/public (package insert, training/education, PDR, product label, medication guide) • Proactive post-market surveillance program (REMS = risk evaluation and mitigation strategy; RMP = risk management plan; pharmacovigilance) – global scope • Continuous assessment of risk:benefit by cross-functional team throughout life cycle of drug • Balanced communication of risk:benefit is essential in our risk-adverse environment

18. Adverse Preclinical Events: Now what? Conclusion • Drug development guidelines both necessary and helpful, but challenges require sound scientific judgment & experience • Clear definition of MoA not always possible • Key to meeting the challenge is identification, characterization, risk evaluation, and risk management of APE MoA = mechanism of action; APE = adverse preclinical event.

19. References • DrugBank. Version 3.0. Referenced 24 July 2011. • Ettlin RA, et al.J. Toxicol. Pathol. 2010; 23:189-211. • Eisenberg, PR. Integrating Risk Management Into Global Drug Development -Opportunities and Challenges. Plenary Session, DIA, Seoul, Korea 28 April 2011. • Kupferberg, N. Drug Information Sources. Ohio State University Library. 5 November 2010.

20. Cynthia J. Davenport, Ph.D.www.tigertox.comcdavenport@tigertox.com Questions and Discussion