Day One

Wednesday, 28th November 2012

8.00 Registration, Coffee & Networking

8.50 Chair’s Opening Remarks

Tom Baillie, Dean, School of Pharmacy, University of Washington

9.00 KEYNOTE: Recent Developments in the Study of Chemically Reactive Metabolites: Towards a Consensus in Risk Mitigation Strategies

Reactive metabolites and idiosyncratic drug toxicity - HLA allelic variants as susceptibility factors
Understanding covalent binding to proteins: Lessons learned from covalent drugs
Integrated preclinical risk assessment strategies for drug candidates subject to metabolic activation

Tom Baillie, Dean, School of Pharmacy, University of Washington

ADVANCED CHEMICAL ASPECTS OF REACTIVE METABOLITE FORMATION

9.30 KEYNOTE: Drug Metabolism Challenges for the Next Generation of Covalent Drugs

Potential reasons for the excellent safety record of marketed covalent agents
Advanced clinical candidates for emerging therapeutic targets in relationship to strategies readily applicable in drug discovery

Amit Kalgutkar, Research Fellow, Pfizer

10.00 Speed Networking & Morning Refreshments

11.30 Successful Medicinal Chemistry Strategies to Mitigate Bioactivation Liabilities in Drug Candidates

Examples discussing SAR studies addressing the formation of reactive metabolites or genetox alerts
Appropriate timing of targeted metabolite ID studies within research operating protocols to maximize benefit
Emphasis on real-time collaboration with medicinal chemistry

Kaushik Mitra, Director, Merck

12.00 Using Structural Alerts to Mitigate Formation of Reactive Metabolites during Drug Discovery

Exploring metabolic activation of relatively inert functional groups/structural motifs
Meticulous assessment of the biochemical reactivity of structural alerts in new drug candidates is critical
A brief introduction to known bioactivation pathways for various functional groups

Amin Kamel, Senior Research Investigator, Novartis

12.30 Introduction to Bioactivation Concepts

Enzyme induction and inhibition are major issues in drug-drug interactions
There are several reasons for drug toxicity and classification is important in avoiding problems
Discovering new approaches being considered for drug toxicity prediction

F. Peter Guengerich, Professor, Vanderbilt University

1.00 Lunch & Networking

2.00 Screening for Reactive Intermediate: Challenges and Pitfalls

Understanding the limitations of current techniques to screen for metabolites
Overcoming common pitfalls when screening drug candidates in preclinical development

Richard Tschirret-Guth, Associate Director, Merck

2.30 Avoiding Bioactivation Pathways during Discovery

Case examples of early identification of RM liability and collaborative strategies to change chemistry
Understanding the benefits of influencing chemistry early on in development

Peter Gorycki, Director, Biotransformation , GSK

PRECLINICAL TOXICITY ASSESSMENT OF REACTIVE METABOLITE SPECIES

3.00 Connecting Reactive Metabolites with Toxicity using Cell-Based Models

Using cell-based models to bridge between reactive metabolite formation, toxicity and relevance for humans
Exploring case study examples from the pharmaceutical and agrochemical industry

Ray Kemper, Research Leader & Group Head, Mechanistic Toxicology, Roche

3.30 Afternoon Refreshments & Networking

4.00 Exploring the Use of Toxicogenomics in Reactive Metabolite Research

A number of drugs cause minimal toxicity in preclinical species but fail late in clinical trials or in postmarketing
Most of these drugs produce a characteristic gene expression signature in rat liver and are thus easily detected
How do we use these data better for decision making?

Michael McMillian, Principal Scientist, Janssen Pharmaceuticals

OVERCOMING REGULATORY HURDLES

4.30 Regulatory Actions Based on Liver Safety: Impact of Reactive Metabolite Screening

Overcome liver toxicity as a major reason for regulatory actions on drugs including failure to approve for marketing and withdrawal from the market
Discover computer models that predict reactive metabolite hepatoxicity across multiple species including man

Paul Watkins, Director, Hamner-UNC Institute for Drug Safety Sciences

5.00 Case Study: An Example of Mitigating Reactive Metabolite Formation in Clinical Development

Clinical study showed safety signal potentially related to reactive metabolites and no prior signal from tox studies
Inhibition of responsible enzyme suppressed reactive metabolite formation

Petra Goelzer, Research Leader DMPK, Roche