The Drug Discovery Process Target selection & validation Discovery Development Target -receptor; -ion channel; -transporter; -enzyme; - signalling molecule Studies of Disease Mechanisms Drug Candidate safety testing Human Studies Phases I,II, III Lead Search -Develop assays (use of automation) -Chemical diversity -Highly iterative process The Drug Discovery Process Molecular Studies Drug Approval and Registration Lead optimization -selectivity -efficacy in animal models -tolerability: AEs mechanism- based or structure-based? -pharmacokinetics -highly iterative process Animal Studies - relevant species - transgenic KO/KI mice - conditional KOs - agonists/antagonists - antibodies - antisense - RNAi

Target Selection & Validation Define the unmet medical need (disease) Understand the molecular mechanism of the disease Identify a therapeutic target in that pathway (e.g gene, key enzyme, receptor, ion-channel, nuclear receptor) Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead compounds, antibodies, RNAi, etc. Here is what we are trying to achieve (refer to slide). Note that you can comment on: We conduct basic animal health research in RY, but our animal health care products are marketed by Merial, a joint venture between Merck and Rhone- Poulenc (note that RP is now known as Aventis (RP merged with Hoechst). Outcomes research is when we attempt to prove that our compounds not only cause important chemical effects in the body (such as reduced blood pressure or reduced cholesterol), but that these effects lead to reduced morbidity and mortality over time. The Zocor 4S study is an example. The research budget for MRL is $2.4 billion this year.

Discovery Develop an assay to evaluate activity of compounds on the target - in vitro (e.g. enzyme assay) - in vivo (animal model or pharmacodynamic assay) Identify a lead compound screen collection of compounds (“compound library”) compound from published literature screen Natural Products structure-based design (“rational drug design”) Optimize to give a “proof-of-concept” molecule—one that shows efficacy in an animal disease model Optimize to give drug-like properties—pharmacokinetics, metabolism, off-target activities Safety assessment, Preclinical Candidate!!! Here is what we are trying to achieve (refer to slide). Note that you can comment on: We conduct basic animal health research in RY, but our animal health care products are marketed by Merial, a joint venture between Merck and Rhone- Poulenc (note that RP is now known as Aventis (RP merged with Hoechst). Outcomes research is when we attempt to prove that our compounds not only cause important chemical effects in the body (such as reduced blood pressure or reduced cholesterol), but that these effects lead to reduced morbidity and mortality over time. The Zocor 4S study is an example. The research budget for MRL is $2.4 billion this year.

Development Pre-Clinical Clinical Process R&D Chem Eng. R&D Manufacturing Bio Process R&D Safety Assessment Toxicology Drug Metabolism (ADME) Pharmacology Pharmaceutical R&D Formulation Regulatory Affairs Project Planning & Management Marketing Clinical Investigator & patient Clinical Pharmacology Clinical Research Statistics & Epidemiology Data Coordination Research Information Systems Information Services

IND Clinical Trials Phase I Phase II Phase III Investigational 20 - 100 healthy volunteers take drug for about one month Remote data entry Product Profile Marketing SOI Information Learned 1. Absorption and metabolism 2. Effects on organs and tissue 3. Side effects as dosage is increased Investigational New Drug application IND Clinical Trials Phase II Several hundred health-impaired patients Treatment Group Control Group Information Learned 1. Effectiveness in treating disease 2. Short-term side effects in health -impaired patients 3. Dose range Phase III Hundreds or thousands of health-impaired patients Information Learned 1. Benefit/risk relationship of drug 2. Less common and longer term side effects 3. Labeling information Compassionate Use

Worldwide Marketing Authorization (WMA) in other countries Advisory Committee Clinical Trials Continued Regulatory Review Team APPROVAL PROCESS (Ex. FDA) Reviews, comments, and discussions Submit to Regulatory Agencies New Drug Application (NDA) APPROVAL Drug Co./Regulatory liaison activities Worldwide Marketing Authorization (WMA) in other countries

Drug Discovery—Convergence of Disciplines Combinatorial Chemistry Synthetic Physical Patent Law Information Technology Modelling Novel Molecule Intellectual Property Structural Activity Pharmacokinetic Properties In Vivo activity Safety Design Pharmaco- dynamics Physiology Biochemistry DMPK Enzymology Immunology Pharmacology Physiology Physiology Safety Assessment Metabolism Pharmacology Pathology Behavior Physiology Physiology