Drug Candidate safety testing

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

2. 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.

3. 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!!!

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

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

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

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