Modern Drug Discovery for Dummies KSEA-NE Symposium March 1, 2008 Taeyoung Yoon

2 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Observation-based Drug Discovery (pre-’90s) Medicine Chemistry Drug Phenotypic Screen

3 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Target-based Drug Discovery (post-’90s) HumanOrganCellProteinGenome Target (Hypothesis) Hit LeadCandidateDevelopment Chemical Library ‘in vitro’ ‘in vivo’ Activity Selectivity Property Exposure Toxicity Safety Efficacy Binding Potency

4 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Frey and Olson, 2003 Pathways, Targets, and Hypothesis Receptors Enzymes Ion Channels PPI (?) NHRs

5 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Genomic Targets; “Genes-to-drugs”  20,000 ~ 25,000 (protein-coding) genes in human  1,000 ~ 2,000 ‘druggable’ genes  ~ 300 targets by ~1,200 unique drugs in the market  Genotype - disease association  Target validation Knock-out animals Knock-down (e.g., RNAi) Gene-level, animal model

6 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Hit Finding  Assay development Biochemical assay Cellular (pathway) assay  High Throughput Screening (HTS) Chemical library (1 ~ 3 million compounds) Completely automated (robots) % Inhibition and dose-response (IC50)  Hit-triaging and Hit validation False positives, frequent hits, non-druggables, etc Counter screen, specificity, etc  Other means of hit finding Patent busting (Fast follower) Fragment-based discovery Virtual screening A A P ATP ADP X Drug IC50 = 0.6 uM Kinas e

7 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Hit-to-Lead, Lead Optimization Full-pledged medicinal chemistry phase  Guided by ‘Structure-Activity Relationships (SAR)’  Iterative optimization of, Activity vs. target -Biochemical activity (IC50) -Cellular (functional) activity Selectivity vs anti-targets and tox targets -Subtype (or homolog) selectivity panel -General receptor, kinase, protease panels -Early tox, e.g., cardiotox, mutagenicity, phototox, etc -Pharmacokinetic properties – ADME

8 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Pharmacokinetics; ADME Ultimate goal is to have an adequate exposure and duration of the drug at the target tissue, as normally extrapolated from systemic (blood) concentration. Portal Vein Gut Lumen Metabolism Systemic Circulation Target Tissue (BBB) Kidney Liver Absorption Excretion Solubility Lipophilicity Formulation!! Microsomal Stability CYP inhibition/induction Distribution Gut Wall

9 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Example; A DPP4 Inhibitor for Type 2 Diabetes M. Eckhardt et al., J. Med. Chem. 2007, 50, 6450 IC50 = 3900 nMIC50 = 35 nMIC50 = 6 nM hERG; 1uM M1 IC50; 25 nM HTS IC50 = 4 nM hERG; 1uM M1 IC50; 6161 nM IC50 = 1 nM hERG; 1uM M1 IC50; 295 nM BAV (rat) = 50.7%

10 | Presentation Title | Presenter Name | Date | Subject | Business Use Only In Vivo Validation; Animal Models  PK/PD Models Look for biomarker of the target pathway  Disease Models Artificially induce the disease symptoms in animals -Externally induced (training, diet, surgery, etc) -Genetically modified (transgenic, knock in, knock out) Validation of animal model is one of the weakest links -Robustness (control, statistics, etc) -Faulted etiology -Genetic vs pharmacological intervention “Mice are not humans” vs. “Models are just models”

11 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Drug Development and Clinical Studies  Preclinical development CMC; Process chemistry (> kg API), Dosage form (formulation) Animal toxicity, Therapeutic index Satisfying the regulatory requirements  Clinical trials Investigational New Drug (IND) registration Phase 1; Safety, tolerability, PK, PD -Dose ranging; Single ascending dose, multiple ascending dose Phase 2; Dosing (2a) and efficacy (2b) Phase 3; Definitive assessment of drug effectiveness -Multi-center, randomized, double-blind, placebo-controlled -“Label expansion” (3b) New Drug Application (NDA), Phase 4; Post-marketing surveillance trial

12 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Progress Report $ 10B $ 20B $ 30B Pharmaceutical R&D

13 | Presentation Title | Presenter Name | Date | Subject | Business Use Only What went wrong? …or did it?  Low hanging fruits are exhausted?  Target biology vs drug biology?  Increasing conservatism? Science - Drugs ‘killed’ based on weakly predictive assays Business - Emphasis on safe, “me-to” drugs Regulation – Safety, safety, safety  Etc, etc, …  An optimist’s view – ‘S-curve theory’ of technology development Induction phase Payback phase Senescence phase

14 | Presentation Title | Presenter Name | Date | Subject | Business Use Only New Grammar of Drug Discovery - Novartis  Pathway-based clinical taxonomy in the post-genomic era  Molecular pathway approach Disease phenotype of genetic disorders Discover druggable, ‘sensitive nodes’ in the pathway  Translational medicine  Advantage in patient stratification in initial clinical trials; ‘orphan drug’  Phase 0 clinical study; eIND, FIH POC (proof-of-concept)  Pathway-based expansion into other diseases  BONUS: Serving unmet medical needs of neglected, rare diseases Mark Fishman, President of NIBR Nature 2005, Vol 437, pp

15 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Muckle-Wells Syndrome  Rare genetic mutation of CIAS1 gene  IL-1  overproduction  Over-sensitive inflammation; rash, fever, deafness, amyloidosis  ACZ885 is an anti-IL-1  antibody in Phase III for MWS

16 | Presentation Title | Presenter Name | Date | Subject | Business Use Only Thank You!