Drug Discovery and Preclinical Development Neal G Simon Ph D Neal G. Simon, Ph.D. Professor Department of Biological Sciences
Disclaimer Those who have knowledge, don t predict. Those who predict, don t have knowledge. Lao Tzu, 6 th Century BC Chinese Poet
Discovery and Preclinical Development I. Background II. The R&D Landscape III. Innovation and Transformation IV. The Preclinical Development Process V. Case Study: Stress-related Affective Disorders
Serendipity or Good Science: Building Opportunity Hoffman Osterhof
I. Background
Drug Development Process
Biopharmaceutical Drug Development: Attrition Drug Discovery Pre-Clinical Clinical Trials FDA Review Large Scale Manufacturing / Phase IV 10,000 Compound s IND Su ubmitted Phase I 20-100 Volunteers 250 Compounds 5 Compounds Phase III 1000-5000 Volunteers NDA Su ubmitted 1 FDA Approved Drug Phase II 100-500 Volunteers 5 years 1.5 years 6 years 2 years 2 years Quelle: Burrell Report Biotechnology Industry 2006
Capitalized Cost Estimates per New Molecule *All R&D costs (basic research and preclinical development) prior to initiation of clinical testing ** Based on a 5-year shift and prior growth rates for the preclinical and clinical periods. DiMasi and Grabowski (2007)
II. The Research & Development Landscape
R&D Expenditures and Return on Investment: A Declining Function Phrma (2005); Tufts CSDD (2005)
Hu et al (2007) R&D Expenditures 1992-2004 and FDA Approvals
NIH Budget by Area
Pharmaceutical Industry: Diminishing Returns That is why the business model is under threat: the ability to devise new molecules through R&D and bring them to market is not keeping up with what s being lost to generic manufacturers on the other end. This situation requires new thinking, new urgency, new capabilities. Fred Hassan, CEO Schering-Plough, h 2005 Saltzmann (2006)
III. Innovation and Transformation
Hu et al (2007) Innovation Models and Transformation
Innovation Models: In-licensing and Acquisitions Saltzmann (2006)
Me Too Drugs: Antidepressants 1986 Fluvoxamine (Luvox; Solvay) SSRI 1987 Fluoxetine (Prozac; Lilly) SSRI 1992 Sertraline* (Zoloft; Pfizer) SSRI/NRI 1993 Venlafaxine (Effexor; Wyeth) SSRI/NRI 1996 Buproprion (Wellbutrin; Wyeth) SNRI/DRI 2002 Escitalopram (Lexapro; Forrest) SSRI 2004 Duloxetine (Cymbalta; Lilly) SSRI/NRI
Personalized Medicine (sort of)
Discovery & Preclinical Development IV. Discovery and Preclinical Development
Discovery and Preclinical Development Lead Selection and Drug Candidate Preclinical Drug Optimization (iterative) Confirmation Characterization Efficacy Assessment: Does it work? ADME Profiling: How can it be delivered and what does the body do? Toxicology/Safety Pharmacology Assessment: Is it safe? Regula atory Subm mission t o FDA Pharmaceutics: Is the manufacture viable and controllable? Adapted from TetraQ
Stage 1: Lead Selection and Optimization Essential Pharmaceutics Structural Characterization Impurity Identification Solubility assessment Prototype formulation Stability testing Screening Efficacy Early ADME Early Toxicology In vitro models In vivo models Other In silico profiling Develop simple analytical method Measure membrane permeability Plasma Stability Off target t screen In vitro cytotoxicity Preliminary AMES herg binding Adapted from TetraQ
Stage 2: Drug Candidate Confirmation Data from Lead Optimization Stage Preliminary CMC (Chemistry, Manufacture and Control) Benchmark in vivo Models ADME Profiling Preliminary Toxicology Formulation for GLP Toxicology Stability testing ti of active ingredient Detailed physicochemical h i characterization Impurity analysis In vivo models Validated models Models in other disease areas Optimized analytical method development Basic pharmacokinetics (PK) &Oral Bioavailability Determine metabolism of drug Maximum tolerated dose (MTD) Repeat Dose (non-glp) Preliminary Cardiovascular Safety Pharmacology Adapted from TetraQ
Stage 3: Preclinical Drug Characteristics Data from Prior Stages Detailed Preclinical CMC Comprehensive ADME GLP Toxicology Package ICH Stability Testing ICH impurity it analysis Develop prototype clinical formulation analytical method development Comprehensive Pharmacokinetics GLP TK Comprehensive identification of metabolites acute study subchronic repeat dose study Genotoxicity Battery Safety Pharmacology Regulatory Submission or Presentation to Pharma Adapted from TetraQ
V. Case Study: Stress-related Affective Disorders
Overview GPCR targeted oral small molecule l drugs for stress, mood, and behavior disorders First compounds: vasopressin receptor antagonists Somewhere between skunk works, serendipity, and good planning
AVP: Biological Diversity Invertebrate & Vertebrate Physiology fluid regulation carbohydrate metabolism thermoregulation reproductive function Vertebrate Behavior communication sexual lbehavior pair bonding paternal/maternal care social memory stress-related disorders impulsivity/violence
Hypothalamic-Pituitary Adrenal Axis
Compound #1 Profile: Novel oral vasopressin AVP receptor antagonist Initial clinical development for stress related affective illness Serenic activity established in rodent models Market: $20+ billion World Wide Market 35 million people affected by anxiety and depression in US alone Status: Phase I completed Phase II in planning
Compound #1: Preclinical Development I. in vitro Biology and PK II. IND-directed Toxicology and Pharmacology III. Behavior and Neuroimaging * NIMH (MH063663), NIH Roadmap Initiative, NCI
Binding and Function at Human AVP Receptor A competitive binding assay was conducted in CHO cells transfected with human AVP receptor (left panel). Compound #1 inhibited AVP- mediated phosphatidyl inositol turnover with a Ki value at 0.16 nm (right panel). 1000 of Bound 3 H-A AVP CPM 800 600 400 200 Inhibition of Human AVP Binding by IC50 = 0.49 nm Ki = 0.30 nm 0-13 -12-11 -10-9 -8-7 -6-5 Concentration: Log M CP PM of 3 H-IP 3 Inhibition of AVP Induced IP3 Production 3500 3000 EC50 = 0.87 nm 2500 Ki = 0.16 nm 2000 1500 1000 500 0-13 -12-11 -10-9 -8-7 -6-5 Concentration: Log M
Compound #1: Selectivity Tested at vs 64 receptors including 35 GPCRs Receptor Class #1 (% inhibition) Vasopressin 1 80.40% Neurotransmitter related -20% to +20% Steroids -20% to +20% Ion channels -20% to +20% Second messengers -20% to +20% Prostaglandins -20% to +20% Growth thfactors/hormones -20% to +20% Brain/gut peptides (not including Vasopressin 1) -20% to +20% Enzymes -20% to +20% *-20% to +20% is considered baseline, which is defined as inactive
Compound #1: IND-Directed Studies Genetic Safety Mammalian Toxicology Pharmacology Toxicology AMES herg 7-day Repeat Oral Chromosomal Aberration herg Rat Irwin Cardiovascular & Pulmonary Safety in Dogs (gavage) in Rats 28-day Repeat Oral (gavage) dose in Rats 7-day DRF in Dogs 28-day Repeat Oral (capsule) dose in Dogs (just completed)
Compound #1: herg Test for QT Prolongation Values shown are Inhibition of Current (%) + SEM Test Compound % Inhibition SEM Compound 1 32.9 1.5 Positive Control 76.7 2.8 (terfenadine 60 nm) Conducted by ChanTest, Inc; Covance GLP study 7252-117 Results: IC50 = 1.9 μm indicating low risk of cardiac arrhythmias based on anticipated clinical dosing
Compound #1 Blocks Vasopressin-induced Increases in Blood Pressure Blood Pressure 25 lood pres ssure (mm m Hg) 20 15 10 B 5 0 Blood Pressure ** ** AVP vehicle Only 0.16 0.4 1 2.5 ** p<0.05 vs vehicle Dose (mg/kg)
Vasopressin is Linked to Stress-related Disorders R. Landgraf (2006). Involvement of the vasopressin system in stress-related disorders. CNS & Neurological Disorders Drug Targets 5, 167-179 Increased synthesis, content, and release of AVP in PVN in HAB and LAB rats under basal conditions
Elevated Vasopressin is Linked to Stress-related Disorders: Rodent Model AVP in the paraventricular nucleus (PVN) flanking the 3rd ventricle (3V) in HAB (high anxiety) and LAB (low anxiety) mice. Elevated Plus Maze Forced Swim Test Bunck et al. (2009)
AVP mrna in Supraoptic and Paraventricular Nuclei from Depressed and Control Individuals AVP mrna in PVN and SON in depressed (n=9) and control patients (n=8) Signal on film in SON and PVN Meynen et al (2006)
fmri: Imaging Stress/Arousal in Awake Animals Piloerection is an index of autonomic activation
Compound #1 Blocks Stress & Arousal: Composite View Mate/Intruder + Compound #1 Imaging on awake rats
Compound #1: Blockade of Stress/Arousal in Major Brain Regions Amygdala Cortex Hippocampus Thalamus Treatment Mate & Intrude er
Activation of Olfactory and Reward Pathways in the Presence of Compound #1 but not Fluoxetine
Serendipity or Good Science: Building Opportunity Hoffman Osterhof
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