drug discovery and preclinical development
TRANSCRIPT
Drug Discovery and Preclinical Development
Neal G Simon Ph DNeal G. Simon, Ph.D.Professor
Department of Biological Sciences
Disclaimer
“Th h h k l d d ’t di t“Those who have knowledge, don’t predict. Those who predict, don’t have knowledge.”
Lao Tzu, 6th Century BC Chinese Poet
Discovery and Preclinical Development
I BackgroundI. Background
II. The R&D Landscape
III I ti d T f tiIII. Innovation and Transformation
IV. The Preclinical Development Process
V. Case Study: Stress-related Affective Disorders
Biopharmaceutical Drug Development: Attrition
Drug Discovery Pre-Clinical Clinical Trials
FDA Review
Large Scale Manufacturing/ Phase IV
Phase I20 100
Phase III
ubm
itted
ubm
itted
250 Compounds 5 Compounds10,000 Com- 1 FDA
A d
20-100 Volunteers
ase1000-5000 Volunteers
IND
Su
ND
A Su250 Compounds 5 Compounds
pounds
Approved Drug
Phase II100-500
5 years 1.5 years 6 years 2 years 2 years
100 500 Volunteers
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)
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 genericis not keeping up with what s being lost to generic manufacturers on the other end. This situation requires new thinking, new urgency, new capabilities.”
F d H CEO S h i Pl h 2005Fred Hassan, CEO Schering-Plough, 2005
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/DRI1996 Buproprion (Wellbutrin; Wyeth) SNRI/DRI
2002 Escitalopram (Lexapro; Forrest) SSRI
2004 Duloxetine (Cymbalta; Lilly) SSRI/NRI
Discovery and Preclinical Development
Lead Selection and Drug Candidate Preclinical DrugLead Selection andOptimization (iterative)
Drug CandidateConfirmation
Preclinical DrugCharacterization
ff ?
Regula
Efficacy Assessment: Does it work?
ADME Profiling: How can it be delivered and what does the body do?
atory Subm
Toxicology/Safety Pharmacology Assessment: Is it safe?
ADME Profiling: How can it be delivered and what does the body do? mission t
Pharmaceutics: Is the manufacture viable and controllable?
Toxicology/Safety Pharmacology Assessment: Is it safe? o FDA
Pharmaceutics: Is the manufacture viable and controllable?
Adapted from TetraQ
Stage 1: Lead Selection and Optimization
• Structural CharacterizationImpurity Identification
Essential Pharmaceutics
• Impurity Identification• Solubility assessment• Prototype formulation• Stability testing
Screening Efficacy
• In silico profiling
Early ADME
Off t t
Early Toxicology
• In vitro models• In vivo models• Other
In silico profiling• Develop simple
analytical method • Measure membrane
permeability
• Off target screen• In vitro cytotoxicity• Preliminary AMES • hERG bindingpermeability
• Plasma Stability
Adapted from TetraQ
Stage 2: Drug Candidate Confirmation
Data from Lead Optimization Stage
Preliminary CMC(Chemistry,
Manufacture and Control)
“Benchmark” invivo Models ADME Profiling Preliminary
Toxicology
• Formulation for GLP ToxicologySt bilit t ti
Control)
I i d l
• Optimized analytical method
• Maximum tolerated dose• Stability testing
of active ingredient
• Detailed h i h i l
• In vivo models• Validated
models• Models in other
di
method development
• Basic pharma-cokinetics (PK) & Oral
tolerated dose (MTD)
• Repeat Dose (non-GLP)
• Preliminaryphysicochemical characterization• Impurity
analysis
disease areas & Oral Bioavailability
• Determine metabolism of drug
Preliminary Cardiovascular Safety Pharmacology
drug
Adapted from TetraQ
Stage 3: Preclinical Drug Characteristics
Data from Prior Stages
Comprehensive ADME
Detailed Preclinical CMC
GLP Toxicology Package
• analytical method development
• Comprehensive
• ICH Stability Testing
ICH i it
• acute study• subchronic repeat
dose studypPharmacokinetics
• GLP TK• Comprehensive
identification of
• ICH impurity analysis
•Develop prototype clinical formulation
y• Genotoxicity
Battery• Safety
Pharmacologymetabolites
gy
Regulatory Submission or Presentation to Pharma
Adapted from TetraQ
Overview
d l ll l l d f GPCR‐targeted oral small molecule drugs for stress,
mood, and behavior disorders
First compounds: vasopressin receptor antagonists
Somewhere between skunk works, serendipity, and p y
good planning
AVP: Biological Diversity
Invertebrate & VertebratePhysiology
Vertebrate Behavior
fluid regulation
b h d t t b li
communication
l b h i carbohydrate metabolism
thermoregulation
sexual behavior
pair bonding
reproductive function paternal/maternal care
social memory
stress-related disorders
impulsivity/violencep y
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 PKI. in vitro Biology and PK
II. IND-directed Toxicology and Pharmacologygy gy
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 phosphatidylAVP receptor (left panel). Compound #1 inhibited AVP- mediated phosphatidyl inositol turnover with a Ki value at 0.16 nM (right panel).
I hibiti f H AVP Bi di b Inhibition of AVP Induced IP3 ProductionInhibition of Human AVP Binding by
800
1000
AVP
3000
3500
EC50 = 0 87 nM
400
600
800
IC50 = 0.49 nMKi = 0.30 nM
of B
ound
3 H-A
1500
2000
2500
3000 EC50 = 0.87 nMKi = 0.16 nM
PM o
f3 H-IP
3
-13 -12 -11 -10 -9 -8 -7 -6 -50
200CPM
-13 -12 -11 -10 -9 -8 -7 -6 -50
500
1000CP
Concentration: Log M Concentration: Log M
Compound #1: Selectivity
Receptor Class #1
Tested at vs 64 receptors including 35 GPCRsReceptor Class #1
(% inhibition)Vasopressin 1 80.40%
N t itt l t d 20% t +20%Neurotransmitter related -20% to +20%Steroids -20% to +20%
Ion channels -20% to +20%Second messengers -20% to +20%
Prostaglandins -20% to +20%G th f t /h 20% t +20%Growth factors/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 MammalianGenetic Toxicology
SafetyPharmacology
Mammalian Toxicology
AMES hERG 7-day Repeat Oral AMES
Chromosomal Aberration
hERG
Rat Irwin
7-day Repeat Oral (gavage) in Rats
28-day Repeat Oral Cardiovascular &
Pulmonary Safety in Dogs
(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 SEMCompound 1 32.9 1.5Positive Control 76.7 2.8(t f di 60 M)(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
20
25
m H
g) Blood Pressure20
25
m H
g)
10
15
ssur
e (m
m
**10
15
ssur
e (m
m
**
5
10
lood
pre
s
**5
10
lood
pre
s
**
0vehicle 0.16 0.4 1 2.5
B0AVP Only 0.16 0.4 1 2.5
Dose (mg/kg)
B
Dose (mg/kg)** p<0.05 vs vehicle
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) inAVP 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
Meynen et al (2006)
Signal on film in SON and PVNAVP mRNA in PVN and SON in depressed (n=9) and control patients (n=8)
fMRI: Imaging Stress/Arousal in Awake Animals
Piloerection is an index of autonomic activationPiloerection 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
er
Amygdala Cortex Hippocampus Thalamus
& In
trud
eM
ate
ent
Trea
tm