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

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

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)

II. The Research & Development Landscapep p

R&D Expenditures and Return on Investment: A Declining Function

Phrma (2005); Tufts CSDD (2005)

R&D Expenditures 1992-2004 and FDA Approvals

Hu et al (2007)

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 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)

III. Innovation and TransformationIII. Innovation and Transformation

Innovation Models and Transformation

Hu et al (2007)

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/DRI1996 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 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

V. Case Study: Stress-related Affective Disorders

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

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 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

Activation of Olfactory and Reward Pathways in the Presence of Compound #1 but not Fluoxetine

Serendipity or Good Science: Building Opportunity

Hoffman Osterhof

Thanks for Your Time and Attention