Grazie per aver scelto di utilizzare a

scopo didattico questo materiale

delle Guidelines 2011 libra.
Le ricordiamo che questo materiale
di propriet dellautore e fornito
come supporto didattico per uso
personale.

Role of industrial research in the development of

new drugs

Malcolm Johnson
GlaxoSmithKline R&D
& NHLI,London

Key issues in formulating an hypothesis in

drug discovery

Biology
Scientific understanding of disease state?
What is the desirable mechanism?

Medical Need

Medicine
Is mechanism acceptable in man?
Can it be tested in man?

Chemistry
What to make?

Discovery/Development Strategies
In house research
In-licencing
External collaborations
Collaborative networks
Promote external innovation

Drug discovery pipeline

Exploratory discovery

Disease
selection

Target
identification
and selection

Drug discovery

Lead
identification

Lead
optimization

Candidate
pre-clinical
evaluation

Clinical
proof of
concept

Drug discovery pipeline

Exploratory discovery

Disease
selection

Target
identification
and selection

Drug discovery

Lead

Lead

identification

optimization

Tissue bioassay

Candidate

Clinical

pre-clinical

proof of

evaluation

concept

Normal
Disease
Primary

Integrative
pharmacology

Isolated cells
Transfection
Immunohistochemistry
Gene microarray
Transgenic models

Normal
Disease
Receptors
Enzymes
Reporter genes

Drug discovery/development pipeline

Drug development

Drug discovery

Disease

Gene to

Function

Target

Hit to

selection

function

to target

to hit

lead

Commit

Commit

to

to

to

disease

product

target

type

Commit Tractable
hit

Lead
optimisation

Safety
and

Phase I

Phase II

developability

Candidate

First time

Proof of

selection

in man

concept

Phase III

Phase IV

Research/development strategy
Therapeutic objective
Biology

Clinical
Project team

Chemistry

Drug candidate
Exploratory development
Full development
Clinical trials
Regulatory authorities
Product licence application
Market

Information
science

How are drugs discovered?

Random screening
Chemistry/compound library
Natural products

Rational design
Based on natural hormones
Based on existing active drugs
Based on molecular modelling

Pre-clinical studies

Purpose

- Determine bilogical activity

- Assess specificity of action

Types of studies

- In vitro studies
- In vivo (animal studies)

Study design

- Dose-response studies

Success rate

- 1 in 1000 compounds tested

Time

- Variable. Approximately 3.5 years

for successful lead compounds

High Throughput Screening

1980:Salmeterol project- 10 compounds/week
2011;100,000 compounds/day:
combinatorial chemistry
smart screens
cloned human receptors
96-well plate format
low volumes
robotics
Future: 10 million /hour:

 Molecular modelling
Bioinformatics
Proteomics
Genetics
Pharmacogenomics

Fluticasone furoate an enhanced-affinity

glucocorticoid
FP

FF

Biggadike et al J Med Chem 2008

Vilanterol in receptor

Toxicology
Acute
Subacute
Chronic

- 2-week studies in 3 or 4 species

maximum tolerated dose
- 6-month studies in 2 species
- 12-month studies in 2 species (rats & dogs)
- Oncogenicity studies
- 18 months in mice

Fertility and
reproductive

- 2 years in rats
- Fertility, teratology and perinatal and
postnatal studies in 2 species

Mutagenicity

(rats and rabbits)

- In vivo and in vitro tests

Phase I clinical trials

Purpose
Type of
studies
Study
population
Study design

Success rate
Time

Determine the primary safety profile

and a safe dosage range
Pharmacokinetic and pharmacodynamic
studies
Normal, healthy volunteers (usually male)
Single dose escalation or short-term
design multiple dose, placebo controlled,
in specialised hospital units
1 in 3
1 year

Phase III clinical trials

Purpose

Type of studies
Study
population
Study design
Success rate
Time

Verify effectiveness, closely monitor

safety in long-term use, establish optimum
dosage
Placebo, dose or comparator controlled
efficacy and safety
1000 to 3000 patients, more heterogeneous
to reflect real patient population
Multiple end-point, double-blind, large
multi-centre
1 in 3
2 to 4 years

New drug development process

12-15 years total
2.5 years

Approval
Regulatory review
Marketing application filed with
regulatory authority

3+ years
2+ years
1 + year

Phase III clinical studies

extensive clinical studies
Phase II clinical studies efficacy studies
Phase I clinical studies pharmacological profile
Regulatory/ethical review committee approval

3+ years

Preclinical laboratory and animal toxicology studies

12-1
5 yr

nt
Pate
3 yr

CH
R
A
E
S
E
R

LO
E
V
DE

T
N
E
PM

Efficacy

Safety

MARKETIN

IRD
Regulato
NDA
ry
Manufacture
Clinical trials
Process research

Volunteer studies
Toxicology

Activity

Patenting
Testing
Screening

New drug development:

A major high-risk undertaking

Time

12-15 years from discovery to market

Cost

900 million

Success

1 in 4000 compounds synthesised or 1 in 5

tested in humans reaches the market

Return

1 in 3 drugs reaching the market recaptures

development costs

Mortality Studies

COPD:
TORCH 6,100 patients studied for 3 years
( Cost 450,000,000 euros; Mortality p=0.052)
UPLIFT 6,400 patients studied for 4 years
(Cost ?; Mortality p=0.086)

External collaborations network

Academic

Academic

Academic

centre

centre

Pharma

Clinical

R&D

centre

centre

Academic

Academic

centre

centre

External collaborations objectives:

Increased product database
efficacy/safety support
Extend product profile

new claims?

Address competitor claims/issues

Increase number/value of citable publications

External Research Collaborations

Non-project related:
Muscarinic receptor mapping in the airways of COPD patients
Role of innate immunity in lung repair in COPD
Project related:
Effects of Relovair on parasternal muscle and diaphragm in
patients with COPD
Functional enhancement of corticosteroid action by LABAs

GR nuclear translocation
Non treatment

FP (10

M)

-10

FF (10

M)

-10

4 hr

30 hr

Ito et al, NHLI

p38-alpha kinase inhibitor (LosmapimodGW 856553) enhances steroid mediated suppression

of IL-8 release in COPD

% IL-8 Suppression
compared with LPS alone

553-9
553-10

20

40

Dex

**

60

80

**

Dex/553-10M
Dex/553-9M

**

** p<0.01 compared
to Dex alone

100
-9

-8

-7

-6

Dex [Log M]

Bhavsar et al, NHLI

MICA
MRC Industrial Collaboration Award
Industrys contribution can be:
Financial (FTEs) or in kind
Consumables
Equipment
Resources
Project Management
% Industrial contribution = industrial costs/total cost

Objectives of ECLIPSE
To define clinically relevant COPD subtypes in
individuals with GOLD stage IIIV COPD
To define the parameters that predict disease
progression over 3 years in the clinically relevant
COPD subtypes
To acquire data on biomarkers that correlate with
clinically relevant COPD subtypes
To identify novel genetic factors and/or biomarkers
that correlate with clinically relevant COPD subtypes

SP-D and COPD: Increased SPD Levels Predict

Occurrence of At Least One Exacerbation
Risk (Odds Ratio) of exacerbation
for each 100ng/mL increase in SP-D*

95% CI

All patients

1.22

1.07 1.39

Upper quartile baseline

level only

1.42

1.02 1.97

Upper quartile baseline

level only, excluding
outliers with SP-D >99th
percentile (382.7ng/mL)

1.58

1.02 2.44

Patients no reporting
exacerbation in year prior
to enrolment

1.23

1.02 -1.49

* Serum SP-D continuous variable in multivariate model adjusting for sex, percentage predicted FEV 1 ,
reversibility and those taking corticosteroids

Lomas DA, et al. Eur Respir J 2009;34:95-102

ECLIPSE/NETT
Genome-wide asssociation study identifies BICD1 as
a susceptibilty gene for emphysema.
p=5.2x10-7 mild emphysema
p=4.8x10-8 moderate/severe emphysema
Kong et al, AJRCCM,2011

IMI
Innovative Medicines Initiative:
Europe-wide public-private initiative aiming to
speed up the development of better and safer
medicines for patients.
Supports collaborative research projects and
builds networks of industrial and academic
experts in order to boost pharmaceutical
innovation in Europe.

CATALYST
GSK: Open Bioscience Innovation Campus
INCUBATOR Small start-up companies
ACCELERATOR - Established companies with
possible leads