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delle Guidelines 2011 libra.Le ricordiamo che questo materiale è

di proprietà dell’autore 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

BiologyScientific understanding of disease state?

What is the desirable mechanism?

ChemistryWhat to make?

MedicineIs mechanism acceptable in man?

Can it be tested in man?

Medical Need

Discovery/Development Strategies

• In house research

• In-licencing

• External collaborations

• Collaborative networks

• Promote external innovation

Diseaseselection

Targetidentificationand selection

Leadidentification

Leadoptimization

Candidatepre-clinicalevaluation

Clinicalproof ofconcept

Drug discovery pipeline

Exploratory discovery Drug discovery

Disease

selection

Target

identification

and selection

Lead

identification

Lead

optimization

Candidate

pre-clinical

evaluation

Clinical

proof of

concept

Drug discovery pipeline

Exploratory discovery Drug discovery

Integrative pharmacology

Tissue bioassay

Isolated cells

Immunohistochemistry

Gene microarray

Transgenic models

Normal

Disease

Primary

Transfection

Normal

Disease

ReceptorsEnzymesReporter genes

Disease

selection

Safety

and

develop-

ability

Phase I Phase II Phase III Phase IVGene to

function

Function

to target

Target

to hit

Hit to

lead

Lead

optimi-

sation

Commit

to

disease

Commit

to

product

type

Commit

to

target

Tractable

hit

Candidate

selection

First time

in man

Proof of

concept

Drug discovery/development pipeline

Drug discovery Drug development

Research/development strategy

Biology

Chemistry

Clinical

Information

science

Therapeutic objective

Project team

Drug candidate

Exploratory development

Full development

Clinical trials

Regulatory authorities

Product licence application

Market

How are drugs discovered?

• Chemistry/compound library• Natural products

Random screening

• Based on natural hormones• Based on existing active drugs• Based on molecular modelling

Rational design

Pre-clinical studies

• Purpose

• Types of studies

• Study design

• Success rate

• Time

- Determine bilogical activity

- Assess specificity of action

- In vitro studies

- In vivo (animal studies)

- Dose-response studies

- 1 in 1000 compounds tested

- 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: lower costs smaller volumes (pl)

• Molecular modelling

• Bioinformatics

• Proteomics

• Genetics

• Pharmacogenomics

Fluticasone furoate– an ‘enhanced-affinity’ glucocorticoid

Biggadike et al J Med Chem 2008

FP FF

Vilanterol in receptor

Toxicology

• Acute

• Subacute

• Chronic

• Fertility and reproductive

• Mutagenicity

- 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

- 2 years in rats- Fertility, teratology and perinatal and

postnatal studies in 2 species

(rats and rabbits) - In vivo and in vitro tests

Phase I clinical trials

• Purpose Determine the primary safety profile and a safe dosage range

• Type of Pharmacokinetic and pharmacodynamic studies studies

• Study Normal, healthy volunteers (usually male) population

• Study design Single dose escalation or short-term

design multiple dose, placebo controlled, in specialised hospital units

• Success rate 1 in 3

• Time 1 year

• Purpose Verify effectiveness, closely monitor safety in long-term use, establish optimum dosage

• Type of studies Placebo, dose or comparator controlled efficacy and safety

• Study 1000 to 3000 patients, more heterogeneous population to reflect real patient population

• Study design Multiple end-point, double-blind, large multi-centre

• Success rate 1 in 3

• Time 2 to 4 years

Phase III clinical trials

New drug development process

12-15 years total

2.5 years

3+ years

2+ years

1 + year

3+ years

Approval

Regulatory review

Marketing application filed withregulatory authority

Phase III clinical studies – extensive clinical studies

Phase II clinical studies – efficacy studies

Phase I clinical studies – pharmacological profile

Regulatory/ethical review committee approval

Preclinical laboratory and animal toxicology studies

MARKETING

IRDNDA

Manufacture

Clinical trials

Process research

Volunteer studies

Toxicology

Patenting

Testing

Screening

Activity

Safety

Efficacy

Regulatory

12-15 yr

RESEARCH

DEVELOPMENT

3 yr

Patent

New drug development:A major high-risk undertaking

Time 12-15 years from discovery to market

Cost

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

£900 million

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)

Academic

centre

Academic

centreAcademic

centre

Academic

centre

External collaborations network

Pharma

Academic

centre

Clinical

centreR & D

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

Ito et al, NHLI

FP (10-10M) FF (10-10M)

4 hr

30 hr

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

of IL-8 release in COPD

0

20

40

60

80

100

Dex/553-9MDex/553-10M

553-9553-10

Dex

-9 -8 -7 -6

*

** p<0.01 comparedto Dex alone

**

****

Dex [Log M]

% I

L-8

Su

pp

res

sio

nc

om

pa

red

wit

h L

PS

alo

ne

Bhavsar et al, NHLI

MICA

• MRC Industrial Collaboration Award

Industry’s 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 II–IV 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 FEV1 , 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