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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