Download Precision medicine strategies for early drug development

Early identification of patient variability and
pharmacogenomics strategies: a new approach to
the development of stratified medicines
The need for improved target validation: many
compounds ineffective in high % of patients
Source: Technology Strategy
Board, “Accelerating Stratified
Medicines in the UK”, 2010.
www.innovate10.co.uk/uploads/
Stratified%20Medicine.pdf
Decline in 24 hr glucose levels (mg/dL)
Urgent need to stratify patients
before designing clinical trials
Clinically-desired goal: drop
by 40 mg/dL
Study mean: overall drop of
28 mg/dL = trial fails
Individual patients with diabetes
Identifying responders and non-responders in
fresh, disease-relevant human tissue
Poor responder
All donors “responders”
Good responder
Responder
Patient variation in drug responses to common bronchodilators, measured in fresh, surgical residual tissues at Biopta’s laboratory. The
graphs show bronchodilatation to increasing concentrations of two beta-adrenoceptor agonists, formoterol and salmeterol in human
isolated airways from three separate individuals.
Objectives of the Collaboration
•
Create a powerful exemplar project showcasing the
combined strengths of Scottish organisations
•
Improve the selection of patient stratification criteria based
on a combination of genomics and associated functional
data from studies in human tissue samples
Workflow
Fresh functional tissues
Whole exome
sequencing of each
patient
25 donors: COPD
25 donors:
Inflammatory
Bowel Disease
VCFs, microRNA
expression and
cytokine data placed
on Aridhia-managed
database at SMS-IC
Send DNA
Fios extracts data from Aridhia
database and conducts analysis
Freeze the tissues
Measure microRNA
Measure drug responses in
living tissues
Bioinformatics review by Prof
Palmer and Prof Satsangi
Review by Group and Steering
Committee
Patient stratification strategies
Relate drug response to genotype and miRNA
(as an assessment of phenotype)
Variation exists between donors when intact fresh tissues are exposed to
common drugs for COPD in the ex vivo culture system
Inter-individual
variation not apparent
from mean data
Each data point is a
different donor:
reveals extent of
patient variation in
drug response
Experimental logic – Buenestado et al. Roflumilast Inhibits Lipopolysaccharide-Induced Tumor
Necrosis Factor-α and Chemokine Production by Human Lung Parenchyma.
PLOS ONE 2013; 8: 9.
Fios analysis
indicates possible
bimodal stratification
in two treatment
groups
Identifying high and low responses
to drug treatment in vitro
Fios report:
“The density plots show bimodal properties for
some of the treatments, in particular "LPS + Rof
(100nM) + Flut(1uM)" and
"LPS + Roflumilast (100nM) + Formoterol (10uM)".
This could indicate a stratification
into two groups for these drug
combinations.”
Could a lower CYP2E1 expressing haplotype
explain the differences in drug responses?
•
Low CYP2E1 expressing haplotype associated
with good anti-inflammatory response to the
test drugs in vitro
(by measuring TNFa reduction)
•
Hypothesis: CYP2E1 increases ROS
(reactive oxygen species) inhibiting drugmediated reductions in TNFa expression.
•
•
•
TT 3/3 = “High responder”
TC 5/8 = “High responder”
CC 10/14 = “Low responder”
Low CYP2E1
A future roadmap for preclinical patient stratification
Research
Pre clinical
Clinical
Medication
Patient
Tissue
Informed
consent
• Fresh and frozen
tissue
Target
market:
Pharma
Residual Tissue
Blood
CRF
miRNA
NGS
• Bioinformatics expertise
• “In vivo- like” culture
methods to test drug
efficacy in each fresh
tissue
Pharma
Sponsored
projects
Proof of
efficacy;
relate efficacy
to genomics
and clinical
history
• Relate fresh tissue
response to gene panels
Value proposition: design smarter clinical trials through improved preclinical
characterisation of reasons for variation in drug response
Maximising opportunities from the
Exemplar: what comes next?
Sep
Oct
Fios: Finalise
reports based on
feedback from
academic experts
Nov
Dec
Jan
Prepare marketing
materials
showcasing
Scotland and all
parties involved in
the project
Meeting between
SMS-IC and
ReproCELL to
discuss routes to
commercial
exploitation
Feb
March
April
Presentations,
posters, conferences
Scientific
publication on the
collaboration
Execute PR plan:
• press
• web/social media
channels
• involve commercial
groups of all parties
Visits to Pharma:
generate
commercial leads
May
June
Win first Pharmafunded projects
Summary: a novel collaboration to link data from
fresh functional tissues to patient stratification
•
Exemplar project that demonstrates uniqueness of the Innovation Centre
•
Offers a new approach to application of pharmacogenomics by providing the missing
links between genomics and translational medicine (measurements of drug efficacy
during preclinical development)
•
Successful collaboration between the NHS, academia and industry
Email: [email protected]
Tel: +44 141 330 3831