The Translational Medicine

Research Collaboration (TMRC)

Catharine A. Goddard, PhD

Principal Translational Scientist, Pfizer

An example of

commercial focus, collaborative spirit and research

excellence

http://www.dundee.ac.uk/biocentre/SLSBDIV1home.htmhttp://www.abdn.ac.uk/chemistry/research/index.htihttp://www.westchem.ac.uk/

2

Overview

Why Pharma needs to forge academic collaborations

The Translational Medicine Research Collaboration

The TMRC ethos

Creating a successful collaboration

Scotland’s resources

Examples of TMRC projects

Utilising genetic variation for human target validation

Patient selection biomarkers to improve success of OA trials

3

Academic/Industrial collaboration is key to

successful drug development

Open innovation networks between

academia and industry: an imperative for breakthrough therapiesTeri Melese, Salima M Lin, Julia L Chang & Neal H Cohen

NATURE MEDICINE volume 15 | number 5 | may 2009

4

Success will come from working together utilizing

each others strengths

Universities bring…

Focus on science

Clinical expertise

Experimental medicine expertise

Patient populations

Pharma brings…

Cutting edge technology

Access to tool compounds and new drugs

Excellent in vitro and in vivo

Pharmacology

Milestone driven.

5

Translational Medicine bridges the gap between

pre-clinical and clinical studies

Clinical DevelopmentDiscovery Research

Translational medicine

Core Mission: to understand the likely behavior of

experimental medicines in humans

Improve internal decision making through the

incorporation of biomarkers

Enables cost-effective determination of efficacy &

safety through use of biomarkers

Target

Validation

Disease Biomarker

& Disease

Modification

Target/

Compound

Interaction

Patient

selection

Pharmaco-

dynamic

Activity

6

In 2006 a unique collaboration was created -

TMRC

A pan-Scotland research collaboration devoted to

translational science and biomarker development

+ + ++

Partnership based on shared goals, complimentary strengths, shared

risk and reward

7

Ideas derived jointly and individually

Research plan peer-reviewed

Project costs paid by company with government infrastructure support

Research plan modified by mutual agreement

Background IP protected with shared ownership of joint IP and data

Results published with TMRC approval

This is a true collaboration with peer-review and

management from all partners

CollaborationGrant Contract

8

TMRC Proposition

Joined-up access to internationally leading clinical research capabilities

Ability to rapidly convene expert groups and PI’s across institutions and therapeutic

areas to come up with project solutions

Speed

Project proposal to multi-partner contract in 4 months

Accelerate NHS approvals, recruitment of key personnel and patients

Ease of interaction

Agreed IP, costing, indemnity, RGF, project management etc terms in place for flexible multi-partner contracting

Control and outputs

Ensure active senior level engagement to help drive project performance and implement change across partners

Culture of collaboration with external partners towards commercial and clinical relevant outputs

9

TMRC Project Management System

Steering Committee and overarching contractual agreements

Wyeth Translational

Medicine

requirements

Workshops in

particular

Therapeutic Area

TMRC Annual Event

Scottish Academic’s

research idea/

technical expertise

TMRI Ltd/

Wyeth

Project development

team

- Academic(s)

- Wyeth Translational

Scientist

- University T.T.O.

- NHS R&D Office

Scientific

Review

Legal

ReviewProject start

TMRI Ltd

Scientific Review Board

Wyeth Legal

Interim

Reviews

- 6 monthly

Wyeth Translational Scientist

Project Final

Report

TMRI Ltd

S.R.B.

TMRI Ltd

S.R.B.

Scientific Monitoring

Financial Monitoring

Intellectual Property Monitoring

Development Review Activity

10

IP Agreements

Cross licences of specified IPR to:

Carry out TMRC Programmes of research

Carry out internal R&D

Exploit IPR arising from TMRC Programmes of research

All IPR generated by TMRC Programmes of research jointly owned by

TMRI and Pfizer

Pfizer retain rights to Therapeutic IPR

Exclusive right for TMRI to exploit IPR in diagnostic and other fields

Pfizer have potential to obtain right in certain circumstances

Agreed royalty sharing terms

11

IP

Optimization

Services

Discovery

Validation

Core Lab

TMRC Core Lab: a Centre of Excellence for Molecular

Biomarker Development & Validation

Capabilities State-of-the-art equipment

Standard methodology

Rigorous quality control

Analytical expertise

Resource optimization

Timeline management

Technical Focus Genomics

Proteomics

Immunoassay

Bioinformatics

12

Scotland has many advantages for a Translational

Medicine collaboration

Stable and static population

A single healthcare provider

University & National Health Service

networks

Patient identifiers, disease data &

registries

Established tissue banks

World-class pre-clinical and clinical

research base

Significant government investment

http://www.scottish-enterprise.com/sedotcom_home.htm

13

The Community Health Index (CHI) – links patient

information since the 1980s from a number of databases in

Tayside

Prescriptions

Cancer registryEpidemiology

Liver disease

HEARTS(Heart disease evidence

based audit & research

Tayside)

Scottish Birth

Record

Hospital out

patients

Hospital acute

staysMental health

records

SCI-DN(Diabetes Network)

TARDIS (Tayside Allergy & Respiratory

disease

Information System)

Laboratory DataBiochem, virology,

haematology,

immunology,

microbiology

GRO Death Certification

Population census data

GP records

Access to linked data adds value to the clinical cohorts

accessible via TMRC

14

Scottish Care Information – Diabetes Collaboration

(Jan 1996 - current)

Information on

Diabetic

patients from

primary care to

specialised

clinics is linked

and accessible

to researchers

Professional IT support and data integration platforms

15

TMRC have been able to utilise a number of the

established tissue banks in Scotland

Experimental Cancer Medicine Centre Edinburgh Uni/NHS Lothian

cancer, breast, colon, rectal, ovarian, prostate

TMA facilities

Tayside Tissue Bank Dundee Uni/NHS Tayside

Member of Confederation of Cancer Biobanks

Fresh frozen and paraffin wax embedded tumour/normal (where practical) tissue from colon, breast, stomach, kidney, skin, uterus, liver, spleen, oesophagus, pancreas, lymph node.

Matching blood samples mainly from breast and colon cases.

Genetics of Diabetes Audit and research Tayside (GoDARTS) Dundee Uni/NHS Tayside

Linked to prescribing, biochemistry and phenotypic historical data

Serum and DNA stored from 9,000 T2DM and 8,000 Controls

RNA (paxgene tubes) is being added into collection

COPD/Asthma (TARDIS & BREATHE) Dundee Uni/NHS Tayside

1,400 DNA samples from COPD patients in Tayside + 6,000 controls

Serum collection underway

16

Target Validation:

PPARd & metabolic disease

Utilising Scotland’s Clinical populations for

biomarker research

Patient Selection:

Active Shape model & Osteoarthritis

17

PPARδ SNP rs2016520 effects markers of

metabolic disease in a gender-specific fashion (1)

BMI HDL-C

p=0.005 p=0.005 p=0.013 p=0.054

Non-diabetic, not on statin therapy.

N= 5850

Whole study population.

N= 11074

LR Burch, CNA Palmer et al JCEM 2010

18

PPARδ SNP rs2016520 effects markers of

metabolic disease in a gender-specific fashion (2)

Leptin TNF-a

Male

Female

p=0.019

p=0.755

p=6 x 10-3 p=0.024

N=5896

N= 300 non-diabetics

100 AA, 100 AG, 100GG

19

PPARd SNP rs2016520 is associated with altered

lipid response to statin therapy

Conclusions

The rs2016520 allele may influence risk of developing metabolic disease

Suggests differential effects of PPARd agonists in males and females with

the rs201650 SNP

Logistic regression analysis of failure to reach target total and LDL-C by genotype

Achieved by using patient CHI number to link to Prescription database

20

Target Validation:

PPARd & metabolic disease

Utilising Scotland’s Clinical populations for

biomarker research

Patient Selection:

Active Shape model & Osteoarthritis

21

Osteoarthritis: A challenging disease for drug

development

Slow and variable disease progression

Limited information on disease activity & severity from routine imaging

Accepted (FDA) endpoint : Radiographic evidence of joint space narrowing (JSN) No direct visualisation of cartilage

Slow rate of change (0-1mm year)

Artefacts from weight bearing and positioning

Typically requires 2 years or more to see significant

changes

Trials relying on JSN have failed to show drug efficacy (Bingham et al Arth +Rheum 2006)

22

Patient Selection: The Active Shape Model

Active Shape Model Captures whole joint, not just

angles/distances

Active Appearance model Includes image inside outline

Applicable to standard X-rays and

DEXA

Output: ‘Mode of variation’ Score The average shape has a score of 0 for

each mode

Each mode score represents the distance

(in std. dev.) from the mean shape

Each mode is statistically independent

23

Shape and appearance both

increase with OA severity

(P < 0.01)

Significant increase over

6-12 month period (P < 0.001)

Shape Appearance

Contr

ol (-

2)

S

evere

OA

(+

2)

Baseline KL grade

The Active Shape Model: Reduces Study duration

by improving predictability of drug efficacy

ASM 90% accurate at predicting hip

fracture (when combined with BMD)1

1-Osteoporos Int 2001;15: 5-11

24

Conclusions

TMRC has

provided Pfizer with access to world leading Scientists in key therapeutic

areas

allowed Scottish PIs to gain access to Pfizer resources to aid research

expedited formation of academic collaborations allowing projects to

outperform industry timelines

enabled research that has provided new models and data which facilitate

decision making and compound development

initiated discoveries that will improve patient care in Scotland, and

beyond

demonstrated how the combination of detailed clinical phenotyping linked

to bio-banks and electronic records can expedite biomarker research