Imaging technologies like MRI, CT, PET, and ultrasound have various applications in drug R&D including assessing mechanisms of disease, evaluating drug effects, and establishing proof of concept. However, imaging modalities require validation and further data in some areas. Software and statistical methods also need development to maximize the utility of imaging data. Functional imaging especially shows promise in areas like CNS, oncology, and respiratory research. Overall, imaging provides quantitative measures for evaluating biological processes but continued technology and methodology advances are still needed.

1. Application, Value and Utility of a
Broad Range of Imaging
Technologies in R & D
Dr Harsukh Parmar
Executive Director, Global Discovery Medicine
Respiratory & Inflammation Therapeutic Area
harsukh.parmar@astrazeneca.com

2. Imaging Technologies
• X-Ray’s
• CT & HRCT
• MRI & fMRI
• PET
• Gamma Scintigraphy
• Ultrasound, Laser Doppler
• Hyperspectral Imaging

3. Imaging Applications
1. In Diagnosis
2. Show Structures & Anatomy in Normal/Pathology
3. Show Changes with Disease Progression
4. Show Changes with Disease Improvement
5. Understand Structure-Function Relationships
6. Establish PoM, PoP and PoC in some diseases
7. Establish regulatory claims for disease modification

4. Imaging Strategy in R & D
Purpose:
•Provide quantitative indices for measurement
of in vivo correlates of defined biological
processes. (The structure/function relationship).
•To develop linkage between Discovery
Targets and indices for use in Clinical Trials.
structure
Experimental
Clinical
Disease
Trials
Models
function
The Challenge:
•To identify and validate shared features of disease
in experimental models and apply them in the Clinic.

5. Imaging & Informatics: From Data to Decisions
Data
flows PK/PD
SAS
1 00
Concentration (ng/ml)
10
Data
GEL
1
0 12 24 36
Tim e ( h)
48 60 72
Coll. Highest Priority DxMed
data
IMAGING Informatics Needs
B
CLINICAL DATA
CLINICAL DATA
SOURCES
SOURCES
(AMOS, COOL)
(AMOS, COOL)
A C
Access
Integration Analysis AZ
Human
across Mining & Best Biomarker
Tissues
domains Practice Results DB
Access
DISCOVERY
DISCOVERY Domain-specific Evaluated analysis
DATA
DATA
SOURCES
SOURCES
Text-Mining applications
Common Information Infrastructure (Ontologies,
Standards, Protocols etc)
Other
DIGS
T-lab
…
IMAGING
Omic data GENETICS
B

6. Imaging informatics/Software/Stats etc
A Critical Need
• Handling of images
– Capture, Reconstruction, Standardization among centers, Archiving,
Storage, Retreval, Interpretation
• Image analysis
– Anatomical designation, parametric maps.
• Quantitative Models and Methods
– Compartment analyses, Statistical Methodology, Regulatory etc
• Protocols and regulatory needs for disease modification
e.g. OA & RA, COPD, Asthma, Cancer etc ?
• How should this be organised ? A central function ?
• (? Discovery / ? Clinical / ? Informatics) but with tailored
methodology for each disease ?

7. Role of Imaging in R &D
Exposure
Proof of
Mechanism
Imaging Safety
Proof of
Principle
Proof of
Concept

8. Imaging-Evaluation of Exposure and PoM
PET Evaluation of CNS Exposure
[11C] Muscarinic Drug (Non-AZ)
<0.4% drug in brain
Most CNS active drugs have 1-3% CNS exposure
No-Go Decision

9. PoM and dose-finding with a CNS-drug
NAD299 (Robalzotan) binding to 5HT1A-receptors (Phase I)
A
100 Neocortex
80
Occupancy (%)
60 Fitted curve
50 Subject 1
40 Subject 2
Subject 3
20 Subject 4
Ki = 72 (61) nmol/L
Subject 5
0
0 50 100 150 200 250 300 350 400
Ctot (nmol/L)
Baseline Robalzotan
The plasma – occupancy
Pretreatment effect in a control subject. relationship allows for
Radioligand: [11C]WAY100635 predictions of occupancy
at any dose/plasma level

10. Proof of Principle in Oncology
Pre
6h
24 h
3 wk
a
b
muscle
• Consistent reduction in blood flow observed. Data constituted
PoP and supported continued phase 2 development.

11. Normal knee OA knee Current (X-ray)
Joint Space •OA – to long, to many patients for PoC
Narrowing
•RA – Current gold standard for PoC
Sagittal 3D segmented Thickness
Future (MRI+) 2
mapping
image slice volume
•OA - reduce time, patients No’s
& identify fast progressers.
•RA – Patient stratification and 1
shorter PoP, PoC

12. Proof of Concept –OA Disease Modification
MRI -40 Knee OA
patients, baseline and
6 months.
Decreased Cartilage Thickness
Increased Cartilage Thickness

13. Safety-Imaging of MMPi-Induced Tendon Damage
Rat MRI Assessment of MMP-inhibitor –Induced Fibrodysplasia
Control MMPi
Normal patellar tendon Thickened patellar tendon

14. Outcomes in RA-Disease Modification
Clinical Endpoints
• ACR score (20, 50, 70) Biomarkers
• DAS (Disease activity • ESR/CRP
score)
• Joint X rays
• Global physician
assessment • Synovial biopsy
• Patient assessment • MRI
• HAQ, Function, QoL
Currently X-ray is the only method of getting a DMARD or
DCART Claim with Regulatory Authorities in EU, US & Japan

15. Structural Damage = Erosions + Joint Space Narrowing (JSN)
Natural Course in Patients Receiving Therapy
Wolfe F and Sharp J, Arthritis Rheum. 1998; 41(9):1571-82.
RA slide kit 15

16. ATTRACT
REMICADE® (infliximab) Impacts
Structural Damage
Median Change in Modified Sharp Score at Week 54
RA slide kit 16

19. Earlier DMARD / structural efficacy readout?
MRI
• Synovitis 4 wks
• Structural 6
mths
XR
• Synovium ?
• Structural 1 year

20. Setting the Correct Expectations for Imaging & Projects
Key Questions to Consider
•What do we want to achieve ? Example PoM, PoP, PoC
•What are the gaps with current technology & methodology?
•Which specific technology is best for your needs ?
•Which modality for which indication ?
•Do we have confidence that we can deliver quantifiable and
reproducible results?
•What are the future investment needs e.g. Informatics, Stats ?
•Timelines for future applications of Imaging against projects ?
•Are we ready for the Informatics requirements-software ?

21. COPD is a syndrome
A Complex Disease
• Chronic Fixed Airway
Obstruction
Chronic Emphysema
Bronchitis • Airspace
Exacerbations
Destruction
• Chronic
Productive • Dyspnoea
Cough
Asthma
• Reversible Airway Obstruction

22. The clinical characteristics of COPD
Continual decline in FEV1
Importance of exacerbations
14
12
10
8
Year 1
6 Year 2
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11

23. COPD - Effect of smoking on lung function decline
Never smoked
100 or not
susceptible
to smoke
FEV (% of value at age 25)
75
FEV1 (% of value at 25)
Smoked
regularly and
50 susceptible to Stopped
its effects at 45
Disability
1
25
Stopped at 65
Death
† †
0
25 50 75
AGE (YEARS)
Fletcher, BMJ, 1977
23/01/2006

24. COPD PoP/PoC
Desmosin Elastin breakdown fragment
Assay fit-for-purpose but not
Tissue turnover validated in disease
Hydroxyproline Collagen breakdown fragment
Assay in development
Emphysema Collagen markers Observed in disease, no assays
available yet, synergy with OA
markers
HR-CT Gold standard for diagnosis
PoC marker that requires 12
months
NH 2
COOH Paraseptal emphysema Centrilobular emphysema
NH2 NH 2
HOOC COOH
N
H 2N COOH
Desmosin

25. Computed Tomographic Measurements of Airway Dimensions and
Emphysema in Smokers Correlation with Lung Function
YASUTAKA NAKANO, SHIGEO MURO, HIROAKI SAKAI, TOYOHIRO HIRAI, KAZUO CHIN,
MITSUHIRO TSUKINO, KOICHI NISHIMURA, HARUMI ITOH, PETER D. PARÉ,
JAMES C. HOGG, and MICHIAKI MISHIMA
Am. J. Respir. Crit. Care Med., Volume 162, Number 3, September 2000, 1102

26. Use of HR-CT in
clinical trials
Dirksen AJRCCM 1999
56 α1-antitrypsin deficient patients
α1-antitrypsin augmentation therapy vs placebo
• No sign. effect on lung function
• Annual loss of lung tissue: active 1.5 g/L, placebo 2.6 g/L (p=0.07)
• CT was twice as sensitive as FEV1 for monitoring the progression of
emphysema

27. The use of a breath actuated nebuliser Halolite
(Kastelik JA et al Pulm Pharm & Therapeut 2002 15 513)
Normal volunteers Cystic Fibrosis

28. The use of 111In-labelled
granulocytes to assess airway
inflammation in COPD,
bronchiectasis and asthma:

29. Granulocyte Imaging in Bronchiectasis

30. Relationship of imaging with
severity of bronchiectasis

31. Methodology-Biomarkers in Early Decision Making (1)
Scanning LDV
flux
•Dose-response for allergic
response to a contact
sensitiser.
•These responses are 48 hrs Scanning LDV
after application of the Area
indicated quantities in
microgrammes

32. New Technology – Hyperspectral Imaging
HYDICE (US Navy)
Lewis (NASA)
• originally developed for military / geological uses
• recent interest in biomedical applications:
– detection / segmentation of cancer
– oxygenation / haemoglobin

33. operation of camera
• computer fits each pixel to complex
function
• estimates ratio of oxy:deoxy haemoglobin
• removes effects of scattering
• conversion to % oxygen (O2) saturation

34. Results - Allergen Trial (QMC, 2005)
15min 06hr 24hr 48hr

35. Quantification
15min 25
area
top left
top right
bottom left
20
Mean Area (cm2)
bottom right
15
upper region
10
5
size calibration
0
15min 06hr 24hr 48hr
90
top left
background % O2 sat top right
bottom left
80 bottom right
Mean SO2 (%)
lower region
70
60
50
15min 06hr 24hr 48hr

36. Future Directions – Photonic Imaging
in vivo spectroscopy in vivo spectroscopy in vivo fluorimetry - in vivo fluorimetry –
- skin - retina mouse human?
- refine analysis - detect changes in rat - spectral imaging of -will require approval of
techiques to look beyond retina for safety studies fluorophores in tumours fluorophores
haemoglobin signatures etc -will be limited in depth
- collaboration in place
e.g. inflammatory cell resolution
with Heriot Watt - allows rejection of
signals
University background
autofluorescence
control arthritis

37. Ranking Imaging Biomarkers - Feasibility
Score = 10 Score = 3 Score = 1
Routine in hospital lab Can be run by Dev Support Research lab only –
group* specialised handling or
equipment
Non-invasive measurement Quantitative & Research Tool
(eg laser doppler, MRI, Reproducible, Software, Needs Validation,
PET, ultrasound) Stats etc Software, Stats etc
Or
Specialised measuring
equipment needed
Feasibility Study Done Validated by Dev Support LO project “screen” only
Group
Little variation Circadian/seasonal Sensitive to Enviornment
variation diet/smoking/etc

38. Ranking Imaging Biomarkers - Relevance
Score = 10 Score = 3 Score = 1
Principle Principle Based on LO
demonstrated in demonstrated in screen
patients animal model
Phase 1/II/III Phase 2a Phase 2b
Depends on disease Stimulus Stimulus added ex
for stimulus administered in vivo
vivo

39. Ranking Imaging Biomarkers – Value
Score = 10 Score = 3 Score = 1
Go/No Go Clinician persuader Publication
Insight into disease Applicable to Project specific
process several projects
Regulatory
endpoint

40. Core Problem:
The migration of raw data into useable knowledge
Current State of
BioPharma Industry Knowledge
User-Integrated Information
• Predictive Modeling:
Information – Disease progression models
– Toxicity Models
– Efficacy Models
Data !Predicive Tools from
Integrated and
Imaging
Raw Data:
• DNA Array Contextualized Data:
• Sequence Data
• Toxicity Data
•Imaging Data
Integration of Orthogonal data types

41. Conclusions
• Many Imaging Modalities exist for R &D
• Some are less developed than others
• Validation is always necessary for greatest utility and
value
• More data and validation required for some
Regulatory approvals e.g. MRI in OA etc
• Software, Stats methods etc need to be developed in
parallel with Imaging technology to have greatest
utility
• Functional Imaging offers great hope in some areas
e.g. CNS, Oncology, Respiratory etc
• Newer technology gaining broader acceptance