Application, Value and Utility of a Broad Range of Imaging Technologies in R & D

Dr Harsukh ParmarExecutive Director, Global Discovery MedicineRespiratory & Inflammation Therapeutic Area

harsukh.parmar@astrazeneca.com

Imaging Technologies

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

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

Purpose:•Provide quantitative indices for measurementof in vivo correlates of defined biologicalprocesses. (The structure/function relationship).•To develop linkage between DiscoveryTargets and indices for use in Clinical Trials.

Experimental Disease Models

Clinical Trials

The Challenge: •To identify and validate shared features of diseasein experimental models and apply them in the Clinic.

Imaging Strategy in R & D

structure

function

Imaging & Informatics: From Data to Decisions

Integration across

domains

Common Information Infrastructure (Ontologies, Standards, Protocols etc)

Evaluated analysis applications

Domain-specific Text-Mining

AZ Biomarker Results DB

CLINICAL DATA SOURCES

(AMOS, COOL)

CLINICAL DATA SOURCES

(AMOS, COOL)

Data flows

0 12 24 36 48 60 721

10

100

Con

cent

ratio

n (n

g/m

l)

Tim e (h)

PK/PD

IMAGING

SAS Data

Analysis Mining & Best

Practice

C

B

HumanTissues

Highest Priority DxMedInformatics Needs

DISCOVERYDATA

SOURCES

DISCOVERYDATA

SOURCES

IMAGINGGENETICS

OtherDIGST-lab…

Omic dataB

Access

Access

A

Coll.data

GEL

Imaging informatics/Software/Stats etcA 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 ?

Role of Imaging in R &D

ImagingProof of Proof of Proof of Proof of

MechanismMechanismMechanismMechanism

ExposureExposureExposureExposure

Proof of Proof of Proof of Proof of PrinciplePrinciplePrinciplePrinciple

Proof of Proof of Proof of Proof of ConceptConceptConceptConcept

Safety

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

Imaging-Evaluation of Exposure and PoM

PoM and dose-finding with a CNS-drugNAD299 (Robalzotan) binding to 5HT1A-receptors (Phase I)

Pretreatment effect in a control subject.Radioligand: [11C]WAY100635

The plasma – occupancy relationship allows for predictions of occupancy at any dose/plasma level

Baseline Robalzotan

Occ

upan

cy (%

)

A

0

20

40

60

80

100

0 50 100 150 200 250 300 350 400

Fitted curve

Subject 1

Subject 2

Subject 3

Subject 4

Subject 5

Occ

upan

cy (%

)

Ki = 72 (61) nmol/L

A

50

Ctot (nmol/L)

Neocortex

Proof of Principle in OncologyPre

6 h

24 h

3 wk

ab

muscle

• Consistent reduction in blood flow observed. Data constituted PoP and supported continued phase 2 development.

Normal knee OA knee Joint Space Narrowing

3D segmented volume

1

2 Sagittalimage slice

Current (X-ray)•OA – to long, to many patients for PoC•RA – Current gold standard for PoC

Future (MRI+)•OA - reduce time, patients No’s & identify fast progressers.•RA – Patient stratification and shorter PoP, PoC

Thickness mapping

Proof of Concept –OA Disease Modification

Decreased Cartilage Thickness

Increased Cartilage Thickness

MRI -40 Knee OA patients, baseline and 6 months.

Rat MRI Assessment of MMP-inhibitor –Induced Fibrodysplasia

Normal patellar tendon Thickened patellar tendon

Control MMPi

Safety-Imaging of MMPi-Induced Tendon Damage

Outcomes in RA-Disease Modification

Clinical Endpoints• ACR score (20, 50, 70)• DAS (Disease activity

score)• Global physician

assessment• Patient assessment• HAQ, Function, QoL

Biomarkers • ESR/CRP• Joint X rays• Synovial biopsy• MRI

Currently X-ray is the only method of getting a DMARD or DCART Claim with Regulatory Authorities in EU, US & Japan

Natural Course in Patients Receiving TherapyNatural Course in Patients Receiving Therapy

Structural Damage = Erosions + Joint Space Narrowing (JSN)

Wolfe F and Sharp J, Arthritis Rheum. 1998; 41(9):1571-82.RA slide kit 15

REMICADE® (infliximab) Impacts Structural Damage

ATTRACTATTRACT

Median Change in Modified Sharp Score at Week 54Median Change in Modified Sharp Score at Week 54

RA slide kit 16

MRI• Synovitis 4 wks• Structural 6

mthsXR• Synovium ?• Structural 1 year

Earlier DMARD / structural efficacy readout?

Setting the Correct Expectations for Imaging & ProjectsKey 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 ?

ChronicChronicBronchitisBronchitis

EmphysemaEmphysema

AsthmaAsthma

•• Reversible Airway ObstructionReversible Airway Obstruction

•• Chronic Fixed Airway Chronic Fixed Airway ObstructionObstruction

•• Chronic Chronic Productive Productive CoughCough

•• AirspaceAirspaceDestructionDestruction

•• DyspnoeaDyspnoeaExacerbationsExacerbations

COPD is a syndromeA Complex Disease

The clinical characteristics of COPDThe clinical characteristics of COPD

0

2

4

6

8

10

12

14

0 1 2 3 4 5 6 7 8 9 10 11

Year 1Year 2

Importance of exacerbationsImportance of exacerbations

Continual decline in FEV1Continual decline in FEV1

23/01/2006

100

75

50

25

025 50 75

Smokedregularly andsusceptible toits effects

Never smokedor notsusceptibleto smoke

Stoppedat 45

Stopped at 65

Disability

Death

AGE (YEARS)

FEV

(% o

f val

ue a

t age

25)

1

† †

Fletcher, BMJ, 1977

FEV

1(%

of v

alue

at 2

5)COPD - Effect of smoking on lung function decline

Tissue turnover

Emphysema

COPD PoP/PoC

N

NH2 COOH

NH2

COOH

NH2 NH2

COOHHOOC

Desmosin

Gold standard for diagnosisPoC marker that requires 12 months

HR-CT

Observed in disease, no assays available yet, synergy with OA markers

Collagen markers

Collagen breakdown fragmentAssay in development

Hydroxyproline

Elastin breakdown fragmentAssay fit-for-purpose but not validated in disease

Desmosin

Paraseptal emphysema Centrilobular emphysema

Computed Tomographic Measurements of Airway Dimensions and Emphysema in Smokers Correlation with Lung Function

Am. J. Respir. Crit. Care Med., Volume 162, Number 3, September 2000, 1102

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

Use of HR-CT in clinical trials

Dirksen AJRCCM 1999

56 α1-antitrypsin deficient patientsα1-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

The use of a breath actuated nebuliser The use of a breath actuated nebuliser HaloliteHalolite((Kastelik Kastelik JA et al JA et al PulmPulm Pharm & Pharm & Therapeut Therapeut 2002 15 513)2002 15 513)

Normal volunteers Cystic Fibrosis

The use of 111In-labelled granulocytes to assess airway

inflammation in COPD, bronchiectasis and asthma:

Granulocyte Imaging in Bronchiectasis

Relationship of imaging with severity of bronchiectasis

•Dose-response for allergic response to a contact sensitiser.

•These responses are 48 hrs after application of the indicated quantities in microgrammes

Scanning LDVflux

Scanning LDVArea

Methodology-Biomarkers in Early Decision Making (1)

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

• computer fits each pixel to complex function

• estimates ratio of oxy:deoxy haemoglobin• removes effects of scattering

• conversion to % oxygen (O2) saturation

operation of camera

15min 06hr 24hr 48hr

Results - Allergen Trial (QMC, 2005)

Quantification15min

background

size calibration

upper region

lower region

0

5

10

15

20

25

Mea

n Ar

ea (c

m2)

top lefttop rightbottom leftbottom right

15min 06hr 24hr 48hr

50

60

70

80

90

Mea

n S

O2

(%)

top lefttop rightbottom leftbottom right

15min 06hr 24hr 48hr

area

% O2 sat

Future Directions – Photonic Imaging

in vivo spectroscopy - retina- detect changes in rat retina for safety studies

- collaboration in place with Heriot Watt University

in vivo spectroscopy - skin- refine analysis techiques to look beyond haemoglobin signatures e.g. inflammatory cell signals

in vivo fluorimetry -mouse- spectral imaging of fluorophores in tumours etc

- allows rejection of background autofluorescence

control arthritis

in vivo fluorimetry –human?-will require approval of fluorophores

-will be limited in depth resolution

Ranking Imaging Biomarkers - Feasibility

Research ToolNeeds Validation, Software, Stats etc

Quantitative & Reproducible, Software, Stats etcOrSpecialised measuring equipment needed

Non-invasive measurement (eg laser doppler, MRI, PET, ultrasound)

Sensitive to Enviornmentdiet/smoking/etc

Circadian/seasonal variation

Little variation

LO project “screen” onlyValidated by Dev Support Group

Feasibility Study Done

Research lab only –specialised handling or equipment

Can be run by Dev Support group*

Routine in hospital lab

Score = 1Score = 3Score = 10

Ranking Imaging Biomarkers - Relevance

Based on LO screen

Principle demonstrated in animal model

Principle demonstrated in patients

Phase 2bPhase 2aPhase 1/II/III

Stimulus added ex vivo

Stimulus administered in vivo

Depends on disease for stimulus

Score = 1Score = 3Score = 10

Ranking Imaging Biomarkers – Value

Regulatory endpoint

PublicationClinician persuaderGo/No Go

Project specificApplicable to several projects

Insight into disease process

Score = 1Score = 3Score = 10

Core Problem:The migration of raw data into useable knowledge

Integrated and Contextualized Data:

Integration of Orthogonal data types

DataDataData

InformationInformationInformation

KnowledgeKnowledgeKnowledge

Raw Data: • DNA Array • Sequence Data • Toxicity Data•Imaging Data

User-Integrated Information • Predictive Modeling:

– Disease progression models – Toxicity Models– Efficacy Models

!Predicive Tools fromImaging

Current State of Current State of BioPharmaBioPharma IndustryIndustry

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