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


              Dr Harsukh Parma...
Imaging Technologies
•   X-Ray’s
•   CT & HRCT
•   MRI & fMRI
•   PET
•   Gamma Scintigraphy
•   Ultrasound, Laser Doppler...
Imaging Applications

1. In Diagnosis

2. Show Structures & Anatomy in Normal/Pathology

3. Show Changes with Disease Prog...
Imaging Strategy in R & D

  Purpose:
  •Provide quantitative indices for measurement
  of in vivo correlates of defined b...
Imaging & Informatics: From Data to Decisions
    Data
   flows                                      PK/PD
               ...
Imaging informatics/Software/Stats etc
             A Critical Need
• Handling of images
   – Capture, Reconstruction, Sta...
Role of Imaging in R &D

Exposure



 Proof of
Mechanism
                  Imaging         Safety
 Proof of
 Principle



...
Imaging-Evaluation of Exposure and PoM
  PET Evaluation of CNS Exposure
[11C] Muscarinic Drug (Non-AZ)




 <0.4% drug in ...
PoM and dose-finding with a CNS-drug
NAD299 (Robalzotan) binding to 5HT1A-receptors (Phase I)

                           ...
Proof of Principle in Oncology
Pre

             6h

                           24 h

                                    ...
Normal knee       OA knee       Current (X-ray)
                Joint Space    •OA – to long, to many patients for PoC
   ...
Proof of Concept –OA Disease Modification

                   MRI -40 Knee OA
                   patients, baseline and
  ...
Safety-Imaging of MMPi-Induced Tendon Damage
 Rat MRI Assessment of MMP-inhibitor –Induced Fibrodysplasia

          Contr...
Outcomes in RA-Disease Modification




 Clinical Endpoints
 • ACR score (20, 50, 70)          Biomarkers
 • DAS (Disease ...
Structural Damage = Erosions + Joint Space Narrowing (JSN)
                    Natural Course in Patients Receiving Therap...
ATTRACT

               REMICADE®    (infliximab) Impacts
                      Structural Damage
          Median Change ...
Earlier DMARD / structural efficacy readout?
MRI
• Synovitis 4 wks
• Structural 6
  mths
XR
• Synovium ?
• Structural 1 ye...
Setting the Correct Expectations for Imaging & Projects
                 Key Questions to Consider
 •What do we want to ac...
COPD is a syndrome
                     A Complex Disease
                    • Chronic Fixed Airway
                     ...
The clinical characteristics of COPD

                                 Continual decline in FEV1




                     ...
COPD - Effect of smoking on lung function decline
                                                                        ...
COPD PoP/PoC
                                        Desmosin            Elastin breakdown fragment
                      ...
Computed Tomographic Measurements of Airway Dimensions and
   Emphysema in Smokers Correlation with Lung Function




    ...
Use of HR-CT in
 clinical trials



Dirksen AJRCCM 1999


56 α1-antitrypsin deficient patients
α1-antitrypsin augmentation...
The use of a breath actuated nebuliser Halolite
     (Kastelik JA et al Pulm Pharm & Therapeut 2002 15 513)




     Norma...
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
Methodology-Biomarkers in Early Decision Making (1)




                                    Scanning LDV
                 ...
New Technology – Hyperspectral Imaging




                            HYDICE (US Navy)



                               ...
operation of camera




• computer fits each pixel to complex
  function
    • estimates ratio of oxy:deoxy haemoglobin
  ...
Results - Allergen Trial (QMC, 2005)
   15min   06hr    24hr    48hr
Quantification
15min                                            25
                                                       ...
Future Directions – Photonic Imaging
in vivo spectroscopy       in vivo spectroscopy        in vivo fluorimetry -         ...
Ranking Imaging Biomarkers - Feasibility
Score = 10                 Score = 3                   Score = 1

Routine in hosp...
Ranking Imaging Biomarkers - Relevance

Score = 10         Score = 3         Score = 1


Principle          Principle     ...
Ranking Imaging Biomarkers – Value

Score = 10           Score = 3           Score = 1

Go/No Go             Clinician per...
Core Problem:
The migration of raw data into useable knowledge
 Current State of
BioPharma Industry                       ...
Conclusions
• Many Imaging Modalities exist for R &D
• Some are less developed than others
• Validation is always necessar...
Imaging In R & D2
Imaging In R & D2
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Imaging In R & D2

  1. 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. 2. Imaging Technologies • X-Ray’s • CT & HRCT • MRI & fMRI • PET • Gamma Scintigraphy • Ultrasound, Laser Doppler • Hyperspectral Imaging
  3. 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. 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. 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. 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. 7. Role of Imaging in R &D Exposure Proof of Mechanism Imaging Safety Proof of Principle Proof of Concept
  8. 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. 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. 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. 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. 12. Proof of Concept –OA Disease Modification MRI -40 Knee OA patients, baseline and 6 months. Decreased Cartilage Thickness Increased Cartilage Thickness
  13. 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. 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. 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. 16. ATTRACT REMICADE® (infliximab) Impacts Structural Damage Median Change in Modified Sharp Score at Week 54 RA slide kit 16
  17. 17. Earlier DMARD / structural efficacy readout? MRI • Synovitis 4 wks • Structural 6 mths XR • Synovium ? • Structural 1 year
  18. 18. 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 ?
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. The use of a breath actuated nebuliser Halolite (Kastelik JA et al Pulm Pharm & Therapeut 2002 15 513) Normal volunteers Cystic Fibrosis
  26. 26. The use of 111In-labelled granulocytes to assess airway inflammation in COPD, bronchiectasis and asthma:
  27. 27. Granulocyte Imaging in Bronchiectasis
  28. 28. Relationship of imaging with severity of bronchiectasis
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. Results - Allergen Trial (QMC, 2005) 15min 06hr 24hr 48hr
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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

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