Presented by Neill Gingles on 27th May 2020

1. Evaluation of clinical and
preclinical
pharmacodynamic
endpoints using non-
invasive imaging
modalities
Neill Gingles
May 27th 2020

2. © 2019 Medicines Discovery Catapult. All rights reserved.
How does imaging relate to PD?
Overview of imaging modalities and how this
fits in drug discovery
Preclinical imaging and PD case studies
Clinical imaging and PD case studies
Summary

3. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?How does imaging relate to PD?
• As discussed - Pharmacodyamics (PD)
describes the action of a medicinal product
on the body following administration
• PD endpoints – outcome measurements that
assess the potential clinical benefit of a
medicinal product – Imaging?

4. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?How does imaging relate to PD?
• Imaging can provide a non-invasive PD approach with both qualitative and quantitative analysis in
preclinical and clinical studies
Imaging can span basic research
through the clinical development

5. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?Imaging modality overview
• Variety of imaging modalities in preclinical and clinical use
• Technology spans the electromagnetic or acoustic spectrum
• Standalone contrast of soft tissue/bone or with addition of
tracer/contrast
• Each modality ranges in spatial resolution and depth of penetration
• Advantages and disadvantages of each modality

6. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?Preclinical imaging
• Most preclinical systems are designed around rodent models
• Imaging PD endpoints – advantage to reduce number of studies and animals used.
• Studies in the literature and main use include:
• Basic research – evaluation/validation of animal model, cell tracking etc
• Part of PK/PD studies for novel drug/medicinal product/delivery system/novel contrast agent
• Validation of PD endpoints early in drug discovery prior to deployment in the clinic – eg FDG-PET
Preclinical imaging
F18-FDG-PET overview

7. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?
Imaging expertise in
multi-parametric imaging
modalities:
Positron Emission Tomography (PET)
Gamma counting biodistribution analysis
Computed Tomography (CT)
High Frequency Ultrasound (HFUS)
Bioluminescence/ NIR imaging (IVIS)
Mass Spectrometry Imaging (DESI, MALDI)
In-Vivo/Ex-vivoanatomical
andfunctionalimaging
Home Office PPL and radiological licence
Access to novel radiochemistry & commercial radiotracers
Access to animal models across disease areas
Access to pre-commercial technologies
Multi-modal enhanced interpretation of functional and molecular data
MolecularPathology
Advanced Microscopy (super-
resolution/confocal/multiphoton)
Digital Spatial Profiler (Nanostring DSP)
Photoacoustic imaging (PIA)
Preclinical imaging at MDC
Currently PET used for majority of PD studies

8. © 2019 Medicines Discovery Catapult. All rights reserved.
Case study: Preclinical imaging PD
Preclinical assessment of FDG-PET – translation biomarker of efficacy
Maynard et al; 2016: https://DOI: 10.1186/s13550-016-0220-9
PI3Kβ/δ inhibitor (AZD8186) preclinical studies
Hypothesis: Tumours with a PTEN deficiency will benefit
from AZD8186 therapy and 18F-FDG is a suitable
pharmacodynamic biomarker
Deliverable: A significant reduction in 18F-FDG uptake
was seen in 786-0 and U87-MG cell lines (both PTEN
null) and not BT474C (PTEN avid)
Conclusion:
These data support the use of 18F-FDG PET imaging as a
sensitive and non-invasive pharmacodynamic biomarker
for use in clinical studies with AZD8186

9. © 2019 Medicines Discovery Catapult. All rights reserved.
Case study: Preclinical imaging PD
Imaging PD endpoints of novel anticoagulants using induced thrombus model
FeCl3 rodent model
induces thrombus
formation
Femoral artery
Femoral vein
Femoral artery • Using two imaging modalities to assess
preclinical PD
• Hind limb functional flow (velocity, 3D
vascularisation, time to occlusion) assessed
• Whole body fibrin binding using PET (clot
volume)
insult
Pre-insult Post-insult
Post-insult18F-FBP8
High Frequency Ultrasound
Positron Emission Tomography

10. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?Clinical imaging
• Imaging is routinely used in clinical trials (e.g. PET/CT, MRI)
• Imaging biomarkers span different therapy areas e.g.:
• Bone mineral density – osteoporosis
• Left ventricular ejection fraction – cardiology
• Carotid intima-media thickness – atherosclerosis
• Objective tumour response (RESIST 1.1) – oncology
• Advanced imaging techniques, such as PET, SPECT, dynamic contrast-
enhanced MRI, and perfusion CT:
• Provide both anatomical and functional information, including
metabolic activity, expression of specific molecular targets, cell
proliferation, and hypoxia

11. © 2019 Medicines Discovery Catapult. All rights reserved.
What can imaging do?
Case study: Clinical imaging PD
Imaging PD endpoints in oncology clinical trials
• Case study with multiple imaging PD biomarkers in a
clinic trial assessing regorafenib therapy in metastatic
colorectal cancer
• Imaging techniques used:
• dynamic contrast enhanced (DCE)-MRI provided
information – blood flow, volume as well as blood
vessel permeability
• PET imaging with FDG to assess metabolic activity
• CT imaging volume change in tumour size via
RECIST V1.1
Khurum Khan et al. Gut 2018;67:1484-1492
• Figure shows (A) DCE-MRI - significant reduction the median
Ktrans(min−1) at day 15 post- treatment
• (B) 3D rendered image by CT performed at baseline and at
week 31 - reduction in lesion volume
• (C) FDG-PET images comparing FDG uptake 4 month
therapy, versus 18 months prior to regorafenib therapy
• (D) Axial CT images - maintained RECIST V.1.1 partial
response (45%) to regorafenib for 31 weeks

12. © 2019 Medicines Discovery Catapult. All rights reserved.
Summary
• Imaging is deployed throughout the drug development cycle
• Preclinically and clinically imaging PD endpoints provide key decision making data through drug
development all the way to regulatory approval
• Linking success rate with translational imaging biomarkers (e.g. FDG-PET) – Mode of Action, Proof of Concept
• Discovery and Research challenging; attrition rate high in development cycle
• Imaging is an important component in potentially reducing the cost of clinical trials
• Preclinical imaging can reduce the study sizes, animal numbers and provide translational biomarker information prior to clinical
deployment
• Technology is always changing improving software/hardware – advances in novel tracers, methodologies
• Imaging will provide a role in future drug discovery with new PD biomarkers

13. © 2019 Medicines Discovery Catapult. All rights reserved.
Get in touch nowAcknowledgements
Medicines Discovery
Catapult
• Sally Price
• Juliana Maynard
• Benedetta Arno
• Gemma Forrest

14. © 2019 Medicines Discovery Catapult. All rights reserved.
Get in touch now
neill.gingles@md.catapult.org.uk
@meddisccat
info@md.catapult.org.uk
01625 238734
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