Presented by Lorraine Mooney on 3rd June 2020

1. 1
USE OF PRECLINICAL MODELS TO DELIVER
PROOF OF CONCEPT EFFICACY
LORRAINE MOONEY
ALDERLEY ONCOLOGY

2. PRESENTATION OUTLINE
• Introduction to Alderley Oncology and services available
• Proof of concept – things to consider
- In vivo Oncology Models
• Case study 1 – Fibroblast growth factor receptor inhibitor
• Case study 2 – PI3K inhibitor and immune oncology
• Summary

3. ALDERLEY ONCOLOGY – IN VIVO PHARMACOLOGY CRO
• Alderley Oncology - in vivo pharmacology service provider, offering high quality in
vivo services for SMEs, Academics and Pharmaceuticals.
• Extensive range of disease relevant subcutaneous and orthotopic mouse xenograft
models available.
Proven track record in pharma based in vivo pharmacology, model development and drug
discovery.
Tumour cell line
Subcutaneous injection of tumour
cells, engraftment and randomisation
CRO
Tumour growth inhibition
Treatment
Vehicle

4. • Services available on a fee for service basis:
ALDERLEY ONCOLOGY SERVICES
Therapeutic
PK studies
Pharmacodynamic Studies –
target engagement in normal
and tumour tissue Efficacy Studies –
Dose and Schedule
Mode of action
Therapeutic Index/Drug-Drug
Interactions
Tolerability
studies
Model
Development
Commercially available or
client models
• Experience with a range therapeutic modalities e.g. small and large molecules, RNA
therapeutics, ADCs
Pharmacodynamic
and Efficacy Studies

5. Cell
Lines
Primary
Cells
In vivo
Systems
Clinical
Studies
Target Validation – key to success and continues throughout
the lifetime of a project
DIFFICULTY
RISK
Organoids

6. EXAMPLE DRUG DISCOVERY CASCADE
Building platform
of evidence for
target in disease
area

7. COMMONLY USED IN VIVO MODELS FOR ONCOLOGY DRUG DISCOVERY
• Preclinical murine models serve as a surrogate for patients in the evaluation of novel
therapeutic cancer treatments
Syngeneic
models
Human cell
line derived
models
Genetically
modified
models
Patient derived
explant models
Humanised
mouse models

8. CONSIDERATIONS FOR ONCOLOGY IN VIVO PROOF OF
CONCEPT STUDIES:
• Model choice - consider mode of action of treatment
- Model characteristics
- Targeted Therapy – Cell line derived xenograft, Patient derived xenograft model ?
- Immune Therapy – Syngeneic model, Humanised Model ?
• Know your model
- Utility
- How to interpret and use the data
• Experimental Design or Combination ?
- Suitable tool molecule for testing (potency, selectivity, PK)
- Understanding of PK - dose and schedule
- PK/PD relationship – not always known at start of in vivo
- Formulation
- Appropriate Controls – Vehicle and Positive Controls
- Monotherapy/Combination
- Samples – PK, tumour for biomarker assessment, other tissues
e.g Immune phenotype of syngeneic models

9. CASE STUDY 1: TARGET - FIBROBLAST GROWTH FACTOR RECEPTOR
Signalling cascades activated by FGFRs
Concept: Inhibition of FGF/FGFR pathway has
the opportunity to impact multiple cancer types
• Fibroblast growth factors (FGF) and their receptors carry out key roles in multiple biologic processes
including tissue repair, hematopoiesis, angiogenesis, and embryonic development
• The fibroblast growth factor (FGF) signalling axis has been implicated in tumorigenesis and chemoresistance
Molecular profiling of FGFR aberrations across
multiple cancer types

10. CASE STUDY: FGFR inhibition by AZD4547 causes significant efficacy in cell
line derived xenograft models where there is a molecular aberration
0 2 4 6 8 10 12 14 16 18
0.0
0.5
1.0
1.5
2.0
MeanTumourvolume(cm3)+/-SEM
Days of treatment
Control
AZD4547 12.5mg/kg qd
65%
0
0.5
1
1.5
2
2.5
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Days of Treatment
MeanTumourvolume(cm3)
Control
AZD4547 12.5mg/kg qd
AZD4547 6.25mg/kg qd
AZD4547 6.25mg/kg bid
AZD4547 3mg/kg qd
AZD4547 3mg/kg bid
AZD4547 1.5mg/kg qd
AZD4547 1.5mg/kg bid
KMS-11 (FGFR3 translocation)
98%
100%
70%
53%
KG1a (FGFR1 translocation) Calu-6 (WT FGFR)
Can Res (2012) 72(8):2045-56
AZD2171
AZD4547
• AZD4547: Potent and selective inhibitor of FGFR1-3,
weak inhibitor FGFR4
• Tumour cell lines with molecular aberrations in FGFR were sensitive to
AZD4547 in vitro – proliferation and target engagement

11. CASE STUDY: AZD4547 – FGFR1 amplified Non small cell lung
carcinoma
FGFR1 amplified
• FGFR1 amplified patient-derived sqNSCLC
explant models are highly sensitive to AZD4547
• Currently in Phase II clinical trials
J. Zhang et al. , Clin Cancer Res 18:6658-6667 (2012)
Lung cancer cell panel
FGFR1 FISH and IHC
Non-amplified

12. CASE STUDY 2: AZD8835 EFFICACY AND MECHANISM OF ACTION OF
USING SYNGENEIC MODELS
• The PI3K signalling pathway is frequently activated
in cancer, promoting tumour cell proliferation and
survival.
• PI3K a and b selective inhibitors (or pan PI3K
inhibitors) are in clinical trials mainly as tumour
targeting agents
• PI3K d and g isoforms regulate immune cell
function (T cells and myeloid cells)
• Aim - to explore the effect of AZD8835 a dual
PI3Ka/d inhibitor and PI-3065 a PI3Kd on the
tumour immune microenvironment using syngeneic
models

13. CASE STUDY 2: EFFICACY AND MECHANISM OF ACTION OF USING
SYNGENEIC MODELS
• The anti-tumour effect was not due to direct effect on tumour cells - CT26 tumours grown in immunocompromised
mice were insensitive to AZD8835 or PI-3065
• Novel mechanisms by which PI3Ka/d inhibitors interact with the immune system and validate AZD8835 as a novel
immunoncology drug independent of effects on tumour cells
CT26 –Remodelling of tumour microenvironment
Not a direct tumour effect
No efficacy in Nude mice
CT26 – Immune mediated efficacy
Changes in myeloid cells in response to PI3Ka/d not PI3Kd
Decrease in Tregs
Increase CD8+/Treg

14. SUMMARY – USE OF PRECLINICAL MODELS TO DELIVER PROOF OF
CONCEPT EFFICACY
• Target validation in vivo - limited opportunity to test your molecule so give it the best chance of
success
- Good tool molecule
- Choose the right model for the scientific question you are asking
- Understand the PK
- Identify PD Biomarker
- Establish PK/PD/Efficacy relationship
• Successful proof of concept pre-clinically for AZD4547 led to clinical trials in Lung Cancer –
clinical POC is on-going
• Exploring proof of concept and mode of action for AZD8835 revealed novel mechanism to
deliver anti-tumour activity for this class of inhibitors

15. Alderley Oncology
Thanks for listening
Contacts:
L.Mooney@sygnaturediscovery.com
J.Kendrew@sygnaturediscovery.com