We can aid decision making from the pre-clinical to the clinical setting, supporting line of sight to the clinic, by identifying and translating crucial biomarker approaches into the real world.

1. Turning
Molecules into
Medicines
What can drug
discovery translational
research do for me?
Gayle
Marshall
Lead Scientist -
Biomarkers

2. © 2019 Medicines Discovery Catapult. All rights reserved.
Why do drugs fail in the clinic?
• >15 years and $2 billion per medicine
• Whilst many compounds and target hypotheses fail before the clinic many
drugs still go onto the clinic to fail there.
• Clinical trials are expensive with high attrition rate due to:
• Lack of efficacy
• PK/PD
• Wrong safety profile
• Wrong strategy
Target
Identification
Target
Validation
Lead
Identification
Lead
Optimisation
Pre-clinical Clinical

3. © 2019 Medicines Discovery Catapult. All rights reserved.
• Applied research to support drug
discovery
• Understand the clinical questions
• Build testable and scientific evidence to
transition between pre-clinical and the
clinical setting
Ensure 5Rs;
• Right Target,
• Right Tissue,
• Right Safety
• Right Patients
• Right Commercial Potential
What is Translational Science?
Generating
testable
scientific
hypothesis to
support drug
development
What dose
level?
What
schedule?
Which
disease?
Which
patients?
Is this better
than current
standards of
care?
Combination
options?
Acquired
resistance?

4. © 2019 Medicines Discovery Catapult. All rights reserved.
• By understanding more about drug and disease using biomarker information.
• Measuring biomarkers allow clinicians to predict, diagnose, or monitor disease.
• While disease symptoms are subjective, biomarkers provide an objective,
measurable way to characterise disease.
• Oncology has made major advances in delivering quality drugs using biomarkers
for targeted therapies, other diseases are slower to adopt.
How do we do this?

5. © 2019 Medicines Discovery Catapult. All rights reserved.
• Gefitinib (ZD1839) is an EGFR tyrosine kinase
inhibitor which blocks signalling through the
epidermal growth factor receptor.
• When Gefitinib was launched in Japan 2002.
• It was approved as monotherapy for the
treatment of patients with locally advanced or
metastatic NSCLC after failure of both platinum-
based and docetaxel chemotherapies.
• EGFR mutations first observed in 2004
• Gefitinib is currently approved for the treatment
of 1st line EGFR M+ advanced NSCLC patients in
85 countries.
• Phoenix from the flames but not every drug has a
happy ending so what can we do to ensure we
know this information from the start?
Impact of biomarkers

6. © 2019 Medicines Discovery Catapult. All rights reserved.
• Understand the biology
• Pre-clinical translational studies
• Determine whether to go down the targeted biomarker route as early as possible
• The tissue is the issue – collect as many samples as possible
• No sample no biomarker
• Pathologists are key
• Conflict between push for faster studies and push for targeted healthcare, fast recruited are not often the most
experienced at sample collection
• A targeted drug needs a diagnostic approach
• It matters
• What you measure
• How you measure it
• How you define a positive cut off
Lessons Learned from these landmark studies

7. © 2019 Medicines Discovery Catapult. All rights reserved.
• There are many potential impactful applications for the use of clinical biomarkers.
• Diagnostics - Patient selection (treatment decision or recruitment onto a clinical study)
• Translational Science – Support clinical development Go/No Go decision making, defining the
right dose and impact on the disease biology.
• Many biomarkers have been identified yet very few have entered the clinic as a diagnostic.
• Biomarker uptake can be due to the fact identified clinical biomarkers may still lack clinical utility.
• Complex and underestimated (variability of the marker)
• Lack of understanding of the pathology and heterogeneity of the disease
• Use of inappropriate samples for discovery and validation
• Methodology Limitations
In 2016 there were more than 768 000 papers indexed in PubMed directly related to
biomarkers. Despite advances in laboratory technology and an enormous expansion in
relevant literature, we seem quite far from widespread clinical use of biomarkers in
discovery, treatment, or monitoring. In fact, in cancer, for example, today there exists
only a few dozen clinically relevant biomarkers in use.
The Challenge

8. © 2019 Medicines Discovery Catapult. All rights reserved.
• Is the underlying biology adequately characterised?
• What is the prevalence and levels within patient tissue
• How heterogeneous?
Scientifically relevant
biomarker(s)
• Can the assay reliably detect the biomarker (e.g.
pharmacodynamics) change we expect to see clinically?
• Go/No Go thresholds defined
Assay Suitability
• Do we know when to take a clinical sample, how to ensure
stability of the marker and how many we will need to
provide a statistically robust decision?
Study design
• Can we deliver this assay in the real world?Sample
Clinical Utility Considerations

9. © 2019 Medicines Discovery Catapult. All rights reserved.
How can MDC help?
Build assays to
identify and test
scientific
hypothesis to
support drug
development
What dose
level?
What
schedule?
Which
disease?
Which
patients?
Is this better
than current
standards of
care?
Combination
options?
Acquired
resistance?
Help identify the key clinical questions and understand the line of sight.
Generate the pre-clinical/clinical evidence for the hypothesis to test
Build the right, robust and clinically ready assays to generate the evidence
Example;
How to identify the right patients for targeted therapy?
• Generate disease linkage data to guide indication selection and targeted patient selection
• Test patient selection hypothesis in clinical trials
• Utilise multiple platforms to maximise information obtained from precious clinical samples
• Evaluate impact of therapy on disease biology
• Monitor responses to therapy and molecular changes in disease over time. Initially can be validated in relevant pre-
clinical models, then understand the role of these markers in the patient.
• Define mechanisms of resistance to standard of care and novel therapies.
• Potential to screen samples from patients who have failed therapy to identify novel resistance mechanisms.
• Evaluate assays for biomarker measurements in accessible tissue (e.g. plasma) to allow serial collections
Monotherapy?
Once Daily?
Line of
Therapy?
Early or late
disease?
Does my
drug hit the
target?

10. © 2019 Medicines Discovery Catapult. All rights reserved.
Scientific Capabilities
Our strategy is built around four interconnected
focus areas, supported by innovative technology
Bringing expertise, drug discovery know-how, and state-of-
the-art technologies into collaborative research
Applicable alone or in combination to address project
questions and remove barriers to medicines discovery
Applying multiple technologies to address scientific
challenges
We are not doing drug discovery – we are helping
other people to do it more successfully

11. © 2019 Medicines Discovery Catapult. All rights reserved.
Better clinical study
design
Cell models that better
reflect the patient
Multiplex readouts for a deeper
understanding of drugs and disease
Back
translation
• PharmacoDynamic (PD) / Proof
of Mechanism (PoM)
• Proof of Principle (PoP)
• Proof of Concept (PoC)
• Predictive biomarkers
• Safety biomarkers
• Additional identification of
markers of resistance along with
combination options
Genomics Analysis
• Mutation analysis
• Genomic loss / gain
• Copy number changes
RNA Analysis
• Transcriptomics
• Gene expression profiling
• Gene Fusion expression analysis
Protein Analysis
• Proteomics
• comparisons to IHC
Metabolite Analysis
• Metabolomics
• (unique chemical Fingerprint)
Lipidomics
Imaging
Biomics
Protein analysis
• Tissue - Frozen and FFPE (mRNA, DNA
mutation, protein, gene fusions, miRNA,
CNV)
• Blood (mRNA, circulating tumour cells,
circulating tumour DNA, PBMCs)
MDC Biomarker Platform
Approach

12. © 2019 Medicines Discovery Catapult. All rights reserved.
Phosphocholine (m/z 772) in
rat brain
RapiFlex Matrix Assisted Laser Desorption Ionisation (MALDI)-MS.
• Higher spatial resolution molecular imaging
• High throughput
• Extended mass range (m/z 50 - >500,000)
Multiplex Imaging Capability– Understanding drug and disease
Mass Spectrometry Imaging
High content, surface analysis provide localisation information on a variety of
molecules.
• Drug distribution in tissue
• Biomarker and drug response analysis with spatially relevant information
• Variety of molecules can be identified from a single tissue sample
Collaboration with Waters allows MDC’s partners to benefit from precommercial
modifications
DESI - MS Phospholipids in rat brain,
displaying differential
localisation.
m/z
810
m/z
772
m/z
844
Pharmacokinetics, Biodistribution
89Zr-PET
Longitudinal
Distribution
Cy-7
Near Infrared
Imaging
(IVIS) Tumour
mAb fAb
Kidney
catabolism
Vascular
perfusion
Pre-clinical Imaging

13. In depth, quantitative, pathways analysis,
supporting PoM and PoP in preclinical and clinical
samples.
Example - in vivo study for SME investigating IO
drug combination, data supporting clinical trial
strategy.
Investigated signatures of tumour, micro-
environment and immune response and drill deeper
into the key pathways involved.
Tumour infiltrating lymphocytes
Identification of key pathways and cell types in drug response from large
disease-relevant pre-defined or custom panels
Pathway Biomarkers
Combo Drug 1 PBS Drug 2

14. © 2019 Medicines Discovery Catapult. All rights reserved.
Digital Micromirror automatically adjusts to the shape of the immune compartment: Contour masking
around macrophage-boundaries reveals spatial heterogeneity of immune responses

15. © 2019 Medicines Discovery Catapult. All rights reserved.
RNA multiplex data
from Nanostring
96-plex IO-targets
mRNA spatially
profiled in many
different tumour
types
GeoMx - RNA Biomarkers

16. © 2019 Medicines Discovery Catapult. All rights reserved.
D538GMutsignalD538GWTsignal
Cycle 1 Day 1 Cycle 1 Day 2 Cycle 1 Day 15
Circulating
biomarkers and
heterogeneity of
resistance
mechanisms to
endocrine
therapy in
metastatic breast
cancers
Protein and nucleic acid biomarkers - Quanterix Simoa
• Multiplex detection
• Measures concentrations of circulating biomarkers at femtogram/ml levels
• Reduced assay volume requirements for multiple precious sample types
• Potential for Longitudinal patient monitoring
Nuceic acid markers/modifications - BioRad ddPCR
• Absolute quantification and Copy number variation analysis
• Rare variant detection
• Gene expression and miRNA analysis
• QC for NGS libraries
• Disease Linkage studies
Multiple technologies to understand circulating markers in patients and pre-clinical models – Hypothesis Driven
Circulating Biomarkers

17. © 2019 Medicines Discovery Catapult. All rights reserved.
• Direct infusion MS can generate data-rich profiles directly from whole blood or
plasma
• Acoustic Mist MS technology not otherwise available outside of large Pharma
• Spectra were generated using AMI-MS from only 200nL of whole blood and no
sample preparation at rates of 10 s per sample – suitable for timecourse studies
Direct Infusion Mass Spectrometry
Multiple technologies to understand circulating markers in patients and pre-clinical models – Hypothesis Free

18. © 2019 Medicines Discovery Catapult. All rights reserved.
Biomarker Discovery Approach

19. © 2019 Medicines Discovery Catapult. All rights reserved.
MDC can help navigate the drug discovery
Process through our Virtual R&D capabilities
Target product profile
(TPP) defines the scientific,
technical, clinical and
market information for the
new drug
VR&D provide
support and
expertise to
customers to
navigate the
drug discovery
pathway

20. © 2019 Medicines Discovery Catapult. All rights reserved.
• Identify Right clinical questions - Bridge the gap between pre-clinical and clinical drug development.
• Develop the Right Biomarker Strategy - Through highly multiplex analysis understand the heterogeneity
of the disease to identify the Right biomarkers.
• Right assays - Design and deliver robust assays to generate preclinical evidence that will translate across
into the clinic. Key to understand the decision-making cut offs.
• Right Samples – understand the variability of the biomarkers identified, collect the best samples to
support the hypothesis through pre-clinical models through to clinical testing.
Turning Molecules into Medicines
Where MDC can make a difference
Which patients will benefit.
Does my drug hit the target?
How long does it need to be engaged to have an effect?
How prevalent is the target in this patient population, how to select patients?
Monotherapy or combination? Is it better than current therapies?
What dosing schedule and delivery?
Need for a resistance strategy?

21. ©2016 Medicines Discovery
Catapult. All rights reserved.
We have grant writing expertise and also
have a growing network of venture capital
companies
Signposting and connecting
Ways we can work together
We help you find the right partner,
collaborator, advisor or supplier who can
deliver what you need
Joint grant applications for collaborative R&D
funding
Shared risk and reward
We work in risk-share collaborations with
partners who gain from our unique help
and where we share in the value of the
outcome
Contracted fee-for-service projects
Where you need managed access to our
skills and assets - and cannot get them
commercially elsewhere - we can adopt a
fee-for-access model

22. © 2019 Medicines Discovery Catapult. All rights reserved.
Acknowledgements
Pre-clinical Imaging – Juliana Maynard
Mass spectrometry Imaging – Philippa Hart
Acoustic Mist – Martin Bachman
Nanostring/Simoa – Andrzej Rutkowski
Virtual R&D – Sarah Brockbank, Lyn Rosenbrier Ribeiro
CSO - Peter Simpson