Oncology drug discovery at Evotec

Evotec, Oncology drug discovery at Evotec, 2016

 Evotec, an ideal partner in
oncology drug discovery
The different ways to work with us

On a specific Starting from a phenotypic On an existing

target or programme assay concept Evotec programme

Access to Evotec drug Access to Evotec phenotypic Sponsor an established

discovery expertise & screening expertise followed theme such as epigenetics,
capabilities to support your by target deconvolution cancer immunotherapy or
programme leading into a drug discovery cancer initiating cells
programme

Flexible commercial solutions:

multiple business models available to suit our partners

Access to expert discovery platform as stand-alone activities or as part of

integrated drug discovery programmes

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 A leading platform for rapid progress and
increased success of your programme
Evotec oncology platform

Significant
1 Experienced Oncology Research team of ~100 FTEs
track record
achieving
Unique expertise in growth factor modulation, cancer metabolism, immuno-oncology and numerous
2 resistance to SoC 1) therapies oncology
milestones
Multidisciplinary project teams working on over 12 active projects in the area of Cancer
including 8
3 Metabolics, Immune evasion, Tumor suppressor biology and DNA damage repair PDCs 2) and
14 clinical
drugs and
Extensive portfolio of drug discovery capabilities:
1 marketed
• Structure-based drug design-driven medicinal chemistry
drug
• Target identification and validation
4 • In vitro and in vivo pharmacology
• Proteomic and metabolomics platform
• Translational biology

PAGE 2 1) SoC: Standard Of Care

2) PDC: Preclinical Drug Candidate
 Supporting all activities from Target ID to clinical
translation through a fully integrated platform
Evotec France (Toulouse) – Centre for integrated oncology research

• Cancer metabolism • Cancer cell proliferation

Research platforms • Tumour microenvironment Modulating • Resistance to SoC therapies
• Growth factor modulation • Cancer immunity

• Target validation / • HTS • Medicinal chemistry • Biomarker discovery • In vivo pharmacology

deconvolution • Virtual screening • In vitro biology and validation (orthotopic, syngeneic)
• Responder identifica- • In silico modelling • ADME • Targeted proteomics • Formulation & PK
tion hypothesis testing and metabolomics • Microdialysis
• IHC, FACS, MSD • Discovery toxicology

Target ID/validation Drug discovery platform Clinical translation

• Epigenetics • Metabolomics • Ex vivo experiments on • Early clinical trial design

• DNA break repair • Bioinformatics fresh tumour samples • Biobank access
• Tumour µenvironment • Molecular dynamics • In vivo imaging • Phase I sample access
• Targeted therapy • Histopathology
resistance

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 Rapid cycle times to efficiently
progress oncology programmes
Structure Based Drug Design-driven Medicinal chemistry

• Rapid synthetic execution & ability Effective delivery of

to address difficult chemistry and clients’ objectives
optimisation of phenotypic Over 30 pre-clinical
screening hits candidates nominated
• Strong expertise in SBDD by our
1 and 20 compounds
outstanding computational chemistry approved for clinical
and structural biology teams trials across all
therapeutic areas
• Very large chemistry group (>180)
synthetic, medicinal and com-
putational chemists, >35% of our Added value
scientists have >8 years prior Evotec medicinal
experience at major Pharma and chemists are named
biotech companies 2 inventors on >275 client
patents covering all
major target and
therapeutic areas

PAGE 4 Journal of Medicinal Chemistry, 2011, Prime et al., 54(1): 312-319

 Supporting target characterisation,
MoA studies & drug optimisation
State-of-the art in vitro oncology pharmacology platform

Molecular Biology Biochemistry Cellular 2D models Integrated 3D models Ex-vivo analysis

Cloning Enzymatic activity Incucyte Assays Mimic hypoxia and Flow Cytometry
• Plasmid construction • e.g. Kinase, protease • Proliferation substrate gradients in a • 9 colour cytometry
• Ecotropic retroviral and metabolic • Apoptosis 3D spheroid culture • Cell to platelet analysis
production (mouse) • Kinetic profiling • Cytotoxicity • Cell sorter
Characterization of
• transfection, trans- • HTRF, FP, RF/MS etc. Migration/invasion spheroids Metabolism
duction (plasmid, High Content • Proliferation rate
Ligand/receptor
shRNA, siRNA) Validation with fresh
binding Assays and IF • Apoptosis
patient tumour material
Gene expression • Localisation etc. • Protein expression
Protein or • Connection with trans-
• PCR, RT-qPCR, qPCR peptide release Flow Cytometry (cytometry, WB)
lational group & clinics
• TLDA • mRNA patterns
Protein expression & Bioassays • Validate biomarkers
• RLU/RFU/abs • Metabolic patterns
Analysis signalling and inhibitors
(ATP, metabolites)
• DNA (plasmid, ge- • WB, BioDot, ELISA, Metabolism developed in vitro on
• Gradient expression
nomic, mitochondrial) cell-based ELISA, • SeaHorse fresh patient samples
(IHC)
• mRNA proteome array, MSD, • Oxphography
• Immunoprecipitation • Hypoxia Evaluation of
• Glycolytic/ compound effects
Second messenger OXPHOS ATP
• Ca2+, cAMP • Metabolite con-
sumption/production

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 Providing a unique clinical
translation for our partners
Tailored pharmacology and biomarker solutions

Animal welfare Biomarker discovery In vivo pharmacology Clinical translation

& target identification
• Trained veterinary staff • Skilled surgeons • Processing of animal &
• MS-based proteomics human samples for ex
• State-of-the-art animal • Development of vivo & biomarker analyses
and metabolomics
facilities, AAALAC bespoke models to • Established relationship
accredited • Target discovery and understand with clinicians at the
− 3,000 m2 for animal selectivity profiling − Tumour biology and Toulouse Oncopole
husbandry, housing new therapeutic • Target expression on
and experimentation • Biomarker validation mechanisms human samples
− PK/PD relationships • Prevalence determination
• Early toxicity
assessments − Efficacy / dose as a function of pathology
dependency • Assistance in the patient
• Rodent species focused stratification process
• In vivo models with high
translational value • Proposal for Phase 1
clinical trial

Breakthrough scientific expertise & integrated teams to support translational biology activities

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 In vivo models exhibit high translational value
The right model for the right drug

Transgenic PDX PDX(s)

Tumour Subcutaneous Orthotopic
animals models orthotopic
models
Tumour phenotype and tumour microenvironment modulations
• Syngeneic and xenograft models (immune response)
• Subcutaneous and orthotopically localised (cross-talk with stroma cells)

Bioanalysis and • Plasma and tumour exposure after single or repeated doses administration
formulation • Formulation and administration route expertise (including aerosolized)

Biomarker • Exploration of circulating (cells, proteins) and tumour parameters

identification • Multi-level analysis of tumour modulation: genes, mRNA, proteins, metabolites

Small animal Preclinical rodent imaging Clinical supply

• 2D/3D bioluminescence imaging
imaging • Patient biopsies
• Laser Doppler blood flow analysis
• Imaging technologies
• X-ray radiography of bone and soft tissues
• 18FDG PET/CT scan (in collaboration with IUC-T) • Translational biomarkers

PAGE 7
 Supporting oncology projects in epigenetics,
immunotherapy, metabolics etc. ...
Chemical proteomics, global proteomics and metabolomics

Chemical proteomics • Cellular compound

• Evotec Cellular Target Profiling™ technology to both selectivity analysis in a
identify and quantify interactions with cellular native context
compound targets • Target de-convolution
• Drug photoaffinity labelling and activity-based protein of hit compounds from
profiling for covalent target capture phenotypic screens

Global Proteomics Platforms • In vivo mode-of-action

• High-end quantitative mass spectrometry to monitor analysis in cells, tissues
protein expression and glycosylation or patients
• Interactome, secretome, surfacome analyses
• Targeted mass spectrometry assay development • Discovery & verification
and deployment of biomarker candidates

Metabolomics • Targeted analysis in

• In vitro and in vivo quantification of metabolites in cells, tissues, body
complex samples using SPE-LC–MS/MS fluids or in vivo

PAGE 8
 Oncology at Evotec, current and future areas of focus
Evotec oncology themes

Cancer immunity & tumour Cancer Novel targeted therapies:

microenvironment metabolism Allosteric interaction
• Target immune suppressive cells • Target metabolic adaptation mech- • Induce conformational change of
(MDSCs & M2 macrophages within anisms (phenotypic screening) receptors leading to their
the tumour microenvironment inactivation
• Target tumour associated • Application to well validated onco-
fibroblasts implicated in: targets (tyrosine kinase receptors
− Cancer cell proliferation, invasion
survival and epithelial
mesenchymal transition
− Regulation of extracellular matrix
(ECM) remodelling, migration &
angiogenesis, recruitment of
stromal cells
− Regulation of Tumour immunity
• For combination with SoC
• For replacement of current targeted
therapies and check point inhibitors
• For combination with SoC therapies therapies (specific kinase inhibitors)

PAGE 9
 Case Study: Hedgehog signaling pathway inhibitors
Screen to development candidate by cellular assay

Partners Programme Target Starting point Outcome

H2L & LO Hedgehog Pathway HCS Hit (EVT) Clinical studies

• SAR developed via a high content assay: Agonist and antagonist focused programs
• Curis partnered programs with Wyeth and Genentech ($170M and $240M respectively)
• Compound from the Curis collaboration CUR 61414 progressed into Phase I clinical trials
F N
O
MeO NH
O N
N
N NH
N Cl NH
N
N H S
N HN N CF3 O O
O O
O O Cl Cl S
Cl
O
O

CUR 61414 Curis/Evotec Curis/Evotec Genentech GDC-0449

• Subsequent work at Genentech based on Evotec starting points led to discovery of vismodegib
(Erivedge; GDC-0449), approved by FDA in January 2012 for treating basal cell carcinoma

PAGE 10 Journal of Medicinal Chemistry, 2008, Brunton et al., 51: 1108-1110

Bioorganic & Medicinal Chemistry, 2010, Brunton et al., 18: 6934-6952
 Case study: Target validation on human tissues
Target validation on human non-invasive bladder tumour

Partners Programme Target Starting point Outcome

Institut Universitaire
Undisclosed FGFR In vivo validation Biomarker
du Cancer (Toulouse)

Validation of the antibody specificity 300-19 cells transfected

Negative control 300-19 cells WT with Receptor 1 with Receptor 2 with Receptor 3 with Receptor 4

Target identification • Validation of antibody specificity

on human samples • Identification of the target on human samples coming
from healthy patients
• Identification of the target on human tumor samples
Sample of human bladder Tumor adapted to the target
(Sample from IUCT) • Set up of a protocol for an automated process (Ventana)

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 Case study: Evaluation on ex-vivo explant
Research of biomarker on human non invasive bladder tumour (T1a-b)

Partners Programme Target Starting point Outcome

Institut Universitaire Biomarker Biomarker

FGFR Clinical data
du Cancer (Toulouse) identification identification

invasive tumour
Monobloc Exerese • Samples collected directly from the surgeon
(~20–500mg) • Dot blot with supernatants
Washing and • Formalin fixation for IHC
cultivation of • Nitroxide freezing for WB
tumour samples
Non invasive tumour • Possibility to obtain patient urine sample
NT EVT 10µM

Protein expression on pErk expression on Protein expression on

supernactant tumor sample tumor sample
Dot plot Western blot Immunohistochemistry
NT EVT NT EVT

Potential to develop this approach on other easily accessible tumour samples (head & neck, skin or colorectal cancer …)

PAGE 12 Collaboration with Pr B. Malavaud ‘s team and anatomopathologist (Dr C. Mazerolles) expert at the IUC-T with a trainee (MD-anatomopathologist)
 Case study:
Approach targeting tumour micro environment
MoA targeting cells involved in tumor-promoting immunosuppression

Partners Programme Target Starting point Outcome

Support to clinic –
Internal project VEGFR3 DC Support PhI
Proof on concept

• Integrated project involving Evotec in vitro biology, • Tumor cells

chemistry, in vivo pharmacology, DMPK and chemical expressing
development platforms the target
• Collaboration with histopathology department of the • Tumor-promoting
Toulouse Oncopole for patient stratification immunosuppression
• In house development of in vitro, in vivo models and • Angiogenesis
biomarkers to stratify patients, and follow compound efficacy • Lymphangiogenesis
• Contract with clinicians to leverage translational biology and
challenge clinical positioning

1 Pre-clinical development candidate identified: promising efficacy and safety for 2 major indications with POC in
relevant in vivo tumor models (SCC, HNSCLC), and access to human patients samples

PAGE 13 Mol Cancer Ther 2012, 11, 1637-1649

Cancers 2014, 6, 472-490
 Case study:
Phenotypic approach for cell metabolism
MoA addressing OXPHOS tumours & targeted therapy resistance

Partners Programme Target Starting point Outcome

Target Validation
Active metabolism
Internal project to development MC1 PhI
modulator
candidate

• Integrated project involving Evotec HTS, in vitro biology, chemistry,

1 Preclinical development candidate
identified with promising efficacy & safety
for 2 major indications with POC in relevant
in vivo orthotopic tumour models (NSCLC,
DLBCL), and human patients samples
in vivo pharmacology, DMPK and chemical development platforms
• Chemical optimisation from natural product (22 steps chemical
synthesis, chiral purification, ADME issues)
• Deorphaning based on metabolomic approach (collaboration with an
academic platform)
• In house development in vitro, in vivo models and biomarker to stratify
patients, and follow compound efficacy
• Contract with clinicians to leverage translational biology and challenge
clinical positioning

PAGE 14
 Why us?
Evotec – The right partner in oncology drug discovery

A track record of State-of-the-art Fully integrated drug Evotec is a low-risk

success means that capabilities and discovery platform outsourcing partner
we consistently scientific excellence and project man- who is continually
deliver on our will maximise your agement expertise investing in its
clients’ needs chances of success will accelerate your platform to the
drug discovery benefit of the
programme customer

Flexible commercial solutions:

multiple business models available to suit our partners

PAGE 15
Your contact:

info@evotec.com