Neuroscience Research at Evotec
Evotec, Neuroscience Research, 2017
PAGE
Evotec, an ideal partner in
neuroscience drug discovery
1
The different ways to work with us
On a specific
target or programme
Starting from a phenotypic
assay concept
On an existing
Evotec programme
Access to Evotec drug
discovery expertise and
capabilities to support
your programme
Access to Evotec phenotypic
screening expertise followed
by target deconvolution
leading into a drug discovery
programme
Sponsor an established
theme in the areas of ALS or
neurodegeneration
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
PAGE
A leading platform for rapid
progress and increased success
2
Evotec neuroscience platform state-of-the art capabilities & 20 years expertise
Dedicated Neuroscience drug discovery team with >100 FTEs1 Proven track
record in
Neuroscience
discovery
with contri-
bution to 19
candidates
(including
back-ups); 11
mechanisms
and 9 com-
pounds
evaluated in
humans
2 Experience and know-how in pursuing phenotypic/pathway paradigms to identify, validate
and prosecute disease-modifying approaches e.g. AD, ALS, HD
3Innovative technologies such as neuronal differentiation and disease modelling from human
iPS cells, phenotypic screening and cellular high-content assays, AAV-based target validation
and high-throughput histology
4
Extensive portfolio of drug discovery capabilities:
Medicinal chemistry and structure-based drug design
Target identification and validation
High Content Screening
In vitro biology, including world class ion channel platform
In vivo pharmacology
Translational biomarker assays
PAGE
Target ID/
validationHit ID H2L / LO Pre-/clinical Clinical
Overview on Evotec’s past and present project success in Neuroscience
3
In-depth expertise across all phases of Neuroscience research
TRP channel/Pharma/Infl. pain
H3R antag/Internal/sleep disorder
mGluR4/Pharma/PD
GPCR/Pharma/Infl. pain
Multiple/Pharma/Neurodeg.
Multiple/CHDI/HD
Kinase/Biotech/Neuroprotect.
Enzyme/Pharma/Infl. pain
Nav1.x/Pharma/Pain
P2X(target 1)/Pharma/Pain
P2X(target 2)/Pharma/Pain
Target / Partner / Indication
PAGE
Experience with key target classes and mechanisms
4
In vitro biology
High quality
screening librariesHTS 400K, Fragments: 21K
1Extensive portfolio of
biochemical and bio-
physical assay systems2
Disease-relevant cellular
assay systems with high
content & other readouts3
Targets
Sleep disorders H3 receptor, Orexin 1&2, GABA-A
Psychatric / epilepsy mGluR, dopamine receptor, various ion channels
Amino acid metabolism KMO, serine racemase, transporters
Excitotoxicity NMDA receptor, mGluR, DAAO
Neuroinflammation P2X, KMO, microglia biology
Neurodegeneration BACE, Neu, protein aggregation, HDAC, NRF2, SLC7A11, Asc-1
Cellular models Primary neurons, microglia, astrocytes, oligodendrocytes and co-cultures, stem cells
Readouts Neuroprotection, spine morphology, synaptic density and function (electrophysiology & others) Synaptophysin / PSD95
PAGE
A mix of proprietary assets and validated assays
5
In vivo pharmacology
1) Evotec is committed to 3R2) Evotec employs own veterinarians3) All animal protocols are approved by IACUC, external animal welfare committee as well as competent authorities
Customized target dependent PK/PD assays based on behavioural,
IHC and histology, blood, CSF, omics (e.g. (R)- a-methylhistamine
induced dipsogenia)
On-line microdialysis evaluation of drug/metabolites
Pharmaco-
dynamic
assays –
PK/PD
Pain/Inflammation: Spinal Nerve Ligation, Visceral pain, Collagen
Antibody-Induced Arthritis & Complete Freund’s Adjuvant, Chemo-
therapy-induced peripheral neuropathy; Mono-iodoacetate arthritis
Huntington: Q175 (mouse), R6/2
Alzheimer disease: AD1 mouse (APPswe and PS1 (ARTE10))
Animal
(disease)
models
Translational
approaches
Visceral pain (ColoRectal/Vaginal Distension) model, Dynamic Weight
Bearing, Radioligand Binding Autoradiography, Tissue microdialysis,
Nerve conduction, Touchscreen cognitive testing
Motor (Locomotor activity, rotarod), Emotion (Elevated Zero Maze,
fear conditioning), Cognition (Novel Object Recognition, spatial
memory), Irwin test, Laboras home cage monitoring
Behavioural
and side effect
profiling
PAGE
Providing best-quality leads
and development candidates
6
Medicinal Chemistry
Experienced drug hunters who under-
stand the quality requirements of the
development process and the major
sources of attrition
Expertise and success in all major
target classes using both structure-
based and ligand-based design
Rapid synthetic execution & ability to
address difficult chemistry
Critical mass – the largest single
chemistry department in the UK
Expert understanding in the areas of
data integrity, IP and patents
Major contributors to >30 pre-clinical
candidates and >20 compounds
approved for clinical trials
Critical success factors
Experienced personnel
Project strategy,
management and
communication
Analysis and design that
address activity and
properties
Problem solving & ability to
address difficult chemistry
Short test-analyse cycles
Experience of risk and
attrition
A track record of success
PAGE
Ion channel biology team: 15 FTEs with industrial drug discovery background
Electrophysiology & pharmacology expertise with
Cell lines, primary tissues (e.g. DRGs) and iPSC derived cell populations
Ion channels from different families (voltage- and ligand-gated or K+, Na+,
Ca2+, Cl-)
Determination of binding kinetics via fast perfusion application
High throughput screening (IonWorks® Quattro™, PatchLiner©, QpatchHTX®,
Synchropatch) through to bespoke mechanism of actions studies including
determination of binding kinetics with fast perfusion
Slice electrophysiology capabilities to demonstrate target engagement in native
tissue environment
In KO animals or ex vivo conditions
96 well multielectrode array platform to assess spontaneous and induced
neuronal activity
Used to characterise iPSC derived neuronal populations
World-class platform for ion channel drug discovery
7
Dedicated group of expert scientists
PAGE
Expertise with Class A,B and C GPCRs
Access expertise in Hit ID through to LO
All assay platforms utilised to address around
endogenous coupling
Receptor occupancy determination
Access pathway profiling/ Biased molecules
Structural biology
Confirmed several published structures in house
Currently developing de-novo structures within
client collaborations
Cutting-edge GPCR Modelling expertise
Homology modelling successfully used to drive
compound design
Number of HTS PAM screens run in last 5 years
Multiple assay formats to identify PAM activity and drive SAR
Access wide expertise in the GPCR arena
8
Built around >15 years experience in GPCR pharmacology
GPCR crystals in LCP
PAGE
High content screening as enabling technology
9
Combining complex disease-relevant cellular models and read-outs
Htt aggregation
Use imaging to access
complex readouts
Subcellular events: protein
aggregation and localisation,
post-translational modifica-
tion, protein levels, others
Cell morphology:
neurite outgrowth, synapse
formation, spine morphology
Cell survival: Apoptosis, ER
stress, mitochondria function
siRNA screening
Autophagy
(LC3 expression)
Motoneuron
protection
Neuroprotection
Neuronal cell death
Stem cell
differentiation
Utilise complex cellular
models to mimic disease
biology
Co-cultures:
neurons and glia
iPS/ES derived neuron
populations
Combined with Evotec´s
experience in primary cell
culture
DRG, neuronal and
microglia, slice cultures
PAGE
The iPSC platform
10
Combining leading technologies are key to success
iPSC cell
banking
iPSC differentiation
and disease-relevant
assays
Phenotypic
screening
MoA / cellular
target profiling
Target deconvolution
Biomarker
identification
Small molecules
Biologics
Disease modelling
Adaptation to high
throughput
Banking
Quality control
Differentiation
Access to patient-
derived iPS cell lines
Customized cell based
assays and cell linesOPERA platformOriginally developed by Evotec
Versatile proteomics
platform
PAGE
A world-class target and compound validation expertise and platform to accelerate and
maximise our partners’ success
AAV and stereotactic
injections
In vivo target modulation
Focal and reproducible
application of rAAVs to
desired brain region
Fast and long-lasting
manipulation of target
expression
High-throughput
Imaging Platform
Large portfolio of
validated antibodies
and staining protocols
High resolution for
intracellular events
High throughput for
cells and tissues
Image
Analysis
Sophisticated image
analysis tool box
Quantitative evaluation
of biomarkers in
disease models
Cell types & morphology
Unbiased
Disease relevant
read-outs
Intracellular, secreted
proteins, phospho-
epitopes, dendritic
spines, protein
aggregation, etc.
Translatable biomarkers
Statistical evaluation
Evotec’s Target and Compound Validation Platform
11
In vivo experiments analysed via high content histology
PAGE
Identification of Novel Mechanisms in AD
12
Patient tissue Expression studies Target hypotheses Validation
Technical and scientific
know-how to execute target
ID campaign using patient
tissue
Neuroscience expertise to
build relevant hypothesis
combined with high-end
technologies for target
validation
Proven target validation and
drug discovery engine
Program
Target validation &
lead discovery
Target
Various
Starting Points
Differentially regu-
lated genes/proteins
in human brain;
association with
genomic evidences
Outcome
Lead compounds
Partners
Pharma / Biotech
Precious collection of high-quality brain
tissue material
Target pathway hypotheses based on
comprehensive study of gene/protein
expression profiling
Established validation platform for
distinct target candidates
CNS-derived biomarker candidates
Valuable asset for driving early stage,
innovative AD research
PAGE
Partners
Histamine H3 antagonist Case Study
13
HTS to Preclinical development
2.5 years from inception of programme to PDC
Evotec carried out HTS, FBS and VS for hit identification as well as all activities in hit
to candidate phase
Several Early DCs identified across multiple chemical series
Clean profile demonstrated through extensive in vitro profiling
Appropriate PK in multiple species
Evotec compounds have demonstrated robust in vivo activity
Cognition, wakefulness (EEG), neurotransmitter release
Clear PK/PD relationship
Up to € 1.5m BMBF research funding to advance the programme up to and through
Phase I clinical studies
Current Status: IND-track PDC
Program
Hit identification and
optimisation
Target
H3
Starting Points
HTS
Outcome
PDC; IND-enabling
studies ongoing
PAGE
CRISPR: Applications in CNS
14
Pooled and arrayed genome wide CRISPR library screening
Arrayed libraries provide access to multiple
screening formats
CRISPR in iPS derived
neuronal systems
Supplement small molecule screening with either
selected target classes or go genome wide
Established protocols for iPS cell manipulation
pre- and post-differentiation
Pooled Screening
Established procedures
No need for specialised equipment for
virus handling
Limited readouts (differential proliferation/FACS)
Arrayed Screening
Novel reagent
High flexibility in terms of readouts:
HCA, RT-PCR, HTRF, RapidFireMS, ...
Plug-and Play into established Evotec platforms
Proliferation Flow Cytometry
Other …
Ion Flux
qPCR
Metabolites
High Content Assays
HTRF
No Virus Control CRISPR
GFP
Neuronal
Marker #1
Neuronal
Marker #2
Target#1
PAGE
Why us?
15
Evotec – The right partner in neuroscience drug discovery
A track record of
success means that
we consistently
deliver on our
clients’ needs
State-of-the-art
capabilities and
scientific excellence
will maximise your
chances of success
Fully integrated drug
discovery platform
and project man-
agement expertise
will accelerate your
drug discovery
programme
Evotec is a low-risk
outsourcing partner
who is continually
investing in its
platform to the
benefit of the
customer
Flexible commercial solutions:
multiple business models available to suit our partners