Neuroscience Research at Evotec

Transcription

1 Neuroscience Research at Evotec Evotec, Neuroscience Research, 2017

2 Evotec, an ideal partner in neuroscience drug discovery The different ways to work with us On a specific target or programme Access to Evotec drug discovery expertise and capabilities to support your programme Starting from a phenotypic assay concept Access to Evotec phenotypic screening expertise followed by target deconvolution leading into a drug discovery programme On an existing Evotec 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 1

3 A leading platform for rapid progress and increased success Evotec neuroscience platform state-of-the art capabilities & 20 years expertise Dedicated Neuroscience drug discovery team with >100 FTEs Experience and know-how in pursuing phenotypic/pathway paradigms to identify, validate and prosecute disease-modifying approaches e.g. AD, ALS, HD Innovative 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 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 Proven track record in Neuroscience discovery with contribution to 19 candidates (including back-ups); 11 mechanisms and 9 compounds evaluated in humans 2

4 Overview on Evotec s past and present project success in Neuroscience In-depth expertise across all phases of Neuroscience research Target / Partner / Indication 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 ID/ validation Hit ID H2L / LO Pre-/clinical Clinical 3

5 Experience with key target classes and mechanisms In vitro biology 1 High quality screening libraries HTS 400K, Fragments: 21K 2 Extensive portfolio of biochemical and biophysical assay systems 3 Disease-relevant cellular assay systems with high content & other readouts Targets Sleep disorders Psychatric / epilepsy Amino acid metabolism Excitotoxicity Neuroinflammation Neurodegeneration Cellular models H3 receptor, Orexin 1&2, GABA-A mglur, dopamine receptor, various ion channels KMO, serine racemase, transporters NMDA receptor, mglur, DAAO P2X, KMO, microglia biology BACE, Neu, protein aggregation, HDAC, NRF2, SLC7A11, Asc-1 Primary neurons, microglia, astrocytes, oligodendrocytes and co-cultures, stem cells Readouts Neuroprotection, spine morphology, synaptic density and function (electrophysiology & others) Synaptophysin / PSD95 4

6 A mix of proprietary assets and validated assays In vivo pharmacology Pharmacodynamic assays PK/PD 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 Animal (disease) models Behavioural and side effect profiling Translational approaches Pain/Inflammation: Spinal Nerve Ligation, Visceral pain, Collagen Antibody-Induced Arthritis & Complete Freund s Adjuvant, Chemotherapy-induced peripheral neuropathy; Mono-iodoacetate arthritis Huntington: Q175 (mouse), R6/2 Alzheimer disease: AD1 mouse (APP swe and PS1 (ARTE10)) Motor (Locomotor activity, rotarod), Emotion (Elevated Zero Maze, fear conditioning), Cognition (Novel Object Recognition, spatial memory), Irwin test, Laboras home cage monitoring Visceral pain (ColoRectal/Vaginal Distension) model, Dynamic Weight Bearing, Radioligand Binding Autoradiography, Tissue microdialysis, Nerve conduction, Touchscreen cognitive testing 5 1) Evotec is committed to 3R 2) Evotec employs own veterinarians 3) All animal protocols are approved by IACUC, external animal welfare committee as well as competent authorities

7 Providing best-quality leads and development candidates Medicinal Chemistry Experienced drug hunters who understand the quality requirements of the development process and the major sources of attrition Expertise and success in all major target classes using both structurebased 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 6

8 World-class platform for ion channel drug discovery Dedicated group of expert scientists 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 +, Ca 2+, 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 7

9 Access wide expertise in the GPCR arena Built around >15 years experience in GPCR pharmacology 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 GPCR crystals in LCP 8

10 High content screening as enabling technology Combining complex disease-relevant cellular models and read-outs Htt aggregation Autophagy (LC3 expression) Use imaging to access complex readouts Subcellular events: protein aggregation and localisation, post-translational modification, protein levels, others Cell morphology: neurite outgrowth, synapse formation, spine morphology Cell survival: Apoptosis, ER stress, mitochondria function sirna screening 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 Neuroprotection Neuronal cell death Motoneuron protection Stem cell differentiation 9

11 The ipsc platform Combining leading technologies are key to success Access to patientderived ips cell lines Customized cell based assays and cell lines OPERA platform Originally developed by Evotec Versatile proteomics platform ipsc cell banking ipsc differentiation and disease-relevant assays Phenotypic screening MoA / cellular target profiling Banking Quality control Differentiation Disease modelling Adaptation to high throughput Small molecules Biologics Target deconvolution Biomarker identification 10

12 Evotec s Target and Compound Validation Platform In vivo experiments analysed via high content histology 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, phosphoepitopes, dendritic spines, protein aggregation, etc. Translatable biomarkers Statistical evaluation A world-class target and compound validation expertise and platform to accelerate and maximise our partners success 11

13 Identification of Novel Mechanisms in AD Patient tissue Expression studies Target hypotheses Validation Partners Program Target Starting Points Outcome Pharma / Biotech Target validation & lead discovery Various Differentially regulated genes/proteins in human brain; association with genomic evidences Lead compounds 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 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 12

14 Histamine H3 antagonist Case Study HTS to Preclinical development Partners Program Target Starting Points Outcome Hit identification and optimisation H3 HTS PDC; IND-enabling studies ongoing 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 13

15 CRISPR: Applications in CNS Pooled and arrayed genome wide CRISPR library screening Arrayed libraries provide access to multiple screening formats CRISPR in ips derived neuronal systems No Virus Control CRISPR Target#1 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 GFP Neuronal Marker #1 Other Metabolites HTRF qpcr Proliferation Flow Cytometry High Content Assays Ion Flux Neuronal Marker #2 Supplement small molecule screening with either selected target classes or go genome wide Established protocols for ips cell manipulation pre- and post-differentiation 14

16 Why us? 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 management 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 15

17 Your contact: