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  • Metrion Biosciences: the ion channel specialists

    www.metrionbiosciences.com

    Metrion Biosciences Overview August 2019

  • C o

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    n Metrion Biosciences

    Metrion Biosciences is a Cambridge, UK-based contract research organisation specialising in providing a range of high quality ion channel drug discovery services for our customers

    2

    • We aim to provide:

    • Exceptional ion channel electrophysiology expertise and services

    • High quality, cost-effective compound screening assays

    • Detailed characterisation of lead compounds in human cells and native tissue

    • Confirmation of efficacy in stem cell and other phenotypic models

    • Rapid reporting and data interpretation by experienced ion channel team

    • A dedicated, flexible service tailored to each customer’s requirements

  • Management team with extensive, varied and proven ion channel expertise • Academic training in leading international labs (Trinity, UCL, Imperial, Cambridge, Baylor, UCSF, Yale)

    • Over 100 years of accumulated manual and automated patch clamp experience

    • Named inventors on >30 composition of matter patents

    • Awarded > £10M in ion channel R&D grants (UK, EU)

    Extensive industry drug discovery and development track record

    • Successful delivery of discovery, preclinical and clinical stage ion channel modulators

    • Broad range of experience at UK, EU, and US biotech, CRO, and pharma companies

    (AZ, BioFocus/CRL, Exelixis, Ionix, Merck, NeuroSolutions, Parke-Davis, Pfizer, Wyeth, Xention)

    Metrion Biosciences: leadership team

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    Te a

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    Andy Southan, PhD

    (CEO, Director) Robert Kirby, PhD

    (Head of Client

    Research Services)

    Anthony Rush, PhD

    (Group Leader,

    Neuroscience and

    Translational

    Assays)

    Marc Rogers, PhD

    (CSO, Director) Edward Stevens, PhD

    (Head of Drug

    Discovery)

    Andrew Lightfoot, PhD

    (Head of Medicinal

    Chemistry and

    Discovery Funding)

    John Ridley, PhD

    (Business

    Manager)

  • Ion channel drug discovery is reliant on sophisticated screening platforms

    • Metrion scientists have decades of accumulated experience utilising such devices

    • All of our electrophysiology platforms deliver high quality recordings and data

    • Flexible support for assay development, primary target screening, hit confirmation, lead optimisation and SAR, mechanistic and phenotypic studies

    • 384-well platforms

    • QPatch-48 (x2)

    • Patchliner (x3)

    • Manual patch clamp (x5)

    • Multi-Electrode Array and impedance (native and iPSC neurons and cardiomyocytes)

    • FlexStation (x2)

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    Ion channel screening: high quality platforms Hig h

    q u

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    Io n

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    s Metrion’s ion channel drug discovery services

    Ion channel screening

    ▪ Generation of biological reagents, such as stable cell lines,

    transient transfection and transduction techniques

    ▪ Assay development

    ▪ Range of high quality ‘gigaseal’ patch clamp and other ion

    channel screening platforms

    ▪ Validated screening assays against an extensive panel of ion channel cell lines and native cells

    Cardiac safety screening

    ▪ Panel of cardiac ion channel screening assays

    ▪ Phenotypic assays utilising human iPSC-derived cardiomyocytes

    ▪ In silico assessment of compound proarrhythmic liability

    Neuroscience services

    ▪ Screening assays against a panel of voltage-gated, ligand-gated,

    inward rectifier and K2P ion channels

    ▪ Phenotypic assays to aid the translation of in vitro neuroscience

    data to the preclinical stage

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    B io

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    Generation of biological reagents

    • Metrion can generate stable ion channel expressing cell lines

    • Metrion also have experience of using conventional lipid-based transfection techniques and viral-mediated transduction to produce the biological reagents required to develop robust compound screening assays

    • For example, BacMam was used to establish a robust assay against a PNS expressed K2P ion channel (A and B).

    • The assay was designed to detect agonists and antagonists.

    • The assay was implemented for over two years to successfully support a SAR campaign

    A)

    B)

  • • Metrion have established high quality assays against a wide range of different ion channels using automated and manual patch clamp platforms

    • Metrion also perform custom assay development services

    • Wherever possible, Metrion design assays to include a readout on MoA

    • Positive controls are routinely run to provide a benchmark of assay performance

    • Experience at developing assays to identify antagonists and agonists

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    Io n

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    Ion channel screening services

    Voltage-gated ion channels Ligand-gated ion channels Inward rectifier K+ channels K2P channels

  • • The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative is a regulatory proposal sponsored by global safety bodies to improve cardiac safety assessment

    • Metrion have established assays for CiPA pillars 1 and 3

    • Severalcurrently available in silico models have been evaluated using Metrion’s QPatch data

    • Data from Metrion’s Pillar 1 assays are being used to train in silico models at the FDA

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    C iP

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    Cardiac safety screening: overview of CiPA

    Sager et al., (2014); Gintant (2014)

    1 2 3 4

    Analysis of compound

    activity in a full panel of human cardiac ion channel

    Use in vitro data for in silico

    modelling to evaluate

    proarrhythmic risk

    Confirm proarrythmia signals

    in human iPSC-derived

    cardiomyocytes

    Clinical evaluation of

    unanticipated effects

  • • Metrion offer screening services against a wide panel of cardiac ion channels

    • Assays available on the QPatch 48 or the manual patch clamp platform

    • Acute assays against iPSC-derived cardiomyocytes are available on manual patch clamp

    and MEA platforms to determine proarrhythmic liability

    • Chronic assays are available on an impedance platform to identify general cardiotoxicants

    C a

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    Cardiac safety screening services

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    Extensive cardiac ion channel assay panel iPSC-derived cardiomyocyte assays Chronic iPSC-derived cardiomyocyte assays

  • • Predictive phenotypic assays are required for successful translation of in vitro hits to the clinic

    • Applies equally to therapeutic programs and safety/ toxicology profiling

    • Native rat neuronal and cardiomyocyte assays available to give preclinical confidence

    • Phenotypic assays using human iPSC cardiomyocytes have been developed

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    P h

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    Phenotypic assays: translating to native tissue

    Cell Type Efficacy Assays Toxicology

    Rat DRG ✓ (e.g. pain) ✓

    Cortical neurones ✓ (e.g. epilepsy) ✓

    Rat cardiomyocytes ✓ (atrial fibrillation) ✓

    Human T cells ✓ (autoimmune) -

    Human DRG ✓ (e.g. pain) ✓

    Cell Type Efficacy Assays Toxicology

    Atrial cardiomyocytes ✓ (e.g. atrial fibrillation) ✓

    Ventricular cardiomyocytes - ✓

    Native cells

    Phenotypic assays using human iPSCs in development

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    Phenotypic neuroscience assays

    • Metrion can provide phenotypic assays using rodent DRG and cortical neurons

    • Frozen rodent DRG and cortical neurons can be purchased

    • Rodent DRG neurons can be freshly isolated by Metrion employees

    • Current clamp and voltage clamp recordings can be made on the manual patch clamp platform

    • Ligand-gated and voltage-gated ion channels can be recorded

    • The effect of compounds on neuronal firing behaviour can be assessed

    • Staining of cells for cellular markers can be incorporated to identify specific cell types (e.g. IB4 positive neurons)

    • Metrion can also provide screening services using multi electrode array (MEA) platforms

  • • Extensive drug discovery expertise

    • Expert provider of ion channel screening assays

    • Proven record of delivering high quality data, on-time and on-budget

    • Staff have been involved with multiple, successful integrated drug d

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