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Metrion Biosciences: the ion channel specialists www.metrionbiosciences.com Metrion Biosciences Overview August 2019

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Page 1: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

Metrion Biosciences: the ion channel specialists

www.metrionbiosciences.com

Metrion Biosciences OverviewAugust 2019

Page 2: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

Co

mp

an

y a

nd

visio

nMetrion 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

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• 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

Page 3: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

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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Tea

m e

xp

erie

nc

e

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)

Page 4: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

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

ua

lity e

lec

trop

hysio

log

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Page 5: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

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Ion

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l serv

ice

sMetrion’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

Page 6: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

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Bio

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ica

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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)

Page 7: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• 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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Ion

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an

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l scre

en

ing

Ion channel screening services

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

Page 8: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• 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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CiP

A: a

n F

DA

reg

ula

tory

pro

po

sal

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

Page 9: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• 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

Ca

rdia

c sa

fety

assa

ys

Cardiac safety screening services

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

Page 10: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• 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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Ph

en

oty

pic

tran

slatio

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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

Page 11: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

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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

Page 12: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• 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 discovery programmes

• Wealth of screening know-how

• Highly experienced with voltage-gated and ligand-gated ion channel families

• Detailed understanding of modulator MOA, compound class issues and safety profiles

• Screening cascade experience from target validation to HTS and SAR

• Translation of ion channel expertise to phenotypic neuronal and cardiac assays

• Automated patch clamp experts

• Over ten years of experience operating a range of gigaseal APC platforms

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In su

mm

ary

Metrion biosciences: strength and expertise

www.metrionbiosciences.com

Page 13: Metrion Biosciences: the ion channel specialists...Ion channel drug discovery is reliant on sophisticated screening platforms •Metrion scientists have decades of accumulated experience

• Strategic partnerships enable integrated drug discovery services

• Class leading technologies, highly experienced personnel

• Programmes managed by one contact point to simplify client interactions

Inte

gra

ted

dru

g d

isco

ve

ry c

ap

ab

ilityIntegrated ion channel discovery services

Target Selection HTS Lead SelectionLead

Optimisation

Preclinical

candidate

Computational chemistry

150,000 small molecule library

Assay development

384 and 1536 well HTS

Automated tissue culture

Computational chemistry

Medicinal chemistry

In vitro ADMET

CiPA compliant safety assays

Translational assays with iPSC-derived cells

Ion channel biology expertise

Translational assays

Electrophysiology screening

Hit validation

State dependent assays

CiPA compliant safety assays

Translational assays

Toxicology

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• Metrion can assist with work packages spanning compound profiling to fully integrated drug discovery