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New Paradigm for drug toxicity

NEXEL Provides Cardiotoxicity testing services Using hiPSC-derived Cardiomyocytes

New Paradigm for drug discovery

NEXEL’S Cardiosight-S®

Cardiotoxicity is one of the leading causes of attrition during drug development.

Currently, the ICH S7B and E14 guidances have been in place to assess drug candidate’s potential cardiotoxicity, prolonged QT interval. In 2013, the FDA proposed new guideline, the Comprehensive in vitro Proarrhythmia Assay (CiPA) to refine cardiotoxicity testing guidelines and it is expected to be implemented across all ICH regions by 2020.

Validation study of human pluripotent stem cell-derivedCardiomyocytes (hPSC-CMs) was performed by the internationalconsortium and suggested that hPSC-CMs are more efficientcardiotoxicity testing model compared to hERG assay which useshERG-overexpressed cell lines.Therefore, the basis of CiPA guideline is hPSC-CMs and assessesthe effect on multiple ion-channels instead of conventionalsingle-channel evaluation. Although the guideline is expected tobe completed in 2020, many organizations have already startedimplementing the CiPA draft guideline.

NEXEL Cardiosight-S® is validated hiPSC-CMs (By Patch Clamp Analysis)

ELECTROPHYSIOLOGICAL PROPERTIES

Cells MDP(mV) Vmax(v/s) APA(mV) APD90(ms)
Human VMsa

-81.8±3.3

215±3.3

106.7±1.4

351±1.4

Cardiosight-S®

-70.2±1.6

96.7±6.6

116.6±2.7

324.9±10.3

a Magyar et al., 2000

DRUG REACTIVITY

*E-4031 blocks hERG-type potassium channels and can prolong the QT-interval.

*Nifedipine blocks calcium channels and prevents calcium-dependent myocyte contraction and vasoconstriction.

*Tetrodotoxin blocks sodium channels and prevents action potential (AP) generation and propagation.

NEXEL Cardiosight-S® is validated hiPSC-CMs (By MEA Analysis)

ELECTROPHYSIOLOGICAL PROPERTIES

DRUG REACTIVITY

*E-4031 blocks hERG-type potassium channels and can prolong the QT-interval.

*Nifedipine blocks calcium channels and prevents calcium-dependent myocyte contraction and vasoconstriction.

WE PROVIDE HIGHLY QUALIFIED human cardiomyocytes derived from hiPSCs

ICH S7B GUIDELINE AND CiPA
ICH S7B CiPA

In vitro/in vivo components

In vitro component/in silico

Single cardiac current (hERG)/only IC50

Multiple currents/ more granular, detailed

In vivo ECG provides integration cellular effects

Integration provided at 2 levels (stem cell-derived cardiomyocytes and in silico extensions)

Primary focus: delayed repolarization

Primary focus: proarrhythmia (ventricular depolarization repolarization)

Follow-up studies (additional mechanisms)

More comprehensive, mechanism-based approach

ADVANTAGES OF NEXEL’s CARDIOTOXICITY TEST

hERG Assay NEXEL's MEA Assay
Cell Source

Cancer Cell Line Only (CHO, HEK)

human cardiomyocytes derived from hiPSCs

Ion Channel Effect

hERG Channel Only

Multi-ion Channel Effect

Method

Patch Clamp Assay

Multi-electrode Assay

*Accuracy

Less than 70%

More than 84%

High-throughput drug screening

Difficult

Easy

*(James Kramer et al., 2013) | (Ksenia Blinova et al., 2018)

OUR SERVICES

CELL SURVIVAL / VIABILITY
Analytic Equipment : Microplate Reader

CELL APOPTOSIS / CELL BINDING
Analytic Equipment : FACS

ELECTROPHYSIOLOGICAL TEST
Beating rates / Field Potential Amplitude / Field potential Duration
Analytic Equipment : Multi-electrode Assay (Axion biosystems, Maestro)

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