CIPA - Replacing the TQT with Non-clinicalProarrhythmia Testing: A New Paradigm

Current status, opportunities, and challenges

Hugo M. Vargas, PhD, DSP

Scientific Director

Safety & Exploratory Pharmacology

Amgen, Inc 19-Feb-2015

Outline

• Introduction to CIPA

Background

• Core Pillars and Supporting Foundation

Human Ionic Currents

In Silico Computer Reconstruction (Human)

Human Stem-Cell Derived Cardiomyocytes

• Challenges and Expectations

• Summary

2For External Use

Comprehensive In Vitro Proarrhythmia Assay: Three Scientific Core Pillars

Drug Effects on

Multiple Human

Cardiac Currents

In Silico

Reconstruction

Human Ventricular

Cellular

Electrophysiology

In Vitro Effects

Human Stem-Cell

Derived Ventricular

Myocytes

Preclinical ECG & Phase 1 ECG Studies: Complementary Data

MEA

VSD

4th Annual Conference on Drug Discovery and Clinical Development

in India | November 14-18, New Delhi, India

4

S7B: Nonclinical Testing Strategy (2005)

Chemical/Pharmacological Class

Integrated Risk Assessment

Follow-up studies

None Weak Strong

Evidence of Risk

Other nonclinical and clinical info

In vivo QT assay

In vitro IKr

assay*

*The hERG (gene for Kv11.1 alpha subunit of IKr)) related current is used

4th Annual Conference on Drug Discovery and Clinical Development

in India | November 14-18, New Delhi, India

ICH S7B/E14 Guidelines:Intended & Unintended Consequences

Successful: no drugs with unrecognized risk being approved or removed from the market

Negative impact on drug development

– Premature discontinuation due to hERG or QT “signal”

• (Inaccurate) perception of risk leading to drug discontinuation

- Estimates of up to 60%

– Development burden: increased costs; labeling

– Many potentially good compounds never get evaluated in humans due to a hERG effect

Goal: A new paradigm for cardiac safety evaluation

of new drugs

Provide a more accurate and comprehensive mechanism-based

assessment of proarrhythmic potential

Improve specificity (vs. preclinical hERG/clinical TQT)

focus on ventricular proarrhythmia (torsade de pointes) rather

than QT interval prolongation

Comprehensive In VitroProarrhythmia Assay

For External Use

How?

Characterize drug effects on multiple human cardiac currents

– beyond hERG channel blockade alone

Utilize in silico reconstructions that provide integrated cellular

electrophysiologic responses of human ventricular myocytes

Verify drug effects using human stem-cell derived myocytes

For External Use 7

Comprehensive In VitroProarrhythmia Assay

8

Repolarization: integrated response of many currents

DELAYED Repolarization: reduced NET OUTWARD CURRENT

- block outward current (hERG)

- enhanced inward current (Na+, Ca++)

during plateau (phases 2, 3)

Balance of inward and outward human currents

that define drug effects on ventricular

repolarization.

Present focus on IKr (hERG) results in premature

and unwarranted drug attrition, misclassification

of risk

Repolarization: Multiple Currents Involved

9

Focus on proarrhythmic vulnerability:

– impaired cellular repolarization &

electrical instability

– not simply hAPD and hQTc

- In extreme form, instability

manifest as early after-depolarizations (EAD’s)

associated with initiation of proarrhythmia

- Impaired repolarization: rank proarrhythmia based on comparisons with

known TdP drugs

Evaluating human proarrhythmic risk

(an integrated, emergent effect) at cellular level

Cellular Proarrhythmia:

Abnormal Emergent Responses affect Repolarization

10

Comprehensive In Vitro Proarrhythmia Assay: Four Components

Evaluation of

Clinical Drugs for

Proarrhythmic

TdP Liability

Drug Effects

on Multiple

Human Cardiac

Currents

In Silico

Reconstruction

Human Ventricular

Cellular

Electrophysiology

In Vitro Effects

Human Stem-

Cell Derived

Ventricular

MyocytesHigh Risk

Intermediate

Risk

Low Risk

Proarrhythmic Potential of Drugs: Need to Consider Multiple Ion Channel Currents

11

Lack of selectivity of drugs on cardiac currents affecting (depolarization and repolarization) necessitates consideration of multiple currents

Calcium current block

(Nifedipine) mitigates

delayed repolarization

with Dofetilide (hERG

block)

Sodium current block

(Lidocaine) mitigates

delayed repolarization

with Dofetilide (hERG

block)

Example: Delayed Repolarization with Dofetilide (hERG Block) Mitigated by Other Currents

Core Component I: Voltage Clamp Studies, Human Currents, Heterologous Expression Systems

Ion Channel Working Group (SPS):

- Develop hERG & non-hERG protocols; testing

- Standardize voltage clamp protocols to establish

best practices, reduce bias and variability,

enable comparisons of automated platforms

across laboratories

- Information on kinetics-, voltage-, and use-

dependence to parameterize models

(hERG essential)

13

Robust characterization of drug effects on human currents

enables in silico reconstructions of integrated responses

14

+ =

Core Component II: Computer Reconstructions of Drug Effects on Human Cellular Electrophysiology

In Silico Group (FDA):

- Multiple currents integrated to describe cellular electrophysiologic effects

- Ability to elicit changes in repolarization instability, early

afterdepolarizations, reduced upstroke velocity using select model

(modified O’Hara-Rudy model: model)

- Ranking of integrated responses compared with clinical examples of

different TdP liabilities

15

Myocyte Group (HESI):Verification of in silico

reconstructions with well

characterized human stem-cell

cardiomyocytes

13 Site Pilot Study Ongoing

- Microelectrode array (MEA, field

potential duration, 4 platforms)

- Voltage-sensing optical (VSO, 4

platforms)

- 3 myocyte types

8 Blinded Compounds

- 4 to calibrate sensitivity

(IKr, IKs, INa, ICa)

- 4 as pilot test set

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ltag

e-S

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sit

ive

Dye

Mic

ro-E

lectr

od

e

Arr

ay

Core Component III: In vitro Effects, Human Stem Cell-Derived Cardiomyocytes

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• Compound Selection/Regulatory (CSRC):

Categorize available drugs for proarrhythmic

risk:

- High, Intermediate, Low risk categories

- Evaluate clinical data for proarrhythmia

- Overall experience, history, patient

population, pharmacokinetics

- 31 drugs nominated for model

development and verification

• Input from clinical developers & regulators

- Validation/acceptance of CiPA paradigm

• Define Phase 1 ECG Verification

TdP Risk

Clinical Foundation:Compound Selection & Clinical Regulatory Group

17

Ion Channels: optimal number of currents, standardization and

reproducibility (e.g. hERG ), adequate characterization (time-, voltage-, and use-dependent block) for input for in silico reconstruction

In Silico: selection and characterization of model, variability of input

data, assessment of emergent responses

Stem Cell-Derived Myocytes: maturity of cells (adult phenotype),

fit for purpose use of preparations, stability, sensitivity, signal strength/granularity, electrophysiologic heterogeneity

Compound Selection/Regulatory: identification/rank-ordering for

TdP risk from clinical experience; Phase 1 ECG Metrics

Challenges:

Identifying Different Phenotypes

TdP Likely

TdPPossible

hERGBlock

QTcprolongation

CIPA Assays Must Differentiate:

• hERG blockers with QTc Prolongation & associated with TdP (1)

• hERG blockers with QTc Prolongation BUT NOTassociated with TdP (2)

• Drugs with no-direct ion channel effects with modest QTc Prolongation (3)

3

2

1

Slide courtesy of D. Leishman (Lilly;

modified with permission)

Summary

CIPA- proarrhythmic risk based on mechanistic understanding of integrated

electrophysiologic drug effects

– Focus: multiple human cardiac currents on cellular level

Expectations- reduce unwarranted attrition early candidates

- enable efficient progression of more drugs

- improve efficiency of drug development by replacing strict dependence

on preclinical hERG and binary clinical QT prolongation & TQT studies

- revise current warning language for some drugs

19

Acknowledgments

For External Use 20

Philip Sager, MD (Stanford Uni)

Gary Gintant, PhD (Abbvie)

Derek Leishman, PhD (Lilly)

CIPA Working Groups

– Ion Channel WG (Safety Pharmacology Society)

– In Silico WG (Food & Drug Admin)

– Myocyte WG (Health & Environmental Science Ins)

CIPA Steering Team

– Regulatory/Government Reps (6)

– Pharma Reps (4)

– Academia (2)

– Private Industry Reps(2)

– HESI (2)

For Internal Use Only. Amgen Confidential. 21

Take Home Messages

For External Use 22

Potential Positive Impact on Drug Development

– Prevent ‘inappropriate’ attrition of novel therapeutics

– TQT waiver = incentive ($2-4M/study)

CIPA Assays: Confidence in Models Uncertain

– Translational performance needs to be understood drive use

Clarity Needed

– Definition of low TdP risk (“safe QTc prolongation”)

– Managing conflicting data signals what is minimal data set?

– Resourcing new assays; timing (front-loaded vs tiered)

– Regulatory Consensus on TQT waiver

Physiological and Pharmacological Effects on QTc

Stimulus ΔHeart Rate ΔQTcf Reference

Day/Night Difference -23 +27 Molnar et al (1996)

Standing from Supine +12 -18 Cuomo et al (1997)

Head Tilt +16 -5 Nakagawa et al (1999)

Hand Grip +7 +16 Frederiks et al (2001)

Exercise +67 -35 Davey et al (2000)

Food +11 +25 Nagy et al (1997)

Atropine +30, +35 +14, -12 Annila et al (1993), Cuomo et al (1997)

Propranolol -7 +3 Cuomo et al (1997)

Adrenaline +15 +39 Lee et al (2003)

Isoprenaline +22 +23 Cuomo et al (1997)

Autonomic Blockade +12, +31 -2, -6 Cappato et al (1993), Burke et al (1997)

Ganglion Blockade +30 +7 Diedrich et al (2002)

Based on literature reports and where necessary back converted to QTcF (D. Leishman, Lilly)

Impact of CIPA on Pharma: The Upside

Positive impact on drug development no TQT

– Prevent ‘inappropriate’ attrition of beneficial candidates

– Improve probability of success of new drug candidates

– Benefits Many:

• Large-sized & Smaller-sized sponsors (emerging)

• Patients

Leverage nonclinical pro-arrhythmia assays

– Opportunity for cost-effective drug development

– Potential to advance drugs with “safe” QTc prolongation

For External Use

Impact of CIPA on Pharma: The Anxiety

CIPA: predicting proarrhythmic risk is unproven

– Multi-channel assays: what protocol & parameters (e.g., kinetics)

– In silico Action Potential evaluation (isAP)

– Human stem cell-derived cardiomyocytes (hSC-CM)

Confidence in Assays: Integrating new risk signals

– S7B paradigm: hERG risk QTc prolong. TdP risk

– CIPA paradigm: [7 channels + isAP + hSC-CM] risk TdP risk

Resource impact

– New assays: apply to all chemical leads or “the one that matters”?

Challenges

– Interpretation of signals what is low pro-arrhythmic risk?

– Conflicting data signals how to progress drug candidates?

For External Use