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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
Vo
ltag
e-S
en
sit
ive
Dye
Mic
ro-E
lectr
od
e
Arr
ay
Core Component III: In vitro Effects, Human Stem Cell-Derived Cardiomyocytes
16
• 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)
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