Successes and Evolving Challenges Posed by the Comprehensive In Vitro Proarrhythmia (CiPA) Initiative
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1 Successes and Evolving Challenges Posed by the Comprehensive In Vitro Proarrhythmia (CiPA) Initiative Gary Gintant Dept. Integrative Pharmacology Integrated Sciences and Technology AbbVie For the CiPA Initiative
2 Outline Introduction and Rationale for CiPA Definition and Overarching Goals Scientific Underpinnings Components: Progress and Challenges Ionic Currents In Silico Reconstruction Stem-Cell Derived Cardiomyocytes Compound Selection/Regulatory Paths Forward and Conclusions 2
3 CiPA: Comprehensive In Vitro Proarrhythmia Assay Goal: Develop a new in vitro paradigm for cardiac safety evaluation of new drugs that provides a more accurate and comprehensive mechanistic-based assessment of proarrhythmic potential - focus on proarrhythmia (not QT prolongation) to improve specificity compared to preclinical herg and clinical TQT studies How? - Define drug effects on multiple human cardiac currents, - Characterize integrated electrophysiologic response using in silico reconstructions of human ventricular electrophysiology, - Verify effects on human stem-cell derived ventricular myocytes 3
4 herg Is Insufficient to Predict Delayed Repolarization REPOLARIZATION: integrated response, multiple currents DELAYED REPOLARIZATION: reduced NET outward current - balance of outward repolarizing current (ikr/herg) vs. inward depolarizing plateau current (Na or Ca) Present (ikr, herg) focus results in premature and unwarranted drug attrition, misclassification of risk 4
5 Drug Effects on Multiple Cardiac Currents Must Be Considered. Lack of selectivity of drugs on cardiac currents (ICaL vs. herg) Effects on multiple channels (multi-channel block) define overall drug response (e.g., verapamil) 5
6 Cellular Proarrhythmia: Abnormal Emergent Responses That Affect Repolarization (not simply hapd or hqtc) Focus on proarrhythmic vulnerability: impaired cellular repolarization, electrical instability - In extreme form, instability manifest as early after-depolarizations (EAD s) associated with initiation of proarrhythmia and l - Proarrhythmic liability (an integrated, emergent effect) manifest on a cellular level with human responses Impaired repolarization used to rank proarrhythmic risk based on comparisons with known clinical TdP drugs 6
7 Comprehensive In Vitro Proarrhythmia Assay: Four Overall Components Drug Effects on Multiple Human Cardiac Currents In Silico Reconstruction Human Ventricular Cellular Electrophysiology In Vitro Effects Human Stem- Cell Derived Ventricular Myocytes Evaluation of Clinical Drugs for Proarrhythmic TdP Liability High Risk Intermediate Risk Low Risk Preclinical ECG & Phase 1 ECG Studies: Complementary Data 7
8 Core Component I. Human Ionic Currents, Voltage Clamp Studies, Heterologous Expression - Ion Channel Working Group (SPS): develop protocols to assess drug effects on currents - Standardized voltage clamp protocols to establish best practices, reduce bias and variability, allow comparisons of automated platforms across laboratories - Information on kinetics-, voltage- and use-dependence to parameterize models (essential for herg) for Robust characterization of drug effects on human currents enables in silico reconstructions of integrated responses 8
9 Core Component II: Computer Reconstructions of Drug Effects on Human Cellular Electrophysiology + = - In Silico Group (FDA): Drug effect multiple human currents integrated to describe cellular electrophysiologic effects - Define changes in repolarization instability, early afterdepolarizations, reduced upstroke velocity using select model (modified O Hara-Rudy model considered) - Ranking of integrated responses compared with clinical examples of different TdP liabilities 9
10 Core Component II. Computer Reconstructions: Progress (FDA Lead) Initial Test Case: d,l Sotalol (known torsadogen) - Recognized for QT prolongation and TdP - O Hara-Rudy model recapitulates delayed repolarization in human ventricular tissues based on IC 50 values for herg, Cav1.2 and Nav1.5 (Kramer et al. (2013) - Not replicated by Grandi or ten Tusscher in silico models - EAD s with prominent ikr/herg block not generated in either Ten Tusscher or Grandi in silico models 10
11 Micro-Electrode Array (MEA) Voltage-Sensitive Dye (VSO) Core Component III: In vitro Effects, Human Stem Cell-Derived Ventricular Cardiomyocytes - Myocyte Group (HESI): Verification of ion channel effects and in silico reconstructions with well characterized human stem-cell cardiomyocytes - Inform on repolarization effects not anticipated from other approaches - channel modulation - emergent effects - physiologic conditions (37 o C) - MEA & VSO approaches 11
12 Core Component III. Cardiomyocytes- Microelectrode Array (MEA) Pilot Study 12 site Pilot Study 12
13 Core Component III. Stem-cell Derived Cardiomyocytes: Progress Test Protocol: - Confluent monolayers prepared according to manufacturer instructions minutes drug exposure - Individual or sequential (cumulative) exposure - 4 concentrations; 3 wells/conc. - Quality controls: stable baseline spontaneous rate, stable conduction across monolayers, post-dose signal quality 8 compound test set (blinded) - 4 Calibration cmpds to test assay sensitivity: IKr, IKs, INaF, ICaL - 4 Test cmpds : preliminary test set, high and low risk examples Pilot Studies - Stem Cell Derived Cardiomyocytes "Calibration" Cmpd & Current "Test" Cmpds Mexiletine (ina) Flecainide Nifedipine* (ical) Moxifloxacin E-4031 (ikr) Quinidine JNJ303 (iks) Ranolazine = "High Risk" Category = "Low Risk" Category = Not Categorized, Channel Specific Prelim. analysis; concordance across VSO & MEA; review ongoing 13
14 Core Component III. Stem-cell Derived Cardiomyocytes: Progress MEA VSO 2 approaches - Multi-electrode arrays (MEA-8 sites) - Voltage-sensing optical (VSO-4 sites) - Dyes or integral sensing proteins 3 Myocyte Vendors - CDI, Axiogenesis, (Stanford University) - Myocytes prepared to vendor specifications; site familiarity 14
15 Sites A & B Cells 1 & 2 Plate 1 Pilot MEA Study: Trends Across 4 sites, 3 compounds, & 2 cells. Compounds 3, 1, 5 Cell A Cell B 15
16 Core Component III. Stem-cell Derived Cardiomyocytes. Voltage sensitive optical probes (VSO) Study Cell providers: Assay companies/groups: B I O S C I E N C E S Voltage sensor Di-4-ANEPPS (small molecule) QuasAr1 (protein) FluoVolt (small molecule) Di-4-ANEPPS (small molecule) Detector Photomultiplier CMOS camera CMOS camera CMOS camera 16
17 VSO: Endpoints Minimum end-points include measures of repolarization timings and arrhythmia detection. Primary end points: Spontaneous beat rate and regularity (adult human 1s) Baseline Drug Action potential rise time (10-90%) (adult human 2-2.5ms) APD at 30%, 50% & 90% (adult human 200ms, 220, 270) AP triangulation index (APD 90 -APD 30 ) (adult human 70ms) 200ms Incidence of early after depolarisation (EADs) Rate sensitivity of the above parameters (paced only) 17
18 APD 30 (% of baseline) APD 50 (% of baseline) APD 90 (% of baseline) Examples: Di-4-ANEPPS as Voltage Sensor C1_Baseline C1_Drug Baseline Drug Baseline Drug Baseline Drug 200ms 200ms 200ms 200ms Vehicle (DMSO) Drug Vehicle (DMSO) Drug * Vehicle (DMSO) Drug *** * *** C1 C2 C3 C4 [Drug] C1 C2 C3 C4 [Drug] C1 C2 C3 C4 [Drug] 18
19 CiPA Pilot Myocyte Workstreams: Opportunities to Assess Experimental Variability CiPA Stem Cell Cardiomyocyte Pilot Studies MicroElectrode Array (MEA) Voltage-Sensing Optical (VSO) CiPA Myocyte Workstream Multiple Multiple MEA Multiple Volunteer List Replicates, Stem Cells Platforms Type Stem Cells 1 Myocyte Type Across 1 Platform 1 Myocyte Type Indicator Across 1 Platform MES Site 1 MEA Site 2 MEA Site 3 MEA Site 4 MEA Site 5 MEA Site 6 MEA Site 7 MEA Site 8 MEA Site 9 MEA Site 10 VSO Site 1 VSO Site 2 VSO Site 3 Di-4-ANEPPS Di-4-ANEPPS QuasAr1 VSO Site 4 FluoVolt 19
20 Clinical Foundations: Compound Selection & Clinical Regulatory Group TdP Risk Compound Selection/Regulatory (CSRC): Categorization available drugs for proarrhythmic risk: - High, Intermediate, Low risk categories - Evaluate clinical data for proarrhythmia - Overall experience, history, patient population, pharmacokinetics - 29 drugs nominated for model development and verification Input from clinical developers/regulators - Validation & acceptance of CiPA paradigm Define Phase 1 ECG Verification Efforts Provides Gold Standard for Calibrating CiPA Studies 20
21 Criteria for Compound Selection - No prominent proarrhythmic / active metabolites - Good solubility - Defined cellular electrophysiology - Ranking compounds based on clinically demonstrated torsadogenic risk and proarrhythmic incidence - published reports, FDA AERS database, additional data sources, expert opinion - Compounds grouped into high, intermediate and very low (i.e., none) risk categories - Intermediate risk compounds grouped into one category - Very low risk no discernable risk - Culled from much larger list of candidates 21
22 Compounds List: CiPA Redfern CiPA Redfern CiPA Redfern HIGH RISK Category INTERMEDIATE RISK Category LOW RISK Category Azimilide 1 Astemizole 2 Diltiazem 5 Bepridil 3 Chlorpromazine - Loratadine 5 Dofetilide 1 Cisapride 2 Metoprolol - Ibutilide 1 Clarithromycin 4 Mexiletine - Quinidine 1 Clozapine - Nifedipine 4 Vandetanib - Domperidone 4 Nitrendipine 5 Methadone - Droperidol - Ranolazine - D,l Sotalol 1 Terfenadine 2 Tamoxifen 5 Pimozide 3 Verapamil 5 Risperidone 5 Ondansetron - 22
23 Group Efforts Against Timelines Parties Involved: Cardiac Safety Research Consortium: Cmpd Selection Team FDA: In Silico Working Group ILSI-HESI: Myocyte Stem Cell Working Group Safety Pharm. Society: Ion Channel Working Group J-iCSA 2015(?) Regulators: FDA, Health Canada, EMEA, Japan Japanese Safety Pharmacology Society Academic Contributors Vendors and Suppliers Timelines: Progress Review: 1Q
24 Future Activities: CiPA 2015 Refinement-Evaluations of Voltage Clamp Protocols Preliminary test of In Silico Reconstructions Based on Ionic Current Studies Assessment of CiPA Stem Cell Cardiomyocyte Pilot Study Results - Planning / Initiation of Validation Studies - Define set of validation compounds - Consult/collaborate/compare with J-iCSA Further discussion with Regulators - Expectations of CiPA Package of regulators, industry - Relation to eqt Clinical Efforts - How to integrate in vitro/in silico preclinical results with emerging clinical eqt approaches 24
25 CiPA: proarrhythmic risk assessment based on mechanistic understanding of integrated, cellular emergent drug effects on multiple human cardiac currents Expectations: - reduce unwarranted attrition early candidates - enable rapid progression of low risk TdP drugs to phase 1 studies (and confirmatory clinical ECG findings) 25
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