Defining the CiPA Paradigm: An Update from the Ion Channel Working Group (ICWG) Bernard Fermini Pfizer Inc. Global Safety Pharmacology For the ICWG

Transcription

1 Defining the CiPA Paradigm: An Update from the Ion Channel Working Group (ICWG) Bernard Fermini Pfizer Inc. Global Safety Pharmacology For the ICWG

2 Ion Channel Working Group (ICWG) CiPA initiative is a consortium composed of a number of collaborators FDA, HESI, CSRC, National Institute of Health Sciences (NIHS, Japan), Health Canada, European Medicines Agency (EMA), Pharmaceutical and Medical Devices Agency (PMDA, Japan) Safety Pharmacology Society (SPS), Japan ips Cardiac Safety Assessment (JiCSA), academics, in silico modelers Partners from Pharmaceutical Industry, CROs, Device companies ICWG (sponsored by SPS) Builds on the considerable experience and expertise of its members in the field of ion channels Task with bringing together expertise and resources required to deliver best practice recommendations for generating ion channel data Ion Channel data needed for development and validation of best in silico model of human ventricular action potentials ( AP) simulations of proarrhythmic liabilities Co-chaired: Bernard Fermini (Pfizer); Najah Abi-Gerges (Anabios) 2

3 Pre-CiPA state of Ion Channel testing Current pre-clinical guidelines (S7B) are just that: guidance and not dogma Allow flexibility both in measurement platform, and experimental protocol As a result, pre-clinical safety profiling can differ from company to company, despite adopting the same guidelines There is a diversity of automated patch clamp systems available offering various levels of performance, leading to some variability in the quality of data generated The lack of standardization in the protocols used within the industry and in the academic environment contributes to variability of data Current cardiac ion channel safety screening strategies focus on conductance block in an effort to define potency (IC 50 ) however; kinetic of drug block can influence use- and voltage- dependency Evaluation of kinetic of block may lead to more complex, but more predictive in silico models It is therefore important to establish best practices for IC studies used to characterize drug effects (voltage protocols, temperature, reagents, etc ) so that consistent electrophysiological data may be obtained, and contribute to better prediction of proarrhythmic risk 3

4 Objectives of ICWG Address important questions related to best practices including: 1. Which ion channels should be selected to support in silico working group (ISWG) AP modelling efforts 2. What properties should be studied (IC 50 determination, kinetics, rate/use/voltage dependence, etc )? 3. What requirements are needed to deliver robust, reliable and reproducible ion channel data in a high throughput screening (HTS) environment 4

5 ICWG Deliverables (1) Which ion channels should be selected to support in silico working group (ISWG) AP modelling efforts ICWG conducted and completed a survey with the purpose of collecting frequency/type data on the commonly used ion channels (ICs) in the various laboratories 5

6 Pre-CiPA state of Ion Channel testing Cardiac ion channels screened for safety (n=65)

7 ICWG Deliverables (1) Which ion channels should be selected to support in silico working group (ISWG) AP modelling efforts ICWG conducted and completed a survey with the purpose of collecting frequency/type data on the commonly used ion channels (ICs) in the various laboratories ICWG identified 7 ICs of interest: Selected outward currents: I Kr (herg), I Ks (KvLQT1/KCNE1), I to (Kv4.3) Selected inward currents: I K1 (Kir2.1), I Ca-L (Cav1.2), I Na (Nav1.5; peak and late) 7

8 Pre-CiPA state of Ion Channel testing Temperature at which assays are performed (n=54) Room Temperature Physiologic Temperature Other 5 0 8

9 ICWG Deliverables (2) What properties should be studied? (IC 50 determination, kinetics, rate/use/voltage dependence, etc ) ICWG designed and delivered two sets of protocols for all 7 ICs 1. Dynamic block protocols that provide data on affinity, kinetics and statedependence of drug-channel interaction To be used by ISWG Keep the process simple: use protocols that are not overly complicated or challenging to apply experimentally Parametrize herg as a first step Dofetilide, cisapride and verapamil data generated Data generated at RT and 37ºC Work in progress 2. Physiological protocols that provide data on IC 50, voltage/rate/use-dependence, activation/inactivation/deactivation rates To be used in FDA sponsored study (David Strauss Lead) Data to be generated at RT and 37 C Pacing rates: 0.1 and 1 Hz Some data obtained using Action Potential voltage protocol Work in progress 9

10 Dynamic Block Protocols: Effects of Dofetilide on herg 22 ± 1ºC 37 ± 1ºC 100 nm Dofetilide 100 nm Dofetilide b b a d a d Data provided by Zenas Technologies 10

11 Dynamic Block Protocols: Effects of Dofetilide on herg 22 ± 1ºC 37 ± 1ºC a b d normalized current nM 100nM 300nM = 8456 ms = 5666 ms 0.0 = NA prepulse duration (ms) normalized current nM 100nM 300nM = ms = 2458 ms = 1026 ms prepulse duration (ms) Data provided by Zenas Technologies 11

12 Physiological Protocols: some examples I to (Kv4.3); I Ks (KvLQT1); I Na (Nav1.5) 12

13 Physiological Protocol Parameters All channels ICWG Protocols Protocol HP (mv) HP (ms) Ramp to (mv) Ramp (ms) Ramp (V/S) Step1 (mv) Step 1 (ms) Step 2 (mv) Step 2 (ms) Ramp to (mv) Ramp (ms) Ramp (V/S) Frequency (Hz) IKr (herg) TBD IK1 (Kir2.1) TBD IKs (KvLQT1/KCNE1) TBD Ito (Kv4.3) TBD INa peak (Nav1.5) TBD INa late (Nav1.5) TBD ICa-L (Cav1.2) TBD 13

14 CiPA Impact on preclinical testing Change the manner in which cardiac safety assessment is performed in the pharmaceutical industry Allow standardization of all in vitro ion channel assays to characterize drug effects on cardiac repolarization Minimize intra- and inter-laboratory variability Prevent early inappropriate compound attrition due to herg liability Provide a complete assessment of proarrhythmic risk Likely reduce animal work Make available a single, common, and fully validated in silico model to quantify the risk of arrhythmia based on the ion channel data Allow sharing of knowledge and expertise with a common goal: defining best practice Accomplish what the S7B guidance was unsuccessful in achieving 14

15 ICWG Next Steps Work closely with ISWG, and FDA. Provide feedback and scientific input/support. Rapid Response Team established to provide timely feedback Revise/modify/optimize protocols, as required Only the most informative protocols will be retained as final Likely that the list of 7 targeted channels will narrow once their role as contributing to proarrhythmia are confirmed, or not Coordinate the generation of additional ion channel pharmacology from CiPA list using standardized protocols (IC 50 + dynamic block) Adapt protocols to HT screening environment Publish the work 15

16 Conclusions The time has come to consider new, more comprehensive ways of preclinical testing for proarrhythmic risks Evolving initiative with evolving workflows addressing extremely complex issues Will require scientific, intellectual and practical contributions from multiple parties Will likely require multiple iterations before it reaches a point of applicability Important initiative that should be supported by all involved in cardiac safety 16

17 CiPA/SPS Ion Channel Working Group (ICWG) Membership Najah Abi Gerges Matthew Bridgland-Taylor Khuram Chaudhary William Crumb Bruce Damiano Gul Erdemli Bernard Fermini Gary Gintant Jules C Hancox John Imredy John Koerner Jim Kramer Derek J Leishman Paul Levesque Anders Lindqvist Carlos Obejero-Paz David Rampe Kohei Sawada David Strauss Jamie Vandenberg Hugo Vargas Affiliation Anabios (co-chair) AstraZeneca GSK Zenas Technologies Janssen Novartis Pfizer Inc (co-chair) AbbVie Bristol University Merck & Co FDA Chantest/CRL Lilly BMS Biolin Scientific Chantest/CRL Sanofi Eisai FDA Victor Chang Cardiac Research Institute Amgen 17