Cardiotoxicity: Issues, Technologies, and Solutions for the Future

SUMMARY

At least 50 companies have a claimed product or service relevant to cardiotoxicity screening, of which 29 have some clear focus on proarrhythmic cardiotoxicity or ion channel screening.

This new report offers in-depth analysis of:

• 50 commercial entities that offer cardiotoxicity screening products/services
• The history and status quo of the current regulatory environment pertinent to drug-induced proarrhythmia
• Methods for assessing the potential for drug-induced cardiotoxicity, with a primary focus on proarrhythmia screening
• Drugs associated with cardiotoxicity, factors that may predispose to drug-induced cardiotoxicity, and current/proposed cardioprotective approaches
• A primer on cardiac anatomy/physiology, with particular consideration given to the various ion fluxes that contribute to the cardiac action potential
• Results of an Insight Pharma Reports cardiotoxicity survey undertaken for this report in December 2007

In addition, this report provides a subjective opinion on the future of cardiotoxicity screening, suggests how regulatory guidelines might change in the future, and outlines some commercial opportunities that might be associated with the current and future cardiotoxicity screening environment.

Ion currents across a cardiac myocyte cell membrane cause a sequence of voltage changes known as the action potential, which is the basis of the heartbeat. Drug-mediated interference with one or more of the ion channels that give rise to the action potential may cause potentially lethal arrhythmias. This could be brought about by direct binding of drug to ion channel proteins, or by indirect interference with ion channel function. The clinical outcome of drug-ion channel interactions could be potentiated by a variety of predisposing factors, such as concurrent disease, medication, genetic variations, age, and gender.

Additionally or alternatively, drugs may have more directly cytotoxic effects on cardiac cells, such as pro-apoptotic effects. In particular, the anthracyclines are commonly used in pediatric malignancies and breast cancer, and are associated with chronic cardiotoxicity. Hence, many cancer survivors have a higher risk of cardiovascular disease than of recurrent cancer.

Cardiotoxicity: Issues, Technologies, and Solutions for the Future provides a full discussion of both direct and proarrhythmic cardiotoxicity. This report identifies and discusses methods, products, and services that are designed to identify cardiotoxic compounds before they reach the market. It also outlines the main commercial competitors and suggests broad types of commercial opportunity and future merger and acquisition activity.

TABLE OF CONTENTS

Chapter 1

• CARDIAC ANATOMY AND PHYSIOLOGY
• 1.1. Anatomy of the Heart
• 1.2. The Cardiac Cycle
• 1.3. The Resting Potential
• 1.4. The Action Potential
• 1.5. Origin of the Heartbeat
• 1.6. Clinical Assessment of Cardiac Function
• 1.7. Cardiac Ion Channels
• 1.8. Summary

Chapter 2

• CARDIOTOXICITY
• 2.1. “Directly Cardiotoxic” Drugs
• 2.2. Mechanism of Toxicity of “Directly Cardiotoxic” Drugs
  • Anthracyclines/Anthracycline-Interacting Anticancer Drugs
  • Other Anticancer Drugs
  • Nonsteroidal Anti-inflammatory Drugs
  • Other Drugs Associated with Direct Toxicity
• 2.3. “Direct Cardiotoxicity”
  • Predisposing Factors
  • Damage Limitation
• 2.4. “Proarrhythmic” Drugs
• 2.5. Mechanism of Cardiotoxicity of Proarrhythmic Drugs
  • Molecular Targets of Proarrhythmic Drugs
  • Drug Interactions with Ion Channels
  • Arrhythmia Generation
• 2.6. Proarrhythmia
  • Predisposing Factors
  • Damage Limitation
• 2.7. Summary

Chapter 3

• REGULATORY ENVIRONMENT AND INDUSTRY RESPONSE
• 3.1. History
• 3.2. ICH Guideline S7B: Preclinical QT Studies
• 3.3. ICH Guideline E14: Clinical QT Studies
• 3.4. Other Regulatory Agency Documents
• 3.5. Regulatory Decision-Making
• 3.6. Industry Concerns
• 3.7. Summary

Chapter 4

• ASSESSING DRUG-INDUCED CARDIOTOXICITY
• 4.1. Surrogate Markers for Proarrhythmia
• Measures of Ion Channel Flux
• Action Potential Morphology and Duration
• Dispersion of Action Potential Duration
  • Temporal Dispersion of Action Potential Duration (Instability)
  • Transmural Dispersion of Repolarization
  • Spatial Dispersion of Repolarization
• QT Interval Prolongation
• Combinations of Measures
• 4.2. Preclinical Proarrhythmia Screening
• In Silico Approaches
• Single-Cell Methods
  • Cell Types
  • Non - Patch Clamp Single-Cell Assay
  • Conventional Patch Clamping
  • Automated Medium-/High-Throughput Patch Clamping
  • Scanning Patch Clamping
• Multicell Methods
  • Purkinje Fiber and Papillary Muscle Systems
  • Ventricular Wedge
  • Whole Heart Systems
    • Langendorff Perfused Heart
    • SCREENIT Perfused Rabbit Heart
  • Future Developments in Multicellular In Vitro Systems
• 4.3. Preclinical Proarrhythmia Screening: In Vivo Methods
• Anesthetized Animals
• Conscious, Telemetrized Animals
• Predisposed Models
  • Methoxamine-Sensitized Rabbits
  • Canine Chronic Atrioventricular Block
  • Canine Pharmacological IKs Block
  • Other Models
• 4.4. Clinical Trials and Postmarketing Surveillance
  • Low Frequency of Arrhythmia Complicates Trials
  • Pharmacogenetics
  • Measurements in the Trial Population
  • Impact of QT Effects Discovered in Clinical Trials
• 4.5. Screening for “Direct” Cardiotoxicity
  • Markers of Cardiac Damage
  • Animal Models
• 4.6. Summary

Chapter 5

• INDUSTRY ATTITUDES AND CARDIOTOXICITY SURVEY RESULTS
• 5.1. Previous Surveys
• 5.2. Insight Pharma Reports Cardiotoxicity Survey - December 2007
  • Survey Population
  • Analysis of Questionnaire Responses
    • In Silico Methods
    • In Vitro Methods
    • In Vivo Methods
    • Clinical Methods
• 5.3. Insight Pharma Reports Expert Interviews
  • Survey Population
  • Analysis of Interview Responses
    • In Silico Methods
    • In Vitro Methods
      • Single-Cell Systems
      • Multicell Systems
    • In Vivo Methods
    • Clinical Methods
    • Views on the TQT Study
    • Timing and Nature of Possible Changes to S7B or E14
      • S7B
      • E14
• 5.4. Summary

Chapter 6

• COMMERCIAL ENVIRONMENT
• 6.1. Cardiotoxicity Screening Segment
• 6.2. Proarrhythmia Screening Product/Service Providers
• 6.3. Summary

Chapter 7

• AN OPINION: THE FUTURE OF CARDIOTOXICITY SCREENING IN DRUG DEVELOPMENT
• 7.1. Proarrhythmia Screening
  • Early-Stage Drug Development
  • Late-Stage Drug Development
• 7.2. Screening for “Direct” Cardiotoxicity
  • Chronic Cardiotoxicity
  • Acute Cardiotoxicity
• 7.3. Summary

Appendix A

• EXPERT INTERVIEWS
• Charles Antzelevitch, PhD, Executive Director and Director of Research, Masonic Medical Research Laboratory, Utica, NY
• Ernest D. Bush, PhD, Vice President and Scientific Director, Cambridge Healthtech Associates, Needham, MA (formerly Head of Non-clinical Drug Safety Department, Hoffmann-La Roche)
• Marek Malik, MD, PhD, Professor of Cardiac Electrophysiology, St. George's Hospital, University of London, UK
• Umesh Patel, PhD, Director, R&D, Ion Channel Group, BioScience Division, Millipore UK, Cambridge, UK
• Katya Tsaioun, PhD, President, Apredica, Watertown, MA
• Benoit Tyl, MD, Medical Director, Europe, MDS Pharma Services/Centralized Cardiac Services

Appendix B

• COMPANIES PROVIDING CARDIOTOXICITY SCREENING PRODUCTS OR SERVICES

Appendix C

• PROFILES OF TOP 29 COMPANIES
• Apredica
• Aurora Biomed
• AVIVA Biosciences
• BioFocus (part of Galapagos)
• bSys GmbH
• Caliper Life Sciences (Xenogen subsidiary)
• Cellectricon
• Cellular Dynamics International
• CEREP
• ChanTest
• Charles River Laboratories
• Cyprotex
• Cytocentrics
• Cytoplex BioSciences
• Essen Instruments
• EvoTec
• Flyion
• Hondeghem Pharmaceutical Consulting
• IonGate Biosciences GmbH
• MDS Pharma Services (part of MDS Inc.)
• Millipore
• MultiChannel Systems GmbH
• Nanion Technologies
• Nerviano Medical Sciences
• NeuroSolutions Ltd.
• QTest Labs
• RxGen
• Sophion
• Zenas Technologies

Appendix D

• INSIGHT PHARMA REPORTS CARDIOTOXICITY SURVEY - DECEMBER 2007