Insight Pharma Reports, a division of Cambridge Healthtech Institute

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Peter Norman, PhD, MBA

Ion channels represent a significant opportunity to address an underexploited class of therapeutic targets. Nearly 150 novel ion channel modulators are reported to be in clinical development. This report examines:

• Ion channel modulators in clinical development and their potential

• Improved molecular understanding of ion channel structure and cellular activity

• High-throughput screening methods for identification of novel modulators

• Prospects for ion channel modulators and commercial successes to date

• Pipeline activities, expert views, and survey results

NEW TECHNOLOGIES FUEL INTEREST IN THIS TARGET CLASS

August 2009

TargeTs and agenTs in developmenT

Ion ChannelModulatorPIPelInes:Ion ChannelModulatorPIPelInes:

Ion Channel Modulator Pipelines: Targets and Agents in Development provides a comprehensive analysis of the ion channel modulator pipeline, breaking it down by company, ion channel type, and therapeutic indication. A number of interesting trends are revealed: Major pharmaceutical com-panies currently only account for just over one-third of all the ion channel modulators in development. The range of chan-nel types targeted by ion channel modulators in develop-ment is relatively limited and heavily skewed toward a few channel types. Eighty percent of these ion channel modula-tors are being developed for diverse CNS indications.

This report also analyzes the approximately 100 ion channel modulators that have been approved for clinical use. These drugs have generated considerable revenues: Even though generic forms of many of these agents are now available, sales of these branded drugs were around $20 billion in 2007. However, relatively few of these were developed us-ing channel-based screening approaches, and many were identified with little or no knowledge of their mechanism of action.

To date, ion channel modulators have been identified by various means, relatively few of which have so far been focused on direct screening of compounds for their activity on the channel(s) of interest. The past few years have seen significant developments that facilitate the identification of novel ion channel modulators. These improvements

in screening methods should lead to more selective agents being identified and progressing into clinical development. We also examine other technical considerations when at-tempting to modulate ion channels, such as target distribu-tion throughout the body, and the structure of ion channels and their multiple states (e.g., each state of the ion channel offers a different conformation for a potential ligand to rec-ognize and thus any ion channel provides multiple potential targets).

Ion Channel Modulator Pipelines: Targets and Agents in Development concludes with a commercial and scientific outlook, expert interviews, and results from a survey gaug-ing trends, current practices, and views on ion channel-fo-cused R&D activity.

FIGuREsIon Channels Modulators in Development by Major

Pharmaceutical CompaniesIon Channel Modulators in Development by Target TypeIon Channel Modulators in Development by IndicationIon Channel Modulator Patents Filed by Seven Major Companies

Published Between January 2005 and March 2009

TAblEsFamilies of Ion ChannelsVoltage-Gated Calcium ChannelsOld and New Nomenclatures of Glutamate-Gated Ion Channels

L-Type Calcium Channel Blockers and 2007 SalesKATP Channel Modulators and 2007 SalesGABAA Channel Modulators and 2007 SalesClass I Antiarrhythmic Agents (Sodium Channel Blockers)Class III Antiarrhythmic Agents (Potassium Channel Blockers)Anticonvulsant Agents and 2007 Sales5-HT3 Antagonists and 2007 SalesIon Channel Modulators Awaiting Regulatory ApprovalIon Channel Modulators in Phase III Studies Ion Channel Modulators in Phase II Studies for CNS Disorders Ion Channel Modulators for Non-CNS Conditions in Phase II

Studies Ion Channel Modulators in Phase I Studies

About the Author: Peter Norman, PhD, MBA, is a pharmaceutical consultant and analyst based in Burnham Beeches, near Windsor, England. He has written and presented widely on various aspects of respiratory disease, drug development, and on the analysis of diverse therapeutic markets. Dr. Norman has over 20 years of experience of the pharmaceutical industry in both R&D and competitive intelligence. His publications include many reviews and 16 original scientific papers and 11 patents, together with a number of management reports. The latter have been published by a number of companies including FT Pharmaceuticals, Urch Publications, SMI and Decision Resources, Informa, and Insight Pharma Reports (a division of Cambridge Healthtech Institute). Dr. Norman holds science degrees from Cambridge University and Brunel University and an MBA degree from the Open University.

Tables and Figures

To order a report, e-mail rlaraia@healthtech.com, call Rose LaRaia at 781-972-5444, or order on-line

Overview

Identification/characterizationof targets

Advances in basic science

Screening technology

Structural information

Other

In what areas of ion channel development are furtheradvances going to be the most critical?

n=26

n=21

n=21

n=14

n=1Source: Insight Pharma Reports

CHAPTER 1: INTRODuCTION1.1. What Are Ion Channels?1.2. Channel ActivationLigand-GatedVoltage-GatedConformational StatesAccessory Proteins and SubunitsSpecificity and Function1.3. Opportunity

CHAPTER 2: TARGET ClAssEs2.1. Overview2.2. Classification 2.3. Voltage-Gated Channels Chloride ClC Channels ClCa CFTRSodiumCalcium Potassium KV Channels KCa Channels KIR Channels K2P ChannelsDegenerinsNon-Specific Cation Channels2.4. Ligand-Gated ChannelsCyclic Nucleotide (CNGA, CNGB,

and HCN) Nicotinic ReceptorsGABAAGlutamate NMDA AMPA KainiteGlycine5-HT3 ReceptorsPurinergic Transient Receptor Potential Channels TRPV TRPM TRPA

CHAPTER 3: TECHNICAl CONsIDERATIONs3.1. Introduction3.2. Target Distribution3.3. Ion Channel StructuresStructural Biology3.4. What to TargetMultiple StatesAccessory ProteinsThe hERG Channel3.5. Screening Issues3.6. Non-Electrical MethodsFLIPR AssaysIsotopic FluxFRET3.7. High-Throughput Electro-

physiology

CHAPTER 4: COMMERCIAllY suCCEssFul ION CHANNEl MODulATORs4.1. Overview4.2. L-Type Calcium Channel

Blockers 4.3. Antidiabetic KATP Modulators

4.4. Benzodiazepine Ligands (GABA Modulators)

4.5. GABA Analogs4.6. Antiarrhythmic Agents (Po-

tassium Channel Blockers)4.7. Anticonvulsants (Sodium

Channel Blockers)4.8. 5-HT3 Antagonists4.9. Nicotinic Receptors4.10. Other Ion Channel Modulators

CHAPTER 5: ION CHANNEl MODulATORs IN ClINICAl DEVElOPMENT5.1. OverviewBy Company Abbott AstraZeneca Eli Lilly GlaxoSmithKline Pfizer sanofi-aventisBy Channel Type By IndicationLate-Stage Development Com-

pounds Tedisamil Vernakalant Dronedarone Eslicarbazepine Indiplon NGX-4010 Zucapsaicin Amifampridine Fampridine SK-3105.2. Phase III Arverapamil CrofelemerAnxiety TIK-101 PD-332334 PagocloneEpilepsy Perampanel Retigabine Dimebolin RPI-78M Safinamide5.3. Phase IICNS Conditions Alzheimer’s Disease Pain TrPv1 antagonists Schizophrenia Anxiety and Depression Parkinson’s Disease Epilepsy Other CNS ConditionsPeripheral Conditions Inflammatory Diseases Cystic Fibrosis Cardiovascular Disease Gastrointestinal Disease Oncology Glaucoma and Tinnitus5.4. Phase I GABAGlutamate Receptors

Nicotinic ReceptorsVoltage-Gated ChannelsTRPV1Other5.5. Outlook

CHAPTER 6: COMPANY PRO-FIlEs6.1. Introduction6.2. Leading Major Companies AstraZenecaEli LillyGlaxoSmithKlineMerck & Co.NovartisPfizersanofi-aventis6.3. Selected Biotechnology

CompaniesAurora Biomed CalciMedicaCellectricon CytoCentrics Epix PharmaceuticalsEvotec Flyion Hydra BiosciencesIcagen iOnGen Lectus TherapeuticsNanion Technologies Neurion PharmaceuticalsNeuromed PharmaceuticalsNeuroSearch Newron Pharmaceuticals Parion SciencesTargacept Xention

CHAPTER 7: OuTlOOK7.1. Commercial Outlook7.2. Scientific Outlook

CHAPTER 8: EXPERT INTERVIEWsJohn Kemp, PhD, Chief research

and Development Officer, Evotec, Hamburg, Germany

John Dunlop, PhD, Director of Neuropharmacology and Neurophysiology, Neuroscience Discovery research, Wyeth research, Princeton, NJ

William A. Catterall, PhD, Chair of Pharmacology at the University of Washington, Seattle, WA

CHAPTER 9: suRVEY REsulTsQuestion 1. Please classify your

organization.Question 2. Under what functional

area do your responsibilities fall?

Question 3. What disease areas do you feel will see signifi-cant treatment advances as a result of ion channel modula-tor development over the next five years?

Question 4. The major thrust of current efforts aimed at ion channel modulators ap-pears to be focused on CNS conditions, with some activity aimed at heart disease and limited interest in other condi-tions. Is this overlooking other potential targets?

Question 5. There has been a recent explosion in interest in the development of TRP chan-nel modulators. Do you think that we are likely to see many modulators of channels other than TRPV1 enter develop-ment in the near term?

Question 6. In your opinion, what type(s) of ion channels have the greatest potential as drug targets?

Question 7. My organization cur-rently targets the following type(s) of ion channels…

Question 8. In what areas of ion channel development are further advances going to be the most critical?

Question 9. Has there been an upsurge of research activity on ion channel targets since the emergence of improved knowledge of their molecular structure and newer screening methods?

Question 10. In your opinion, has the lack of reliable screening assays been the major factor in decisions of large pharma to avoid the pursuit of many ion channel targets?

Question 11. In your opinion, what is currently the greatest bar rier to successful development of ion channel modulators?

Question 12. Do you think that the low conductance of many types of ion channels has been a major barrier to both their study and the identifica-tion of selective modulators?

Question 13. How has your organization’s level of activity changed in the past five years in terms of developing ion channel modulators?

Question 14. Does your organiza-tion plan to change its level of involvement with ion channels over the next three years?

Question 15. Do you have any additional observations about the discovery and develop-ment of ion channel modulators?

REFERENCEs

COMPANY INDEX WITH WEb ADDREssEs

Table of Contents

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