Ion Channel Modulator Pipelines: Targets and Agents in Development

  • September 2009
  • -
  • CHI Insight Pharma Reports


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

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 companies currently only account for just over one-third of all the ion channel modulators in development. The range of channel types targeted by ion channel modulators in development is relatively limited and heavily skewed toward a few channel types. Eighty percent of these ion channel modulators 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 using 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 attempting to modulate ion channels, such as target distribution 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 recognize 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 gauging trends, current practices, and views on ion channel-focused R&D activity.

 
 

Table Of Contents

CHAPTER 1 - INTRODUCTION 1

1.1. What Are Ion Channels?
1.2. Channel Activation
Ligand-Gated
Voltage-Gated
Conformational States
Accessory Proteins and Subunits
Specificity and Function
1.3. Opportunity

CHAPTER 2 - TARGET CLASSES

2.1. Overview
2.2. Classification
2.3. Voltage-Gated Channels
Chloride
ClC Channels
ClCa
CFTR
Sodium
Calcium
Potassium
KV Channels
KCa Channels
Kir Channels
K2P Channels
Degenerins
Non-Specific Cation Channels
2.4. Ligand-Gated Channels
Cyclic Nucleotide (CNGA, CNGB, and HCN)
Nicotinic Receptors
GABAA
Glutamate
NMDA
AMPA
Kainate
Glycine
5-HT3 Receptors
Purinergic
Transient Receptor Potential Channels
TRPV
TRPM
TRPA

CHAPTER 3 - TECHNICAL CONSIDERATIONS

3.1. Introduction
3.2. Target Distribution
3.3. Ion Channel Structures
Structural Biology
3.4. What to Target
Multiple States
Accessory Proteins
The hERG Channel
3.5. Screening Issues
3.6. Non-Electrical Methods
FLIPR Assays
Isotopic Flux
FRET
3.7. High-Throughput Electrophysiology

CHAPTER 4 - COMMERCIALLY SUCCESSFUL ION CHANNEL MODULATORS

4.1. Overview
4.2. L-Type Calcium Channel Blockers
4.3. Antidiabetic KATP Modulators
4.5. GABA Analogs
4.6. Antiarrhythmic Agents (Potassium Channel Blockers)
4.7. Anticonvulsants (Sodium Channel Blockers)
4.8. 5-HT3 Antagonists
4.9. Nicotinic Receptors
4.10. Other Ion Channel Modulators

CHAPTER 5 - ION CHANNEL MODULATORS IN CLINICAL DEVELOPMENT

5.1. Overview
By Company
Abbott
AstraZeneca
Eli Lilly
GlaxoSmithKline
Pfizer
sanofi-aventis
By Channel Type
By Indication
Late-Stage Development Compounds
Tedisamil
Vernakalant
Dronedarone
Eslicarbazepine
Indiplon
NGX-4010
Zucapsaicin
Amifampridine
Fampridine
SK-310
5.2. Phase III
Gastrointestinal Disorders
Arverapamil
Crofelemer
Anxiety
TIK-101
PD-332334
Pagoclone
Epilepsy
Perampanel
Retigabine
Other CNS Indications
Dimebolin
RPI-78M
Safinamide
Cystic Fibrosis
VX-770
5.3. Phase II
CNS Conditions
Alzheimer’s Disease
Pain
Schizophrenia
Anxiety and Depression
Parkinson’s Disease
Epilepsy
Other CNS Conditions
Peripheral Conditions
Inflammatory Diseases
Cystic Fibrosis
Cardiovascular Disease
Gastrointestinal Disease
Oncology
Glaucoma and Tinnitus
5.4. Phase I
GABA
Glutamate Receptors
Nicotinic Receptors
Voltage-Gated Channels
TRPV1
Other
5.5. Outlook 93

CHAPTER 6 - COMPANY PROFILES

6.1. Introduction
6.2. Leading Major Companies
AstraZeneca
Eli Lilly
GlaxoSmithKline
Merck and Co.
Novartis
Pfizer
sanofi-aventis
6.3. Selected Biotechnology Companies
Aurora Biomed
CalciMedica
Cellectricon
CytoCentrics
EPIX Pharmaceuticals
Evotec
Flyion
Hydra Biosciences
Icagen
iOnGen
Lectus Therapeutics
Nanion Technologies
Neurion Pharmaceuticals
Neuromed Pharmaceuticals
NeuroSearch
Newron Pharmaceuticals
Parion Sciences
Targacept
Xention

CHAPTER 7 - OUTLOOK

7.1. Commercial Outlook
7.2. Scientific Outlook

CHAPTER 8 - EXPERT INTERVIEWS

CHAPTER 9 - RESULTS FROM INSIGHT PHARMA REPORTS’ ION CHANNELS SURVEY, JULY 2009

Question 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 significant treatment advances as a result of ion channel modulator development over the next five years?

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

Question 5. There has been a recent explosion in interest in the development of TRP channel modulators. Do you think that we are likely to see many modulators of channels other than TRPV1 enter development 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 currently 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 barrier 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
identification 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 organization 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 development of ion channel modulators?
REFERENCES 133
COMPANY INDEX WITH WEB ADDRESSES 149

Tables

Table 2.1. Families of Ion Channels
Table 2.2. Voltage-Gated Calcium Channels
Table 2.3. Old and New Nomenclatures of Glutamate-Gated Ion Channels
Table 4.1. L-Type Calcium Channel Blockers and 2007 Sales
Table 4.2. KATP Channel Modulators and 2007 Sales
Table 4.3. GABAA Channel Modulators and 2007 Sales
Table 4.4. Class I Antiarrhythmic Agents (Sodium Channel Blockers)
Table 4.5. Class III Antiarrhythmic Agents (Potassium Channel Blockers)
Table 4.6. Anticonvulsant Agents and 2007 Sales
Table 4.7. 5-HT3 Antagonists and 2007 Sales
Table 5.1. Ion Channel Modulators Awaiting Regulatory Approval
Table 5.2. Ion Channel Modulators in Phase III Studies
Table 5.3. Ion Channel Modulators in Phase II Studies for CNS Disorders
Table 5.4. Ion Channel Modulators for Non-CNS Conditions in Phase II Studies
Table 5.5. Ion Channel Modulators in Phase I Studies

Figures

Figure 5.1. Ion Channels Modulators in Development by Major Pharmaceutical Companies
Figure 5.2. Ion Channel Modulators in Development by Target Type
Figure 5.3. Ion Channel Modulators in Development by Indication
Figure 6.1. Ion Channel Modulator Patents Filed by Seven Major Companies Published Between January 2005 and March 2009

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10 Companies

Company Profiles

Immuron Ltd.

Australia

ASX Ltd.

Australia

Cipla Ltd.

India

GlaxoSmithKline PLC

United Kingdom

Cision AB

Sweden

Staples UK Retail Ltd.

United Kingdom

AstraZeneca PLC

United Kingdom

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