Advances in Ion Channel Drug Discovery

The report highlights the most promising areas for ion channel discovery enabled by technology and target validation advances. Channel families with major potential are discussed to highlight the most promising areas for investigation. New technologies and the companies exploiting these are identified. The relative prospects of programs in late-stage development are assessed.

Features and benefits

• Understand the competitive landscape in ion channel modulation and compare the pipelines of specialist companies operating in this area
• Identify the most promising targets from a "likelihood of success" viewpoint.
• Identify the targets with scope for ion channel intervention and major market opportunity.
• Understand which advances in target discovery, technology, and clinical development will have biggest impact to move the area forward.
• Benchmark available technologies against the gold standard for ion channel discovery.

Highlights

Approximately 13% of approved drugs have mechanisms involving the modulation of ion channel activity, which makes ion channels the second-largest mechanistic class of marketed compounds. Currently approved drugs address important disease areas including diabetes, epilepsy, hypertension, cardiac arrhythmia, anxiety, and pain.

Approximately 35% of agents in development have big pharma sponsorship, with the remaining 65% under development by smaller biotech. CNS indications account for 45% of development programs. Agents in late-stage development include several first-in-class agents acting at the cystic fibrosis transmembrane regulator, and new NMDA and AMPA antagonists.

Earlier-stage programs focus on selective Nav blockers (following on from genetic validation of Nav1.7 involvement in pain), subtype-selective NMDA and AMPA blockers, and a large number of TRP family members for a variety of indications.

Your key questions answered

• Why have ion channels been underexploited and what is changing to enable greater realization of these targets' potential?
• What disease areas offer further scope for new ion channel modulators, and which are likely to have the best market potential?
• Which companies have the most promising late development candidates?
• Which companies are offering innovative technologies to facilitate the discovery of drugs acting at ion channel targets?
• What challenges remain to be overcome in fully exploiting the possibilities presented by modulation of ion channel targets?

Table Of Contents

About the author
Disclaimer

EXECUTIVE SUMMARY
Introduction
Characteristics of ion channels
Commercial exploitation
Discovery approaches
New opportunities
Specialist company profiles
Outlook

Introduction
Summary
Introduction
Ion channels in the human genome
Factors that support ion channels as therapeutic targets
Factors that are challenges to ion channels as therapeutic targets
Additional opportunities (non-human targets)
Commercially validated targets
Potential to provide a much wider range of drug targets

Characteristics of ion channels
Summary
Introduction and general principles
Classification
Target families
Cation channels
Ligand-gated cation channels
Anion channels
Ligand-gated anion channels

Commercial exploitation
Summary
Introduction
Current successes
Antihypertensives
Antiarrhythmics
Sedatives and anxiolytics
Antidiabetics
Antiemetics
Anticonvulsants
Analgesics
Miscellaneous agents
Active programs in late clinical development
Active programs at earlier stages
Unexplored targets

Discovery approaches
Summary
Introduction
Target validation
Design approaches
Structure-based methods
Knowledge-based methods
Molecular dynamics simulations
Screening methods
Electrophysiology
Membrane binding assays
Ion flux assays
Membrane potential assays
Safety
Opportunities
Allosteric modulators
Polypharmacology
Improved selectivity
Transcriptional and epigenetic gene regulation

New opportunities
Summary
Introduction
Alternative ways of modifying channel activity
Gene therapy
RNA interference
Antibodies
Intrabodies
Aptamers
Chaperone proteins and accessory proteins
Disease areas with further scope for ion channel intervention
Depression
Neurodegenerative conditions
Cancer
Autoimmune disease
Pain
Enabling technologies
Online tools

Specialist company profiles
Summary
Introduction
Specialist equipment, compound, and service providers
Aurora Biomed
Axiogenesis
Biotron Healthcare
B’Sys Ion Channel Research
Cellectricon
Cellular Dynamics International
Chantest
CytoCentrics
Essen Bioscience
Fluxion Biosciences
Flyion
Genescript
Life Technologies
Molecular Devices
Nanion Technologies
NMI
Otavachemicals
Scottish Biomedical
Sophion Bioscience
Discovery and development organizations
Actelion
Algomedix
Argenta
Avanir Pharmaceuticals
Biofocus
CalciMedica
Convergence
Cortex Pharmaceuticals
Dart NeuroScience
Evotec
Galapagos
Genegrafts
Gilead
Glenmark
Hydra Biosciences
Icagen
Ion Channel Innovations
Napo Pharmaceuticals
Naurex
Neuromed Pharmaceuticals
Neurop
NeuroSearch
Newron Pharmaceuticals
Parion Sciences
Soricimed
Sucampo Pharmaceuticals
Synta
Targacept
Xenon Pharmaceuticals
Xention
Zalicus

Outlook
Summary
Introduction
What can be learned from recent failures and successes?
What is needed to move ion channel discovery forward?
Projections for 2012 / 2013

Appendix
Scope
Methodology
Primary research
Secondary research
Abbreviations
References
Chapter 1 references
Chapter 2 references
Chapter 3 references
Chapter 4 references
Chapter 5 references
Chapter 6 references

List Of Tables

Table: Ion channel specific toxins (part 1)
Table: Ion channel specific toxins (part 2)
Table: Ion channel specific toxins (part 3)
Table: GABAA isoforms, selective modulators, and major pharmacological effects (part 1)
Table: GABAA isoforms, selective modulators, and major pharmacological effects (part 2)
Table: Company-reported sales of drugs acting at ion channel targets ($m), 2010–16 (part 1)
Table: Company-reported sales of drugs acting at ion channel targets ($m), 2010–16 (part 2)
Table: Ion channels targeted by selected antihypertensive agents
Table: Selected antiarrhythmic agents currently marketed and in development
Table: Mechanisms of selected anticonvulsant agents (part 1)
Table: Mechanisms of selected anticonvulsant agents (part 2)
Table: Ion channels targeted by selected analgesics
Table: Miscellaneous approved drugs with effects achieved by action at ion channels
Table: Ion channel modulators in late-stage development (part 1)
Table: Ion channel modulators in late-stage development (part 2)
Table: Comparison of auto-patch clamp systems (part 1)
Table: Comparison of auto-patch clamp systems (part 2)
Table: Involvement of ion channels in cancer progression
Table: TRP programs in clinical development

List Of Figures

Figure: Gene family distribution of the molecular targets for approved drugs
Figure: Ion channel families by family size and number of approved drugs
Figure: Typical organization of a pore-forming channel
Figure: Binding sites for GABA and benzodiazepines at the GABAA receptor
Figure: Major ion currents underlying the human cardiac action potential
Figure: Number of preclinical, Phase I, and Phase II programs per target class
Figure: Timeline of major disclosures relating to channel structure
Figure: FluxOR method of K + flux measurement
Figure: Measurement of change in membrane potential by FRET
Figure: Relative positioning of ion channel modulators in the top 200 drugs by 2010 US sales
Figure: Prescribing indications of the top 20 drugs by 2010 US sales
Figure: FDA approval of ion channel modulators versus all approvals and NMEs submitted
Figure: EMA approval of ion channel modulators versus all approvals