2DG - a glucose analogue and glycolytic inhibitor with anticonvulsant and antiepileptic actions

Tom Sutula, MD, PhD Department of Neurology, University of Wisconsin Chief Scientific Officer, NeuroGenomex, Inc.

The novel mechanism of 2DG: why 2DG is a glycolytic inhibitor cannot undergo isomerization



Completed preclinical efficacy studies

Animal Models of Acute & Chronic Epilepsy in vitro Models of Seizure Induction

    

protection against seizures evoked by 6Hz stimulation protection against audiogenic seizures in Fring’s mice 2-fold slowing of latency to status epilepticus onset by kainic acid, pilo 2-fold slowing of kindling progression evoked from different brain sites time course of action & dose range effective against seizure progression when administered up to 10 minutes after a seizure 2DG reduces epileptic discharges evoked by:



K + (7.5mM, ictal & interictal)



bicuculline (GABA antagonist)

 

4AP (K + channel antagonist) DHPG (metabotropic glutamate agonist )



Completed preclinical efficacy studies

Animal Models of Acute & Chronic Epilepsy in vitro Models of Seizure Induction

    

protection against seizures evoked by 6Hz stimulation protection against audiogenic seizures in Fring’s mice 2-fold slowing of latency to status epilepticus onset by kainic acid, pilo 2-fold slowing of kindling progression evoked from different brain sites time course of action & dose range effective against seizure progression when administered up to 10 minutes after a seizure 2DG reduces epileptic discharges evoked by:



K + (7.5mM, ictal & interictal)



bicuculline (GABA antagonist)

 

4AP (K + channel antagonist) DHPG (metabotropic glutamate agonist )



implies that actions of 2DG at the cellular level are “broad spectrum” against different mechanisms of network synchronization



these properties are unlike ANY other marketed drugs



2DG is disease modifying against progressive adverse effects of seizures



efficacy studies support clinical utility for both ACUTE and CHRONIC uses



Completed preclinical efficacy studies

Animal Models of Acute & Chronic Epilepsy in vitro Models of Seizure Induction

    

protection against seizures evoked by 6Hz stimulation protection against audiogenic seizures in Fring’s mice 2-fold slowing of latency to status epilepticus onset by kainic acid, pilo 2-fold slowing of kindling progression evoked from different brain sites time course of action & dose range effective against seizure progression when administered up to 10 minutes after a seizure 2DG reduces epileptic discharges evoked by:



K + (7.5mM, ictal & interictal)



bicuculline (GABA antagonist)

 

4AP (K + channel antagonist) DHPG (metabotropic glutamate agonist )



implies that actions of 2DG at the cellular level are “broad spectrum” against different mechanisms of network synchronization



these properties are unlike ANY other marketed drugs



2DG is disease modifying against progressive adverse effects of seizures



efficacy studies support clinical utility for both ACUTE and CHRONIC uses



Completed preclinical efficacy studies

Animal Models of Acute & Chronic Epilepsy in vitro Models of Seizure Induction

    

protection against seizures evoked by 6Hz stimulation protection against audiogenic seizures in Fring’s mice 2-fold slowing of latency to status epilepticus onset by kainic acid, pilo 2-fold slowing of kindling progression evoked from different brain sites time course of action & dose range effective against seizure progression when administered up to 10 minutes after a seizure 2DG reduces epileptic discharges evoked by:



K + (7.5mM, ictal & interictal)



bicuculline (GABA antagonist)

 

4AP (K + channel antagonist) DHPG (metabotropic glutamate agonist )



implies that actions of 2DG at the cellular level are “broad spectrum” against different mechanisms of network synchronization



these properties are unlike ANY other marketed drugs



2DG is disease modifying against progressive adverse effects of seizures



efficacy studies support clinical utility for both ACUTE and CHRONIC uses



Completed preclinical efficacy studies

Animal Models of Acute & Chronic Epilepsy in vitro Models of Seizure Induction

    

protection against seizures evoked by 6Hz stimulation protection against audiogenic seizures in Fring’s mice 2-fold slowing of latency to status epilepticus onset by kainic acid, pilo 2-fold slowing of kindling progression evoked from different brain sites time course of action & dose range effective against seizure progression when administered up to 10 minutes after a seizure 2DG reduces epileptic discharges evoked by:



K + (7.5mM, ictal & interictal)



bicuculline (GABA antagonist)

 

4AP (K + channel antagonist) DHPG (metabotropic glutamate agonist )



implies that actions of 2DG at the cellular level are “broad spectrum” against different mechanisms of network synchronization



these properties are unlike ANY other marketed drugs



2DG is disease modifying against progressive adverse effects of seizures



efficacy studies support clinical utility for both ACUTE and CHRONIC uses

2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant

2DG is preferentially delivered to regions with high energy needs by activity-dependent neurovascular coupling involving neurons, glia, and endothelial cells in the “neurovascular unit” 18F-2DG PET scan during status epilepticus H3-2DG autoradiogram during 1 hz stimulation

• • •

Implications for clinical applications likely useful for acute epileptic conditons with ongoing seizures (eg., status epilepticus, clusters) potentially useful for peri seizure administration to optimize delivery and minimize side-effects potentially novel methods of delivery in combination with stimulation /device therapies

2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant

2DG is preferentially delivered to regions with high energy needs by activity-dependent neurovascular coupling involving neurons, glia, and endothelial cells in the “neurovascular unit” 18F-2DG PET scan during status epilepticus H3-2DG autoradiogram during 1 hz stimulation

• • •

Implications for clinical applications likely useful for acute epileptic conditons with ongoing seizures (eg., status epilepticus, clusters) potentially useful for peri seizure administration to optimize delivery and minimize side-effects potentially novel methods of delivery in combination with stimulation /device therapies

2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant

2DG is preferentially delivered to regions with high energy needs by activity-dependent neurovascular coupling involving neurons, glia, and endothelial cells in the “neurovascular unit” 18F-2DG PET scan during status epilepticus H3-2DG autoradiogram during 1 hz stimulation

• • •

Implications for clinical applications likely useful for acute epileptic conditons with ongoing seizures (eg., status epilepticus, clusters) potentially useful for peri seizure administration to optimize delivery and minimize side-effects potentially novel methods of delivery in combination with stimulation /device therapies

2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant

2DG is preferentially delivered to regions with high energy needs by activity-dependent neurovascular coupling involving neurons, glia, and endothelial cells in the “neurovascular unit” 18F-2DG PET scan during status epilepticus H3-2DG autoradiogram during 1 hz stimulation

• • •

Implications for clinical applications likely useful for acute epileptic conditons with ongoing seizures (eg., status epilepticus, clusters) potentially useful for peri seizure administration to optimize delivery and minimize side-effects potentially novel methods of delivery in combination with stimulation /device therapies

Activity-dependent effects of 2DG on synaptic transmission

Activity-dependent effects of 2DG on synaptic transmission

no effects on synaptic properties in normal conditions

Activity-dependent effects of 2DG on synaptic transmission

2DG reduces amplitude and frequency of sEPSCs after exposure to conditions that increase activity

Activity-dependent effects of 2DG on synaptic transmission

•

modification in mEPSCs is activity-dependent

•

implicates presynaptic vesicle release as a mechanism of action of 2DG NOT SHOWN: “homeostatic” effects on synaptic plasticity

2DG in the pipeline

Efficacy



distinctive pattern of effectiveness in pre-clinical models



disease-modifying against progressive adverse effects of seizures



novel acute and chronic anti epilepsy mechanisms of action



2DG concentrates in areas of ictal epileptic activity Toxicology



PET imaging agent for 30+ years



Favorable toxicity history

• • •

Completed Phase 1 in cancer More than 20 other investigator clinical studies with > 300 subjects Need to confirm safety in effective dose (ED) range – cardiac toxicity observed with chronic dosing at 10X > ED range, and mild potentially reversible cardiac autophagy in ED range Intellectual Property



IP licensed from WARF: 1 patent issued and 1 pending in US (has been issued in Australia)



NGX has exclusive license from WARF for all human therapeutic use Remaining preclincal studies



bioanalytical assay development , toxicity, PK, TK, ADME studies underway in 2010 Q2

2DG in the pipeline

Efficacy



distinctive pattern of effectiveness in pre-clinical models



disease-modifying against progressive adverse effects of seizures



novel acute and chronic anti epilepsy mechanisms of action



2DG concentrates in areas of ictal epileptic activity Intellectual Property



IP licensed from WARF: 1 patent issued and 1 pending in US (has been issued in Australia)



NGX has exclusive license from WARF for all human therapeutic use Toxicology



PET imaging agent for 30+ years



Favorable toxicity history

• • •

Completed Phase 1 in cancer More than 20 other investigator clinical studies with > 300 subjects Need to confirm safety in effective dose (ED) range – cardiac toxicity observed with chronic dosing at 10X > ED range, and mild potentially reversible cardiac autophagy in ED range Remaining preclincal studies



bioanalytical assay development , toxicity, PK, TK, ADME studies underway in 2010 Q2

IND filing anticipated 2011 Q1

Current Development Plan

Complete preclinical toxicity, formulation, CMC, and filing of IND

“IND-enabling preclinical studies of 2DG for treatment of epilepsy” (awaiting NIH RAID, anticipated start Q2 2010)

Will complete preclinical studies including bioanalytical assay development, pharmacokinetic, toxicological, toxicokinetic, manufacturing, formulation, and clinical trial designs, and regulatory documentation for submission of an IND.

Investigator-initiated first in humans Phase I/II clinical trial in patients with intractable epilepsy

“A Preliminary Tolerability and Efficacy Study of 2DG in Intractable Epilepsy” Nathan Fountain, MD, University of Virginia (EpilepsyTherapy Project-ERF, WARF, NGX, anticipated start in Q4 2010)

This will be a preliminary study of 2DG that will seek to detect an efficacy signal and assess tolerability in 10-15 intractable patients with frequent seizures.

Development of delayed release formulations

Zeeh Experimental Pharmacy Station (University of Wisconsin) (E. Elder, PhD, supported by WARF)

This program is developing delayed release formulations to exploit the activity-dependent uptake and short t 1/2 (~ 40 min) enabling chronic administration at lower total doses.