2DG - a glucose analogue and glycolytic inhibitor with anticonvulsant and antiepileptic actions
-
Upload
materia-perrin -
Category
Documents
-
view
28 -
download
1
description
Transcript of 2DG - a glucose analogue and glycolytic inhibitor with anticonvulsant and antiepileptic actions
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.
cannot undergo isomerization
The novel mechanism of 2DG: why 2DG is a glycolytic inhibitor
Completed preclinical efficacy studiesAnimal Models of Acute &
Chronic Epilepsyin 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 studiesAnimal Models of Acute &
Chronic Epilepsyin vitro Models of Seizure
Induction
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 reduces epileptic discharges evoked by:
K+ (7.5mM, ictal & interictal) bicuculline (GABA antagonist) 4AP (K+ channel antagonist) DHPG (metabotropic glutamate agonist)
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
implies that actions of 2DG at the cellular level are “broad- spectrum” against different mechanisms of network synchronization
Completed preclinical efficacy studiesAnimal Models of Acute &
Chronic Epilepsyin vitro Models of Seizure
Induction
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 reduces epileptic discharges evoked by:
K+ (7.5mM, ictal & interictal) bicuculline (GABA antagonist) 4AP (K+ channel antagonist) DHPG (metabotropic glutamate agonist)
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
Completed preclinical efficacy studiesAnimal Models of Acute &
Chronic Epilepsyin vitro Models of Seizure
Induction
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 reduces epileptic discharges evoked by:
K+ (7.5mM, ictal & interictal) bicuculline (GABA antagonist) 4AP (K+ channel antagonist) DHPG (metabotropic glutamate agonist)
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
Completed preclinical efficacy studiesAnimal Models of Acute &
Chronic Epilepsyin vitro Models of Seizure
Induction
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 reduces epileptic discharges evoked by:
K+ (7.5mM, ictal & interictal) bicuculline (GABA antagonist) 4AP (K+ channel antagonist) DHPG (metabotropic glutamate agonist)
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
• 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
Implications for clinical applications
2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant
18F-2DG PET scan during status epilepticus
H3-2DG autoradiogram during 1 hz stimulation
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”
• 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
Implications for clinical applications
2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant
18F-2DG PET scan during status epilepticus
H3-2DG autoradiogram during 1 hz stimulation
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”
• 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
Implications for clinical applications
2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant
18F-2DG PET scan during status epilepticus
H3-2DG autoradiogram during 1 hz stimulation
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”
• 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
Implications for clinical applications
2DG delivery to neurons and circuits is activity-dependent: a novel advantageous property for an anticonvulsant
18F-2DG PET scan during status epilepticus
H3-2DG autoradiogram during 1 hz stimulation
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”
Activity-dependent effects of 2DG on synaptic transmission
Activity-dependent effects of 2DG on synaptic transmission
no effects on synaptic
properties in normal conditions
2DG reduces amplitude and frequency of sEPSCsafter exposure to conditions that increase activity
Activity-dependent effects of 2DG on synaptic transmission
• modification in mEPSCs is activity-dependent
• implicates presynaptic vesicle release asa mechanism of action of 2DG
Activity-dependent effects of 2DG on synaptic transmission
NOT SHOWN: “homeostatic” effects on synaptic plasticity
2DG in the pipeline
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
bioanalytical assay development , toxicity, PK, TK, ADME studies underway in 2010 Q2
Toxicology 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
Efficacy
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
Intellectual Property
Remaining preclincal studies
2DG in the pipeline
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
bioanalytical assay development , toxicity, PK, TK, ADME studies underway in 2010 Q2
Toxicology 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
Efficacy
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
Intellectual Property
Remaining preclincal studies
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 formulationsZeeh 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 t1/2 (~ 40 min) enabling chronic administration at lower total doses.