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
2DG reduces epileptic discharges
evoked by:
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




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
2DG reduces epileptic discharges
evoked by:
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
 these properties are
unlike ANY other
marketed drugs




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 “broadspectrum” against different
mechanisms of network
synchronization
 2DG is diseasemodifying 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
2DG reduces epileptic discharges
evoked by:
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
 these properties are
unlike ANY other
marketed drugs




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 “broadspectrum” against different
mechanisms of network
synchronization
 2DG is diseasemodifying 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
2DG reduces epileptic discharges
evoked by:
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
 these properties are
unlike ANY other
marketed drugs




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 “broadspectrum” against different
mechanisms of network
synchronization
 2DG is diseasemodifying 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
2DG reduces epileptic discharges
evoked by:
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
 these properties are
unlike ANY other
marketed drugs




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 “broadspectrum” against different
mechanisms of network
synchronization
 2DG is diseasemodifying 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”
Implications for clinical
applications
18F-2DG PET scan during
status epilepticus
H3-2DG autoradiogram during
1 hz stimulation
•
likely useful for acute epileptic
conditons with ongoing
seizures (eg., status
epilepticus, clusters)
•
potentially useful for periseizure 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”
Implications for clinical
applications
18F-2DG PET scan during
status epilepticus
H3-2DG autoradiogram during
1 hz stimulation
•
likely useful for acute epileptic
conditons with ongoing
seizures (eg., status
epilepticus, clusters)
•
potentially useful for periseizure 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”
Implications for clinical
applications
18F-2DG PET scan during
status epilepticus
H3-2DG autoradiogram during
1 hz stimulation
•
likely useful for acute epileptic
conditons with ongoing
seizures (eg., status
epilepticus, clusters)
•
potentially useful for periseizure 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”
Implications for clinical
applications
18F-2DG PET scan during
status epilepticus
H3-2DG autoradiogram during
1 hz stimulation
•
likely useful for acute epileptic
conditons with ongoing
seizures (eg., status
epilepticus, clusters)
•
potentially useful for periseizure 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-
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
Intellectual Property
• 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
 IP licensed from WARF: 1 patent
Remaining preclincal studies
epilepsy mechanisms of action
 2DG concentrates in areas of ictal
epileptic activity
issued and 1 pending in US (has
been issued in Australia)
 NGX has exclusive license from
WARF for all human therapeutic use

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-
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
Intellectual Property
• 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
 IP licensed from WARF: 1 patent
Remaining preclincal studies
epilepsy mechanisms of action
 2DG concentrates in areas of ictal
epileptic activity
issued and 1 pending in US (has
been issued in Australia)
 NGX has exclusive license from
WARF for all human therapeutic use

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 t1/2 (~ 40
min) enabling chronic administration at lower total doses.