Title: 2DG - a glucose analogue and glycolytic inhibitor with anticonvulsant and antiepileptic actions
12DG - 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.
2The novel mechanism of 2DG why 2DG is a
glycolytic inhibitor
cannot undergo isomerization
3Completed preclinical efficacy studies
Animal Models of Acute Chronic Epilepsy
in vitro Models of Seizure Induction
- 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 Frings
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
4Completed preclinical efficacy studies
Animal Models of Acute Chronic Epilepsy
in vitro Models of Seizure Induction
- 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 Frings
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
- 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
5Completed preclinical efficacy studies
Animal Models of Acute Chronic Epilepsy
in vitro Models of Seizure Induction
- 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 Frings
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
- 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
6Completed preclinical efficacy studies
Animal Models of Acute Chronic Epilepsy
in vitro Models of Seizure Induction
- 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 Frings
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
- 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
7Completed preclinical efficacy studies
Animal Models of Acute Chronic Epilepsy
in vitro Models of Seizure Induction
- 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 Frings
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
- 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
82DG 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
- 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
H3-2DG autoradiogram during 1 hz stimulation
18F-2DG PET scan during status epilepticus
92DG 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
- 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
H3-2DG autoradiogram during 1 hz stimulation
18F-2DG PET scan during status epilepticus
102DG 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
- 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
H3-2DG autoradiogram during 1 hz stimulation
18F-2DG PET scan during status epilepticus
112DG 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
- 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
H3-2DG autoradiogram during 1 hz stimulation
18F-2DG PET scan during status epilepticus
12Activity-dependent effects of 2DG on synaptic
transmission
13Activity-dependent effects of 2DG on synaptic
transmission
no effects on synaptic properties in normal
conditions
14Activity-dependent effects of 2DG on synaptic
transmission
2DG reduces amplitude and frequency of
sEPSCs after exposure to conditions that increase
activity
15Activity-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
162DG in the pipeline
Toxicology
Efficacy
- PET imaging agent for 30 years
- Favorable toxicity history
- Completed Phase 1 in cancer
- More than 20 other investigator clinical studies
with gt 300 subjects - Need to confirm safety in effective dose (ED)
range cardiac toxicity observed with chronic
dosing at 10X gt ED range, and mild potentially
reversible cardiac autophagy in ED range
- 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
Remaining preclincal studies
- 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
- bioanalytical assay
- development , toxicity, PK,
- TK, ADME studies underway
- in 2010 Q2
172DG in the pipeline
Toxicology
Efficacy
- PET imaging agent for 30 years
- Favorable toxicity history
- Completed Phase 1 in cancer
- More than 20 other investigator clinical studies
with gt 300 subjects - Need to confirm safety in effective dose (ED)
range cardiac toxicity observed with chronic
dosing at 10X gt ED range, and mild potentially
reversible cardiac autophagy in ED range
- 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
Remaining preclincal studies
- 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
- bioanalytical assay
- development , toxicity, PK,
- TK, ADME studies underway
- in 2010 Q2
IND filing anticipated 2011 Q1
18Current 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 (EpilepsyTher
apy 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.