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

1
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.

2
The novel mechanism of 2DG why 2DG is a
glycolytic inhibitor
cannot undergo isomerization
3
Completed 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

4
Completed 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

5
Completed 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

6
Completed 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

7
Completed 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

8
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

• 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
9
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

• 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
10
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

• 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
11
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

• 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
12
Activity-dependent effects of 2DG on synaptic
transmission
13
Activity-dependent effects of 2DG on synaptic
transmission
no effects on synaptic properties in normal
conditions
14
Activity-dependent effects of 2DG on synaptic
transmission
2DG reduces amplitude and frequency of
sEPSCs after exposure to conditions that increase
activity
15
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
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2DG 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

17
2DG 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
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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 (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.